The American Journal of Cardiology

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1 The American Journal of Cardiology Volume 96, Issue 9, Pages (1 November 2005) 1. Editorial board EDITORIAL BOARD Page A3 Coronary Artery Disease 2. Effect of Depression on Five-Year Mortality After an Acute Coronary Syndrome ARTICLE Pages Sherry L. Grace, Susan E. Abbey, Moira K. Kapral, Jiming Fang, Robert P. Nolan and Donna E. Stewart 3. Usefulness of Left Ventricular Diastolic Wall Motion Abnormality as an Early Predictor of Left Ventricular Dilation After a First Acute Myocardial Infarction SHORT COMMUNICATION Pages Mirza Husic, Betina Nørager, Kenneth Egstrup and Jacob E. Møller 4. A Multistate Comparison of Patient Characteristics, Outcomes, and Treatment Practices in Acute Myocardial Infarction ARTICLE Pages Shadi S. Saleh, Edward L. Hannan and Larry Ting 5. N-Terminal Pro-Brain Natriuretic Peptide and Tombstoning ST-Segment Elevation in Patients With Anterior Wall Acute Myocardial Infarction SHORT COMMUNICATION Pages János Tomcsányi, András Marosi, Béla Bózsik, Miklós Somlói, András Zsoldos, Tibor Vecsey, Hrisula Arabadzisz and Erzsébet Nagy 6. Impact of Bleeding Severity on Clinical Outcomes Among Patients With Acute Coronary Syndromes ARTICLE Pages Sunil V. Rao, Kristi O Grady, Karen S. Pieper, Christopher B. Granger, L. Kristin Newby, Frans Van de Werf, Kenneth W. Mahaffey, Robert M. Califf and Robert A. Harrington 7. Intensity of Lipid Lowering With Statins and Brachial Artery Vascular Endothelium Reactivity After Acute Coronary Syndromes (from the BRAVER Trial) ARTICLE Pages Jocelyn Dupuis, Jean-Claude Tardif, Jean-Lucien Rouleau, Joseph Ricci, Malcolm Arnold, Eva Lonn, René Roux, Lawrence M. Title, Robert Amyot, Nickie Bonafede et al.

2 8. Frequency of Abdominal Aortic Aneurysm in Patients >60 Years of Age With Coronary Artery Disease SHORT COMMUNICATION Pages Juraj Madaric, Ivan Vulev, Jozef Bartunek, Augustin Mistrik, Katia Verhamme, Bernard De Bruyne and Igor Riecansky 9. Gender Differences in Carotid Intima-Media Thickness in Patients With Suspected Coronary Artery Disease ARTICLE Pages Anna Kablak-Ziembicka, Tadeusz Przewlocki, Wieslawa Tracz, Piotr Pieniazek, Piotr Musialek and Andrzej Sokolowski 10. Gender-Based Differences in Brachial Artery Flow-Mediated Vasodilation as an Indicator of Significant Coronary Artery Disease SHORT COMMUNICATION Pages Ayan R. Patel, Jeffrey T. Kuvin, Kathleen A. Sliney, William M. Rand, Jessica C. Chiang, James E. Udelson, Natesa G. Pandian and Richard H. Karas 11. Outcome in Patients Transferred for Percutaneous Coronary Intervention (A National Registry of Myocardial Infarction 2/3/4 Analysis) ARTICLE Pages David M. Shavelle, M. Leila Rasouli, Paul Frederick, C. Michael Gibson, William J. French and National Registry of Myocardial Infarction Investigators 12. Relation of Terminal QRS Distortion to Left Ventricular Functional Recovery and Remodeling in Acute Myocardial Infarction Treated With Primary Angioplasty SHORT COMMUNICATION Pages Riccardo Bigi, Antonio Mafrici, Paola Colombo, Dario Gregori, Elena Corrada, Antonia Alberti, Annamaria De Biase, Pedro Silva Orrego, Cesare Fiorentini and Silvio Klugmann 13. Impact of Intravascular Ultrasound Lesion Characteristics on Neointimal Hyperplasia Following Sirolimus-Eluting Stent Implantation SHORT COMMUNICATION Pages Hideaki Kaneda, Tomomi Koizumi, Junya Ako, Mitsuyasu Terashima, Yoshihiro Morino, Yasuhiro Honda, Paul G. Yock, Martin B. Leon, Jeffrey W. Moses, Peter J. Fitzgerald and SIRIUS Investigators

3 14. Impact of Coronary Culprit Lesion Calcium in Patients Undergoing Paclitaxel-Eluting Stent Implantation (a TAXUS-IV Sub Study) ARTICLE Pages Issam Moussa, Stephen G. Ellis, Michael Jones, Dean J. Kereiakes, Daniel McMartin, Barry Rutherford, Roxana Mehran, Michael Collins, Martin B. Leon, Jeffrey J. Popma et al. 15. Neurological Complications Following Percutaneous Coronary Interventions (A Report from the New York State Angioplasty Registry) SHORT COMMUNICATION Pages S. Chiu Wong, Robert Minutello and Mun K. Hong 16. Predictors of Edge Stenosis Following Sirolimus-Eluting Stent Deployment (A Quantitative Intravascular Ultrasound Analysis from the SIRIUS Trial) SHORT COMMUNICATION Pages Ryota Sakurai, Junya Ako, Yoshihiro Morino, Shinjo Sonoda, Hideaki Kaneda, Mitsuyasu Terashima, Ali H.M. Hassan, Martin B. Leon, Jeffrey W. Moses, Jeffrey J. Popma et al. 17. Relation of Early Saphenous Vein Graft Failure to Outcomes Following Coronary Artery Bypass Surgery ARTICLE Pages Abdul R. Halabi, John H. Alexander, Linda K. Shaw, Todd J. Lorenz, Lawrence Liao, David F. Kong, Carmelo A. Milano, Robert A. Harrington and Peter K. Smith Preventive Cardiology 18. Therapeutic Lifestyle Changes and Drug Treatment for High Blood Cholesterol in China and Application of the Adult Treatment Panel III Guidelines ARTICLE Pages Paul Muntner, Dongfeng Gu, Robert F. Reynolds, Xigui Wu, Jichun Chen, Paul K. Whelton and Jiang He 19. Gemfibrozil Reduces Small Low-Density Lipoprotein More in Normolipemic Subjects Classified as Low-Density Lipoprotein Pattern B Compared With Pattern A ARTICLE Pages H. Robert Superko, Kaspar K. Berneis, Paul T. Williams, Manfredi Rizzo and Peter D. Wood

4 20. Relation of Plasma Glucose and Endothelial Function in a Population-Based Multiethnic Sample of Subjects Without Diabetes Mellitus SHORT COMMUNICATION Pages Carlos J. Rodriguez, Yumiko Miyake, Cairistine Grahame-Clarke, Marco R. Di Tullio, Robert R. Sciacca, Bernadette Boden-Albala, Ralph L. Sacco and Shunichi Homma 21. Experience With Statin Use in Patients With Chronic Hepatitis C Infection SHORT COMMUNICATION Pages Kimberly Gibson and Joseph P. Rindone 22. Relation of the Prothrombotic State to Increasing Age (from the Framingham Offspring Study) ARTICLE Pages Geoffrey H. Tofler, Joseph Massaro, Daniel Levy, Murray Mittleman, Patrice Sutherland, Izabela Lipinska, James E. Muller and Ralph B. D Agostino 23. Relation of Coronary Atherosclerosis Determined by Electron Beam Computed Tomography and Plasma Levels of N-terminal Pro-Brain Natriuretic Peptide in a Multiethnic Population-Based Sample (The Dallas Heart Study) ARTICLE Pages Shuaib M. Abdullah, Amit Khera, Sandeep R. Das, Harold G. Stanek, Russell M. Canham, Anne K. Chung, David A. Morrow, Mark H. Drazner, Darren K. McGuire and James A. de Lemos 24. Effect of Rosuvastatin on C-Reactive Protein and Renal Function in Patients With Chronic Kidney Disease SHORT COMMUNICATION Pages Anil Verma, Karthik M. Ranganna, Rani S. Reddy, Mandeep Verma and Neil F. Gordon Arrhythmias and Conduction Disturbances 25. Prognostic Significance of Nonsustained Ventricular Tachycardia During Dobutamine Stress Echocardiography SHORT COMMUNICATION Pages David E. Cox, Laurance D. Farmer,John R. Hoyle and Gretchen L. Wells

5 Systemic Hypertension 26. Analysis of Left Ventricular Systolic Function Using Midwall Mechanics in Patients >60 Years of Age With Hypertensive Heart Disease and Heart Failure ARTICLE Pages Craig S. Vinch, Gerard P. Aurigemma, Helge U. Simon, Jeffrey C. Hill, Dennis A. Tighe and Theo E. Meyer Heart Failure 27. Effect of Dynamic Left Ventricular Dyssynchrony on Dynamic Mitral Regurgitation in Patients With Heart Failure Due to Coronary Artery Disease SHORT COMMUNICATION Pages Patrizio Lancellotti, Pierre-Yves Stainier, Florence Lebois and Luc A. Piérard Cardiomyopathy 28. Differences in Diagnostic Value of Four Electrocardiographic Voltage Criteria for Hypertrophic Cardiomyopathy in a Genotyped Population ARTICLE Pages Tetsuo Konno, Masami Shimizu, Hidekazu Ino, Noboru Fujino, Kenshi Hayashi, Katsuharu Uchiyama, Tomoya Kaneda, Masaru Inoue, Takashi Fujita, Eiichi Masuta et al. Congenital Heart Disease 29. Usefulness of Magnetic Resonance Angiography for Diagnosis of Scimitar Syndrome in Early Infancy ARTICLE Pages Muhammad A. Khan, Alejandro J. Torres, Beth F. Printz and Ashwin Prakash 30. Echocardiographic Doppler Assessment of the Biophysical Properties of the Aorta in Pediatric Patients With the Marfan Syndrome SHORT COMMUNICATION Pages Timothy J. Bradley, James E. Potts, Mary T. Potts, Astrid M. DeSouza and George G.S. Sandor Miscellaneous 31. Prospective Evaluation of Aggressive Medical Therapy for Atherosclerotic Renal Artery Stenosis, With Renal Artery Stenting Reserved for Previously Injured Heart, Brain, or Kidney ARTICLE Pages George Hanzel, Helena Balon, Oliver Wong, Daniel Soffer, Daniel Taehee Lee and Robert David Safian

6 32. Chronotropic Incompetence as a Predictor of Death Among Patients With Normal Electrograms Taking Beta Blockers (Metoprolol or Atenolol) ARTICLE Pages Mohammed N. Khan, Claire E. Pothier and Michael S. Lauer 33. Efficacy and Safety of Sildenafil Added to Treprostinil in Pulmonary Hypertension SHORT COMMUNICATION Pages Mardi Gomberg-Maitland, Vallerie McLaughlin, Martha Gulati and Stuart Rich 34. Relation of Brachial Artery Flow-Mediated Vasodilation to Significant Coronary Artery Disease in Patients With Peripheral Arterial Disease ARTICLE Pages Pasquale Perrone-Filardi, Alberto Cuocolo, Gregorio Brevetti, Antonio Silvestro, Giovanni Storto, Santo Dellegrottaglie, Luigi Corrado, Maria Cafiero, Roberta Camerino, Michele Polimeno et al. 35. Predictors of Left Atrial Spontaneous Echocardiographic Contrast or Thrombus Formation in Stroke Patients With Sinus Rhythm and Reduced Left Ventricular Function ARTICLE Pages Michael Handke, Andreas Harloff, Andreas Hetzel, Manfred Olschewski, Christoph Bode and Annette Geibel 36. Intrasubject Variability of Radial Artery Flow-Mediated Dilatation in Healthy Subjects and Implications for Use in Prospective Clinical Trials ARTICLE Pages Robert Brook, Meghan Grau, Christine Kehrer, Santo Dellegrottaglie, Bobby Khan and Sanjay Rajagopalan

7 EDITOR IN CHIEF William C. Roberts, MD Baylor Heart & Vascular Hospital Baylor University Medical Center Wadley Tower No Gaston Avenue Dallas, Texas (214) Fax: (214) ASSOCIATE EDITOR Paul A. Grayburn ASSISTANT EDITORS Thomas C. Andrews Calixto A. Romero Robert C. Kowal Robert L. Rosenthal Carlos E. Velasco EDITORIAL BOARD CARDIOVASCULAR MEDICINE In Adults Jonathan Abrams Robert J. Adolph Joseph S. Alpert Martin A. Alpert Ezra A. Amsterdam Jeffrey Anderson William F. Armstrong Richard W. Asinger Donald S. Baim Gary John Balady Thomas M. Bashore Eric Bates George A. Beller David G. Benditt Peter C. Block William E. Boden Monty M. Bodenheimer Robert O. Bonow Jeffrey S. Borer Harisios Boudoulas Martial G. Bourassa Eugene Braunwald Jeffrey A. Brinker Bruce R. Brodie Alfred E. Buxton Michael E. Cain Richard O. Cannon III Samuel Ward Casscells Bernard R. Chaitman Kanu Chatterjee John S. Child Robert J. Cody Lawrence S. Cohen Marc Cohen C. Richard Conti Michael H. Crawford Robert F. DeBusk Prakash C. Deedwania Gregory J. Dehmer Efthymios N. Deliargyris James A. de Lemos Anthony N. DeMaria Pablo Denes Nicholas L. DePace Richard B. Devereux George A. Diamond John P. DiMarco Michael J. Domanski Gerald Dorros John S. Douglas, Jr. Pamela S. Douglas Eric J. Eichhorn Mark J. Eisenberg Uri Elkayam Kenneth A. Ellenbogen Myrvin H. Ellestad Stephen G. Ellis Toby R. Engel Andrew E. Epstein N. A. Mark Estes, III Michael Ezekowitz Rodney H. Falk John A. Farmer David P. Faxon Robert L. Feldman Ted Feldman Jack Ferlinz Jerome L. Fleg Gerald F. Fletcher Nancy C. Flowers James S. Forrester Joseph A. Franciosa Gary S. Francis Victor F. Froelicher, Jr. W. Bruce Fye William H. Gaasch William Ganz Julius M. Gardin Bernard J. Gersh Mihai Gheorghiade Raymond Gibbons D. Luke Glancy Stephen P. Glasser Michael R. Gold Samuel Z. Goldhaber Robert E. Goldstein Sidney Goldstein Steven A. Goldstein J. Anthony Gomes Antonio M. Gotto, Jr. K. Lance Gould Donald C. Harrison Richard H. Helfant Gary V. Heller Philip D. Henry L. David Hillis David R. Holmes, Jr. Mun K. Hong William G. Hundley Abdulmassih S. Iskandrian Allan S. Jaffe William B. Kannel Norman M. Kaplan Joel S. Karliner John A. Kastor Sanjiv Kaul Kenneth M. Kent Richard E. Kerber Dean J. Kereiakes Morton J. Kern Spencer B. King III Robert E. Kleiger George J. Klein Lloyd W. Klein Paul Kligfield Robert A. Kloner John B. Kostis Charles Landau Richard L. Lange Carl J. Lavie Carl V. Leier Joseph Lindsay, Jr. Gregory Y.H. Lip Joseph Loscalzo G.B. John Mancini Francis E. Marchlinski Frank I. Marcus Barry J. Maron Randolph P. Martin Attilo Maseri Dean T. Mason Michael D. McGoon Raymond G. McKay Jawahar L. Mehta Richard S. Meltzer Franz H. Messerli Eric L. Michelson Richard V. Milani Alan B. Miller Gary S. Mintz Fred Morady Arthur J. Moss James E. Muller Robert J. Myerburg Gerald B. Naccarelli Navin C. Nanda Christopher O Connor Robert A. O Rourke Erik Magnus Ohman Antonio Pacifico Richard L. Page Eugene R. Passamani Richard C. Pasternak Alan S. Pearlman Carl J. Pepine Joseph K. Perloff Ileana Pina Bertram Pitt Philip J. Podrid Arshed A. Quyyumi Charles E. Rackley C. Venkata Ram Nathaniel Reichek Robert Roberts William J. Rogers Melvin M. Scheinman Nelson B. Schiller David J. Schneider John S. Schroeder Pravin M. Shah Prediman K. Shah Jamshid Shirani Robert J. Siegel Marc A. Silver Mark E. Silverman Ross J. Simpson, Jr. Steven N. Singh Sidney C. Smith, Jr. Burton E. Sobel John C. Somberg David H. Spodick Lynne W. Stevenson John R. Stratton Jonathan M. Tobis Eric J. Topol Byron F. Vandenberg Hector O. Ventura George W. Vetrovec Ronald G. Victor Robert A. Vogel Frans J. Wackers David D. Waters Nanette K. Wenger William B. White Robert Wilensky James T. Willerson Miguel Zabalgoitia Barry L. Zaret Douglas P. Zipes In Infants and Children Hugh D. Allen Bruce S. Alpert Arthur Garson, Jr. Stanley J. Goldberg Warren G. Guntheroth Howard P. Gutgesell John D. Kugler James E. Lock John W. Moore Lowell W. Perry David J. Sahn Richard M. Schieken CARDIOVASCULAR SURGERY Eugene H. Blackstone Lawrence I. Bonchek Lawrence H. Cohn John A. Elefteriades Thomas L. Spray RELATED SPECIALISTS L. Maximilian Buja Michael Emmett Barry A. Franklin Charles B. Higgins Jeffrey E. Saffitz Renu Virmani Redford B. Williams A3

8 Effect of Depression on Five-Year Mortality After an Acute Coronary Syndrome Sherry L. Grace, PhD a,b, *, Susan E. Abbey, MD b,c, Moira K. Kapral, MD, MSc b,c,d, Jiming Fang, PhD d, Robert P. Nolan, PhD, CPsych b,c, and Donna E. Stewart, MD b,c Previous research has established a relation between depression at the time of cardiac hospitalization and patient mortality. The objective of this study was to examine the role of depressive history and symptomatology during hospitalization on 5-year all-cause mortality after admission for an acute coronary syndrome. We recruited 750 patients who had unstable angina pectoris and myocardial infarction from 12 coronary care units between 1997 and Measurements included sociodemographic and clinic data and the Beck Depression Inventory (BDI). Data were linked to an administrative database to determine 5-year all-cause mortality. Survival data were adjusted using a Cox s proportional hazards model. One hundred seventy-four participants (23.2%) self-reported a history of depressed mood for >2 weeks, 235 (31.3%) had elevated BDI scores at index hospitalization, with 105 (14.0%) reporting persistent depressive symptomatology. One hundred fifteen participants (15.3%) died by 5 years after hospitalization. After adjusting for prognostic indicators, such as cardiac disease severity, medical history, and smoking, depressive symptomatology during hospitalization was significantly predictive of mortality, but depressive history was not. Hazard ratios associated with BDI scores <10 versus those >10 at hospitalization ranged from 1.90 (95% confidence interval 1.12 to 3.24) at 2 years to 1.53 (95% confidence interval 1.04 to 2.24) at 5 years. In conclusion, the significance of depressive symptomatology at the time of, but not before, hospitalization underlines the need for early identification of increased distress and renews calls to identify treatments that not only improve quality of life but also decrease the risk of mortality Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) It is depressive symptomatology as assessed during hospitalization that is so robustly related to long-term mortality after an acute coronary syndrome (ACS). 1 Most studies that have demonstrated the relation between depression and mortality have assessed depression only 1 time. However, it is well documented that a history of depression is related to future depressive episodes 2 (even among patients who have cardiac problems 1,3 6 ) and to the onset of ACS. 7 9 This study examined the concurrent effects of depressed mood before ACS and depressive symptomatology at the index cardiac event on all-cause mortality across a 5-year period after the index hospitalization. We postulated that such Methods Design and procedure: This was a longitudinal observational study that followed participants from admission for myocardial infarction or unstable angina for 5 years. Details concerning the methods of this study have been described previously. 10 Eligible patients were recruited between August 1997 and January 1999 in the coronary care unit by research nurses on the second to fifth days of hospitalization. Those who met the study criteria and agreed to participate signed a consent form and were provided with a self-report questionnaire. Consent was also obtained to link participants self-report questionnaire data with their clinical data. Data were later linked to population-based administrative databases using unique encrypted identifiers, including the Ontario Registered Persons Database and the Discharge Abstract Database of the Canadian Institute of Health Information. Measurements: The self-report survey completed in the hospital consisted of questions about sociodemographic characteristics, medical history, and depressive symptoma York University, b University Health Network; c University of Toronto; and d Institute for Clinical and Evaluative Services, Toronto, Ontario, Canada. Manuscript received April 13, 2005; revised manuscript received and accepted June 20, Drs. Abbey and Stewart were supported by research grants from The Heart and Stroke Foundation of Ontario, Ottawa, Ontario, and Samuel Lunenfeld Foundation, Toronto, Ontario, Canada. Dr. Kapral is supported by the University Health Network Women s Health Program and the Canadian Stroke Network, Toronto, Ontario, Canada. * Corresponding author: Tel: , ext 22364; fax: address: sgrace@yorku.ca (S.L. Grace). persistent depressive symptomatology would have detrimental effects on mortality /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

9 1180 The American Journal of Cardiology ( Table 1 Nurse-reported characteristics of participants versus nonparticipants (ineligible, refused) at time of index hospitalization Variable Participants (n 910) Nonparticipants (n 890) Women 320 (35.0%) 385 (43.7%)* Married 667 (73.1%) 551 (62.5%)* Myocardial infarct 478 (52.4%) 490 (55.6%) Age (yrs) 62 (12.00) 69 (12.25)* *p atology. The sociodemographic data included age, gender, marital status, education level, and family income. Participants were asked whether they had a history of depressed mood for 2 weeks (yes/no). Survey data were linked with clinical data that were compiled by coronary care unit nurses, which included Killip s class 11 as an indicator of illness severity and medical history (i.e., hypertension, diabetes, congestive heart failure, or previous myocardial infarction). Depressive symptoms at the time of hospitalization were assessed by the Beck Depression Inventory (BDI), 12 a reliable and well-validated 21-item scale that uses a forcedchoice 4-alternative response format that has been widely used in the general population and in populations with long-term illness, including cardiac problems Higher scores reflect greater depressive symptomatology, with scores 10 reflecting mild to severe symptomatology. The internal consistency of the BDI had an value of 0.87 in the present sample. Based on the universal and centralized health care system in the province, we were able to obtain comprehensive follow-up information on the sample of participants using the Registered Persons Database. Linkage to a Discharge Abstract Database enabled determination of co-morbidity to compute the Charlson Comorbidity Index. 18 Participants: Consecutive patients who were diagnosed with myocardial infarction or unstable angina in 12 coronary care units across south-central Ontario, Canada, were approached for the study. Characteristics of participants and nonparticipants are listed in Table 1. Of the almost 1,800 patients who were approached, participants were significantly younger than those who refused or were ineligible to participate (t 13.08, p 0.001). Significantly more men than women agreed to participate (chi-square 14.00, p 0.001), and more married and fewer widowed patients agreed to participate (chi-square 21.46, p 0.001). Nine hundred ten patients (590 men and 320 women, 69% response rate) consented to participate in the study. Patients were 31 to 93 years old (mean ). Seventy-four percent of participants (n 664) were married, and 45% (n 340) had a family income above $50,000 Canadian (i.e., $32,000 United States) annually. Fifty-three percent (n 482) had a confirmed myocardial infarction, and 47% (n 424) were diagnosed as having unstable angina after appropriate diagnostic tests. From the initial cohort of 910 participants who were recruited, we were able to match 867 of these participants with unique encrypted identifiers (43 participants lost, 4.7%), and link 856 to the Canadian Institute of Health Information Discharge Abstract Database (11 patients lost, 1.2% of overall cohort). No cases were lost while linking to the Registered Persons Database. Of this cohort, 836 had complete baseline BDI depression scores (20 patients lost, 2.2% of overall cohort), and 750 had a valid history of depression responses (86 patients lost, 9.5% of overall cohort). Statistical analyses: Statistical analyses were performed with SAS 8.2 (SAS Institute, Cary, North Carolina). Data were cleaned and screened to evaluate statistical assumptions. A descriptive examination of the variables was performed, and baseline participant characteristics were compared based on differences in mortality and depressive symptomatology (BDI score 10 vs 10). For survival analysis, time to event was measured from the index hospitalization. Cox s proportional hazard model was used to estimate the hazard ratio and 95% confidence intervals for all-cause mortality as based on history of depressed mood, depressive symptomatology at index hospitalization, and their interaction. A backward stepwise model was computed, with 0.1 as the significance level for keeping an explanatory variable in the model. Within Cox s model, we compared all-cause mortality rates with adjustment for the prognostic factors: gender, age, education level, family income, marital status, smoking status, Killip s class, diagnosis (myocardial infarction or unstable angina), hypertension (systolic blood pressure 130 mm Hg), previous myocardial infarction or congestive heart failure, diabetes, and the Charlson Co-morbidity Index (0 vs 1 co-morbid condition). Results Differences in participant characteristics based on self-reported depressive symptomatology at index hospitalization: As presented in Table 2, participants who had a BDI score 10 during hospitalization were more likely to be women, have lower family income, be widowed, separated, or divorced, have fewer years of education, be a smoker, have a diagnosis of unstable angina, have greater disease severity (as operationalized by Killip s class), have more co-morbid conditions, and have a medical history of diabetes and congestive heart failure. Relation of timing and persistence of depressive symptomatology to all-cause mortality: Depressive symptomatology before and at the time of the index ACS event is presented in Table 3. During the 5-year follow-up, there were 115 deaths (Table 2). Analyses showed an interaction between depressive history and depressive symptomatology during hospitalization on 5-year mortality. As presented in Table 3, the lowest mortality rate was found in participants who had a history of depressive symptomatology and no

10 Coronary Artery Disease/Depression and Mortality in Cardiac Patients 1181 Table 2 Participant characteristics of those with subthreshold depressive symptomatology (Beck Depression Inventory 10) versus those with depressive increased symptomatology (Beck Depression Inventory 10) at index hospitalization Overall Depressive Symptoms p Value Subthreshold (BDI 10) High (BDI 10) Sample (68.7%) 235 (31.3%) Men 486/750 (64.8%) 376/515 (73%) 110/235 (46.8%) Age (yrs) Killip s class I 591/711 (83.1%) 414/486 (85.2%) 177/225 (78.7%) Family income $50,000 Canadian 359/646 (55.6%) 231/451 (51.2%) 128/195 (65.6%) Married 555/744 (74.6%) 399/510 (78.2%) 156/234 (66.7%) Education level below high school 506/738 (68.6%) 336/510 (65.9%) 170/228 (74.6%) Index diagnosis of myocardial infarction 392/750 (52.3%) 294/515 (57.1%) 98/235 (41.7%) Systolic blood pressure 130 mm Hg 309/719 (43%) 214/490 (43.7%) 95/229 (41.5%) Charlson Co-morbidity Index 1 531/750 (70.8%) 384/515 (74.6%) 147/235 (62.6%) Diabetes mellitus 182/750 (24.3%) 108/515 (21%) 74/235 (31.5%) Previous myocardial infarction 537/750 (71.6%) 378/515 (73.4%) 159/235 (67.7%) Congestive heart failure 88/750 (11.7%) 47/515 (9.1%) 41/235 (17.4%) Smoker 241/745 (32.3%) 152/514 (29.6%) 89/231 (38.5%) Length of hospital stay BDI History of depressed mood 174/750 (23.2%) 69/515 (13.4%) 105/235 (44.7%) Death status Died 1 yr after discharge 39/750 (5.2%) 20/515 (3.9%) 19/235 (8.1%) Died 2 yrs after discharge 56/750 (7.5%) 30/515 (5.8%) 26/235 (11.1%) Died 3 yrs after discharge 77/750 (10.3%) 45/515 (8.7%) 32/235 (13.6%) Died 4 yrs after discharge 95/750 (12.7%) 57/515 (11.1%) 38/235 (16.2%) Died 5 yrs after discharge 115/750 (15.3%) 69/515 (13.4%) 46/235 (19.6%) Values are means SD or numbers of patients (percentages). increased depressive symptoms at the time of index hospitalization, whereas the highest mortality rate occurred in participants who had no history of depressed mood and developed increased depressive symptoms at the time of the index hospitalization. Based on pairwise comparisons (Table 4), those who had increased depressive onset only at the time of the index hospitalization were at significantly greater risk of mortality than were participants who had no depressive symptomatology at any time point or those who previously had only a depressed mood. With regard to depressed mood, participants who had depressive symptoms onset at the index hospitalization were 4 times more likely to die (hazard ratio 4.6). The stepwise Cox s proportional hazards models for allcause mortality across 5 years after index hospitalization are presented in Table 5, after adjusting for gender, age, family income, marital status, education level, diagnosis, high systolic blood pressure, smoking, Killip s class, co-morbid conditions, and a medical history of diabetes, myocardial infarction, or congestive heart failure. Depressive symptomatology at the time of index hospitalization remained a significant predictor of all-cause mortality across years 2 through 5; however, depressive history and its interaction with depressive symptomatology at the time of hospitalization did not remain in the adjusted models during any year of follow-up. The hazard ratio associated with subthreshold symptomatology (BDI score 10) compared with increased depressive symptomatology (BDI score 10) at the time of hospitalization ranged from 1.90 at 2 years to 1.53 at 5 years after index hospitalization. Kaplan-Meier adjusted survival curves for 5-year all-cause mortality by age, systolic blood pressure, co-morbidity, and medical history of congestive heart failure using the corrected group prognosis method are presented in Figure 1. Discussion Depressive symptomatology and major depressive disorders are common among patients who have ACS. 10,19 Similar to previous findings, 5 23% of participants reported a history of depressed mood. The prevalence of major depression at the time of hospitalization ranges from 15% to 20% in the literature, 20 which is approximately threefold higher than those of age-matched community-based prevalence studies. 21,22 In our sample, 31% had increased depressive symptomatology at the time of hospitalization, 14% of whom had a persistent depressed mood before the index hospitalization. We were interested in the prognostic significance of historical and persistent depressive symptomatology on mortality to build on the findings of Lesperance et al. 1,5 Although a strong body of literature demonstrates that depressive history is related to onset of ACS, 7 9 our results suggest that this history is not as salient to mortality among patients who have established disease compared with de-

11 1182 The American Journal of Cardiology ( Table 3 Participants who were alive versus those who died five years after discharge Variable Overall Status p Value Alive Died Sample (84.7%) 115 (15.3%) Men 486/750 (64.8%) 418/486 (86%) 68/486 (14%) Women 264/750 (35.2%) 217/264 (82.2%) 47/264 (17.8%) Age (yrs) Killip s class I 591/711 (83.1%) 515/591 (87.1%) 76/591 (12.9%) I 120/711 (16.9%) 86/120 (71.7%) 34/120 (28.3%) Family income $50, /646 (55.6%) 298/359 (83%) 61/359 (17%) $50, /646 (44.4%) 255/287 (88.9%) 32/287 (11.1%) Marital status Not married 189/744 (25.4%) 145/189 (76.7%) 44/189 (23.3%) Married 555/744 (74.6%) 485/555 (87.4%) 70/555 (12.6%) Education level Below high school 506/738 (68.6%) 418/506 (82.6%) 88/506 (17.4%) Above high school 232/738 (31.4%) 206/232 (88.8%) 26/232 (11.2%) Index diagnosis Unstable Angina 392/750 (52.3%) 331/392 (84.4%) 61/392 (15.6%) Myocardial Infarction 358/750 (47.7%) 304/358 (84.9%) 54/358 (15.1%) Systolic blood pressure 130 mm Hg 309/719 (43%) 250/309 (80.9%) 59/309 (19.1%) 130 mm Hg 410/719 (57%) 357/410 (87.1%) 53/410 (12.9%) Charlson Co-morbidity Index 1 531/750 (70.8%) 484/531 (91.1%) 47/531 (8.9%) 1 219/750 (29.2%) 151/219 (68.9%) 68/219 (31.1%) Diabetes mellitus 182/750 (24.3%) 143/182 (78.6%) 39/182 (21.4%) Previous myocardial infarction 537/750 (71.6%) 445/537 (82.9%) 92/537 (17.1%) Congestive heart failure 88/750 (11.7%) 45/88 (51.1%) 43/88 (48.9%) Smoker 241/745 (32.3%) 216/241 (89.6%) 25/241 (10.4%) Length of hospital stay BDI History of depressed mood 174/750 (23.2%) 155/174 (89.1%) 19/174 (10.9%) BDI score /750 (68.7%) 446/515 (86.6%) 69/515 (13.4%) /750 (31.3%) 189/235 (80.4%) 46/235 (19.6%) History of depressed mood BDI* 1(0 0) 446/750 (59.5%) 381/446 (85.4%) 65/446 (14.6%) (0 1) 130/750 (17.3%) 99/130 (76.2%) 31/130 (23.8%) 3(1 0) 69/750 (9.2%) 65/69 (94.2%) 4/69 (5.8%) 4(1 1) 105/750 (14%) 90/105 (85.7%) 15/105 (14.3%) Values are means SD or numbers of patients (percentages). *1 no history of depression and BDI score 10; 2 no history of depression and BDI score 10; 3 history of depression and BDI score 10; 4 history of depression and BDI score 10. Table 4 Pairwise comparisons of interaction between history of depression and presence of increased depressive symptomatology at index hospitalization Pairwise Comparison* Chi-square p Value Hazard Ratio 95% Confidence Interval (0,1) vs (0,0) (1,0) vs (0,0) (1,1) vs (0,0) (0,1) vs (1,0) (0,1) vs (1,1) (1,0) vs (1,1) *0 depression absent; 1 depression present. pressive severity at the time of hospitalization. This was also shown in a study by Berkman et al, 23 where depressive symptomatology was assessed up to 3 years before a myocardial infarction and was not related to mortality 6 months after a myocardial infarction. In addition, Bush et al 3 found no difference in mortality risk at 4 months based on a history of depression. With regard to the persistence of depressive symptomatology, the prognostic implications of this have been relatively unexplored. 24 Contrary to expectation, our results reveal that persistent depressive symptomatology that recurs at the time of hospitalization is not of prognostic importance

12 Coronary Artery Disease/Depression and Mortality in Cardiac Patients 1183 Table 5 Adjusted stepwise Cox s model by year since index hospitalization Years Since Index Hospitalization Variables Chi-Square p Value Hazard Ratio 95% Confidence Intervals 1 BDI score Age Systolic blood pressure 130 mm Hg Charlson Co-morbidity Index BDI score Age Congestive heart failure BDI score Age Systolic blood pressure 130 mm Hg Congestive heart failure BDI score Gender Age Marital status Systolic blood pressure 130 mm Hg Congestive heart failure BDI score Age Systolic blood pressure 130 mm Hg Charlson Co-morbidity Index Congestive heart failure Figure 1. Kaplan-Meier adjusted survival curves for 5-year all-cause mortality by a history of depression (History Dep) and depressive symptomatology at the time of index hospitalization (In Hosp; BDI score 10 vs 10). compared with severity only at the time of hospitalization. This runs counter to findings from the cohort presented by We also created a variable for no increased depressive symptomatology at any time point, depressive symptomatology before or at index hospitalization, and depressive symptomatology at the 2 times. This was not related to mortality in the Cox s models. Lesperance et al, 5 in which patients who had recurrent depressive symptomatology at the time of hospitalization were at significantly increased risk of 18-month mortality compared with those who had depressive onset only at the time of hospitalization. However, their analysis was not conducted within an adjusted Cox s model. Further research using longitudinal community cohorts and diagnostic as-

13 1184 The American Journal of Cardiology ( sessments is needed to elucidate the role of depression chronicity and timing in mortality. The significant interaction between history of depressed mood and depressive symptomatology at the time of hospitalization is intriguing and replicates the findings of Lesperance et al. 5 They also found that the group with the lowest risk of mortality consisted of patients who had a history of depression and did not report increased depressive symptomatology in the hospital. Lesperance et al speculated that those who had a history of depression and managed to resist the stresses of ACS had enhanced physical or psychic resources that enabled them to survive. However, in the full Cox s model, this interaction was superceded by the importance of depressive symptomatology at the time of hospitalization. Nevertheless, this interaction deserves further thought and inquiry, particularly with regard to mechanisms. The negative prognostic effect of acute onset depressive symptomatology at the time of hospitalization raises further questions with regard to pathophysiologic, 20 rather than behavioral, mechanisms. These results corroborate that even mild depressive symptoms at the time of cardiac hospitalization are not benign symptoms solely attributable to a life-threatening event, somatic complaints, or hospital setting but are robust symptoms with important prognostic implications for years to follow. They also highlight the importance of early identification of depressive symptomatology during hospitalization. Once identified, patients who have increased symptomatology should be offered evidence-based treatments. 25 Although treating depression in the context of ACS does improve quality of life and functional capacity, 25 it is unclear whether treating depression may have beneficial effects on cardiac prognosis. 20,26 There is much current research that is examining potential behavioral and physiologic mechanisms that link depression to prognosis and how psychotherapeutic and psychopharmacologic treatment might mitigate this relation. Caution is warranted when interpreting these results. First, the generalizability of the study is limited by the differences between participants and refusers and the loss of participants in the linkage process. However, we adjusted for these differences in the Cox s model to statistically control for these biases. Second, our self-report measurement of depressive symptomatology assessed severity only and does not provide diagnostic information. Moreover, our self-report measurement of depressive history may be hampered by retrospective bias and was not verified through a structured diagnostic interview. However, 2 recent metaanalyses concluded that assessments by self-report questionnaires of symptomatology and clinical interviews based on diagnostic criteria are related to mortality and that, for these purposes, neither type of depressive assessment is superior. 27,28 Our outcome of mortality was not broken down by cardiac and noncardiac causes but was based on all-cause mortality only. Third, our results are limited by the small number of deaths in the group of participants who had a history of depressed mood and BDI scores 10. Further examination and replication in a larger population-based sample is warranted. Acknowledgment: We acknowledge Linda Green, PhD, and the coronary care unit nurses for their diligence in participant recruitment and Claus Wall, MSc, for data linkage. 1. Lesperance J, Frasure-Smith N, Talajic M, Bourassa M. Five-year risk of cardiac mortality in relation to initial severity and one-year changes in depression symptoms after myocardial infarction. Circulation 2002; 105: Keller M, Lavori P, Lewis CE, Klerman GL. Predictors of relapse in major depressive disorder. JAMA 1983;250: Bush D, Ziegelstein R, Tayback M, Richter D, Stevens S, Zahalsky H, Fauerbach JA. Even minimal symptoms of depression increase mortality risk after myocardial infarction. Am J Cardiol 2001;88: Hance M, Carney RM, Freedland KE, Skala J. Depression in heart patients with coronary heart disease: a 12-month follow-up. Gen Hosp Psychiatry 1996;18: Lesperance F, Frasure-Smith N, Talajic M. Major depression before and after myocardial infarction: its nature and consequences. Psychosom Med 1996;58: Schrader G, Cheok F, Hordacre A-L, Guiver N. Predictors of depression three months after cardiac hospitalization. Psychosom Med 2004; 66: Hemingway H, Marmot M. Evidence based cardiology: psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies. BMJ 1999;318: Rugulies R. Depression as a predictor for coronary heart disease: a review and meta-analysis. Am J Prev Med 2002;23: Wulsin L, Singal B. Do depressive symptoms increase the risk for the onset of coronary disease? A systematic quantitative review. Psychosom Med 2003;65: Grace SL, Abbey S, Pinto R, Shnek Z, Irvine J, Stewart DE. Longitudinal course of depressive symptomatology following a cardiac event: effect of gender and cardiac rehabilitation. Psychosom Med 2005;67: Killip T, Kimball JT. Treatment of myocardial infarction in a coronary care unit: a two year experience with 250 patients. Am J Cardiol 1967;20: Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression. Arch Gen Psychiatry 1961;4: Steer RA, Cavalieri TA, Leonard DM, Beck AT. Use of the Beck Depression Inventory for primary care to screen for major depression disorders. Gen Hosp Psychiatry 1999;21: Frasure-Smith N, Lesperance F, Talajic M. Depression following myocardial infarction: impact on six-month survival. JAMA 1993;270: Shnek ZM, Irvine J, Stewart DE, Abbey S. Psychological factors and depressive symptoms in ischemic heart disease. Health Psychol 2001; 20: Beck AT, Steer RA, Garbin MG. Psychometric properties of the Beck Depression Inventory: twenty-five years of evaluation. Clin Psychol Rev 1988;8: Frasure-Smith N. In-hospital symptoms of psychological stress as predictors of long-term outcome after acute myocardial infarction in men. Am J Cardiol 1991;67: Charlson M, Pompei P, Ales K, MacKenzie C. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40:

14 Coronary Artery Disease/Depression and Mortality in Cardiac Patients Abbey SE, Stewart DE. Gender and psychosomatic aspects of ischemic heart disease. J Psychosom Res 2000;48: Lett H, Blumenthal J, Babyak M, Sherwood A, Strauman T, Robins C, Newman NF. Depression as a risk factor for coronary artery disease: evidence, mechanisms, treatment. Psychosom Med 2004;66: Blazer DG, Kessler RC, McGonagle K, Swartz M. The prevalence and distribution of major depression in a national community sample: the national comorbidity survey. Am J Psychiatry 1994;151: Lavie C, Milani R, Cassidy M, Gilliland Y. Effects of cardiac rehabilitation and exercise training programs in women with depression. Am J Cardiol 1999;83: Berkman LF, Leo-Summers L, Horwitz RI. Emotional support and survival after myocardial infarction: a prospective, population-based study of the elderly. Ann Intern Med 1992;117: Burg M, Benedetto M, Soufer R. Depressive symptoms and mortality two years after coronary artery bypass surgery in men. Psychosom Med 2003;65: Swenson J, O Connor S, Barton D, Van Zyl L, Swedberg K, Forman LM, Gaffney M, Glassman AH. Influence of depression and effect of treatment with sertraline on quality of life after hospitalization for acute coronary syndrome. Am J Cardiol 2003; 92: Davidson K, Rieckmann N, Lesperance J. Psychological theories of depression: potential application for the prevention of acute coronary syndrome recurrence. Psychosom Med 2004;66: Barth J, Schumacher M, Herrmann-Lingen C. Depression as a risk factor for mortality in patients with coronary heart disease: a metaanalysis. Psychosom Med 2004;66: van Melle J, De Jonge P, Spijkerman T, Tjisssen J, Ormel J, van Veldhuisen D, van den Brink RHS, van den Berg MP. Prognostic association of depression following myocardial infarction with mortality and cardiovascular events: a meta-analysis. Psychosom Med 2004;66:

15 Usefulness of Left Ventricular Diastolic Wall Motion Abnormality as an Early Predictor of Left Ventricular Dilation After a First Acute Myocardial Infarction Mirza Husic, MD a, Betina Nørager, MD b, Kenneth Egstrup, MD, DMSc a, and Jacob E. Møller, MD, PhD c, * To determine the relation between regional diastolic wall motion abnormality and left ventricular remodeling after acute myocardial infarction (AMI), Doppler echocardiography and color kinesis with assessment of global and regional systolic and diastolic functions were performed in 84 patients who developed AMI within 24 hours of admission. In a multivariate logistic regression analysis, the percentage of left ventricular myocardial segments with diastolic wall motion abnormality (p 0.008), absence of myocardial viability (p 0.01), and overall diastolic function (p 0.001) were predictors of remodeling after AMI Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Remodeling after an acute myocardial infarction (AMI) is a complex process of change in size, shape, and function of the left ventricle, 1 which plays an important role in the development of chronic heart failure after AMI. 2 Previous studies have suggested that a restrictive transmitral filling pattern that is suggestive of global left ventricular (LV) diastolic dysfunction identifies patients at risk of remodeling after AMI, 3 5 but less is known of regional diastolic function. Using color kinesis, we tested the hypothesis that diastolic wall motion abnormality is predictive of LV remodeling after AMI. Among 154 consecutive patients who had a first AMI, 84 were recruited at Svendborg Hospital (Svendborg, Denmark). Due to death before 6-month follow-up (n 16), poor compliance (n 10), coronary bypass surgery (n 29), myocardial reinfarction within 6 months (n 10), or poor acoustic window or paced rhythm (n 5), 70 patients were excluded from the initial cohort. The diagnosis of AMI was based on a documented transient increase in biochemical markers of myocardial necrosis, presence of typical symptoms, and/or electrocardiographic signs of AMI according to guidelines of the European Society of Cardiology/American College of Cardiology. 6 The protocol was approved by the regional scientific ethical committee, and all enrolled patients gave informed written consent. Echocardiography was performed on a Sonos 5500 ultrasound machine (Hewlett Packard, Andover, Massachusetts) within 24 hours of admission and was repeated 6 months after AMI. Five consecutive beats were measured The a Department of Medicine, Svendborg Hospital, Svendborg; the b Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen; and the c Department of Cardiology, Odense University Hospital, Odense, Denmark. Manuscript received March 8, 2005; revised manuscript received and accepted June 13, * Corresponding author: Tel: ; fax: address: jem@dadlnet.dk (J.E. Møller). for Doppler indexes and 2 consecutive beats for 2-dimensional and color kinesis parameters. All analyses were performed blinded for clinical characteristics. Regional wall motion score and index were assessed according to recommendations of the American Society of Echocardiography. 7 LV volumes and ejection fraction were estimated using Simpson s modified biplane method. 7 At hospital discharge, a low-dose dobutamine echocardiogram was obtained to assess myocardial viability. Dobutamine was infused at dosages of 5 and 10 g/kg/min for 3 minutes each, with images obtained at baseline and at 10 g/kg/min infusion. Myocardial viability was defined as improved wall motion in 2 contiguous infarct zone segments or in all infarct zone segments if 3 segments were basically asynergic. 8 Using the acoustic quantification system, LV end-systolic and end-diastolic color-encoded images were acquired in the apical window, and images were automatically divided into 16 segments as previously described Different colors were used to encode pixel transition between blood and myocardial tissue (Figure 1). From end-diastolic color overlays, pixels of each color were counted in each segment. Pixel counts were used to quantify regional endocardial motion during LV emptying and filling in terms of incremental fractional area change and filling fraction Temporal evaluation of systolic and diastolic endocardial motions was expressed by mean time of ejection and filling, which was calculated for each segment Quantitative regional wall motion was evaluated on a segment-by-segment basis by comparing a patient s data with the corresponding normal range. The normal range was based on previously established normal values for indexes of endocardial motion derived from color kinesis, 12 with the normal range defined as 2 SDs around the mean. A segment was considered asynchronous in systole when the incremental fractional area change was below the lower limit of normal or the mean time of ejection was above the upper limit of normal. A segment was considered as being abnor /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

16 Coronary Artery Disease/Regional Diastolic Dysfunction and LV Dilation After AMI 1187 Figure 1. End-diastolic color kinetic images show regional wall motion abnormalities after ST-segment elevation AMI in 1 patient (left) and after non ST-segment elevation AMI in another (right). The image of ST-segment elevation AMI shows narrow color bands in the mid-septal, apicoseptal, and apicolateral segment, reflecting decreased magnitude (hypokinesia) of endocardial motion. The image of non ST-segment elevation AMI displays broad color bands, but with more late colors (yellow and orange) in the mid-septal and apicoseptal segments, reflecting delayed endocardial motion (tardokinesis). mal in diastole when the filling fraction was below the lower limit of normal (hypokinesia) or the mean time of filling was above the upper limit of normal (tardokinesis). Areas of systolic and diastolic wall motion abnormalities were expressed as percentages of the LV cavity size in end-systole and end-diastole, respectively. Mitral inflow was recorded from the apical 4-chamber view by placing the pulse-wave Doppler sample volume between the tips of mitral leaflets during diastole. Color M-mode echocardiography was performed from the apical 4-chamber view with the color M-mode cursor aligned parallel with LV inflow and the aliasing velocity set to 45 cm/s. 13 The flow propagation velocity was measured as previously described. 13 Diastolic filling was categorized as normal, impaired relaxation, pseudonormal, or restrictive by integrated assessment of E-wave deceleration time and flow propagation velocity, as previously validated. 4,13 LV dilation was defined as an increase in end-diastolic volume 20% from baseline to 6-month follow-up. 14 Patients were categorized into 2 groups according to this cutoff. Blood samples were collected 3 days after AMI by vein puncture and serum was subsequently analyzed with an Elecsys N-terminus pro brain natriuretic peptide (NT pro- BNP) sandwich immunoassay on an Elecsys 2010 analyzer (Roche Diagnostics) for serum concentration of NT pro- BNP. Continuous data are expressed as mean SD unless otherwise specified. Student s t test was used for analysis of continuous variables and the chi-square test for categorical variables. NT pro-bnp was log-transformed due to positively skewed distribution. Multivariate logistic regression analysis with forward selection was performed to identify predictors of an increase in LV end-diastolic volume 20% 6 months after AMI. Entry and retention in the model was considered statistically signficant at p In 64 patients (76%), no significant increase in LV enddiastolic volume was seen (group I), whereas an increase 20% was seen in 20 patients (24%, group II; Tables 1 and 2). Using color kinetic assessment of regional myocardial function was feasible in 1,301 of 1,344 myocardial segments (97%). Abnormal diastolic filling fraction was detected in 255 segments (19%) and abnormal filling time in 208 myocardial segments (15%). Of these 463 segments, 227 also demonstrated abnormal systolic function, whereas diastolic function alone was abnormal in 236 segments. The percentage of myocardial segments with diastolic wall motion abnormalities was 35 16%, and that with systolic wall motion abnormalities was 17 16%. The area of diastolic wall motion abnormality was larger in patients who had no infarct zone viability (45 14 vs 31 17, p ) and was significantly correlated with NT pro-bnp (r 0.69, p ). Patients who had LV dilation at 6 months had larger areas of diastolic wall motion abnormality than did patients who had no dilation at 6 months (Figure 2). In addition, the area of diastolic wall motion abnormality was significantly correlated with a change in end-diastolic volume (r 0.61, p ). Further, the number of segments with diastolic wall motion abnormality but preserved systolic function was larger in group II ( vs , p 0.001). In group II (LV dilation), diastolic wall motion abnormality 31% (median) was present in all patients, and 85% (17 patients) had no infarct zone viability. In contrast, diastolic wall motion abnormality 31% and no infarct zone viabil-

17 1188 The American Journal of Cardiology ( Table 1 Clinical characteristics of patients with and without an increase in left ventricular end-diastolic volume 20% Characteristic LV Dilation p Value No (n 64) Yes (n 20) Age (yrs) Men 47 (73%) 10 (50%) 0.05 Current smoker 29 (45%) 9 (45%) 0.56 Hypertension 16 (25%) 3 (15%) 0.35 Diabetes mellitus 9 (14%) 2 (5%) 0.65 Angina pectoris 27 (27%) 7 (35%) 0.47 ST-segment elevation AMI 36 (56%) 13 (65%) 0.49 Anterior wall AMI 20 (31%) 9 (45%) 0.26 Killip s class 2 11 (17%) 11 (55%) Log NT pro-bnp (pmol/l) Peak creatine kinase-mb (U/L) In-hospital treatment Thrombolytic therapy 31 (48%) 8 (40%) 0.50 Low-molecular-weight heparin 33 (52%) 12 (60%) 0.51 Intravenous diuretic 9 (14%) 5 (25%) 0.25 Discharge medication -blocking agents 58 (90%) 16 (80%) 0.43 Angiotensin-converting enzyme 25 (39%) 7 (35%) 0.67 inhibitor/angiotensin II receptor antagonists Diuretics 9 (14) 10 (50%) Angioplasty during follow-up 33 (52%) 6 (30%) 0.09 Data are expressed as mean SD or numbers of patients (percentages). Figure 2. Area of diastolic wall motion abnormality according to degree of LV dilation 6 months after AMI. ity was seen in only 5 patients (8%) in group I (no LV dilation). In a multivariate logistic regression analysis with forward selection of variables, area of diastolic wall motion abnormality (odds ratio 1.12 for 1% increase in wall motion abnormality, 95% confidence interval 1.07 to 1.22, p 0.008), lack of myocardial viability (odds ratio 10.9, 95% confidence interval 1.95 to 33.8, p 0.01), and overall diastolic function (odds ratio 6.25 for a 1-grade increase, 95% confidence interval 1.94 to 20.1, p 0.001) were predictors of an increase in LV end-diastolic volume 20%. Table 2 Echocardiographic characteristics of patients with and without an increase in left ventricular end-diastolic volume exceeding 20% Characteristic LV Dilation p Value No (n 64) Yes (n 20) Baseline LV ejection fraction (%) LV end-diastolic volume index (ml/m 2 ) LV end-systolic volume index (ml/m 2 ) Wall motion score index E-deceleration time (ms) Flow propagation velocity (cm/s) Diastolic function Normal 40 (63%) 0 Grade 1 17 (27%) 2 (10%) Grade 2 5 (7%) 13 (65%) Grade 3 2 (3%) 5 (25%) Diastolic wall motion abnormality (%) Systolic wall motion abnormality (%) Infarct zone viability 48 (77%) 3 (15%) mo follow-up LV ejection fraction (%) LV end-diastolic volume index (ml/m 2 ) LV end-systolic volume index (ml/m 2 ) Wall motion score index Data are expressed as mean SD or numbers of patients (percentages).

18 Coronary Artery Disease/Regional Diastolic Dysfunction and LV Dilation After AMI 1189 Log NT pro-bnp (p 0.06) and ejection fraction (p 0.07) were of borderline importance. Age (p 0.84), enzymatic infarct size (p 0.32), and angioplasty (p 0.33) were not predictors. The present study confirms that advanced diastolic dysfunction and increased concentrations of NT pro-bnp in the immediate postinfarct state are predictors of LV remodeling after AMI. Further, the study demonstrates that the extent of abnormal diastolic wall motion in the acute phase of AMI is associated with the degree of LV dilation at 6 months. Previous experimental and clinical studies have demonstrated that persistent regional diastolic impairment may be present after an ischemic myocardial injury, although systolic function is preserved This seems to be the case especially in myocardial segments that are adjacent to infarcted segments and segments with subendocardial injury. 15 An explanation for this phenomenon could be that regional diastolic function has a lower injury threshold than systolic function. 18 In accordance with this notion, we found that the extent of regional diastolic hypokinesia or tardokinesis exceeded the extent of regional systolic function in most patients. Further, we found that the extent of abnormal regional function during filling correlated well with the increase in LV end-diastolic volume during follow-up, NT pro-bnp levels, and absence of myocardial viability. Azevedo et al 15 recently demonstrated that regional diastolic impairment is related to microvascular obstruction (no reflow phenomena), a phenomenon that, after primary angioplasty, has been demonstrated to predict LV dilation. 19 Thus, abnormal regional diastolic function may identify areas with microvascular damage that may act as a substrate for adverse remodeling. 1. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction. Experimental observations and clinical implications. Circulation 1990;81: St John SM, Pfeffer MA, Plappert T, Rouleau JL, Moye LA, Dagenais GR, Lamas GA, Klein M, Sussex B, Goldman S. Quantitative twodimensional echocardiographic measurements are major predictors of adverse cardiovascular events after acute myocardial infarction. Circulation 1994;89: Cerisano G, Bolognese L, Carrabba N, Buonamici P, Santoro GM, Antoniucci D, Santini A, Moschi G, Fazzini PF. Doppler-derived mitral deceleration time: an early strong predictor of left ventricular remodeling after reperfused anterior acute myocardial infarction. Circulation 1999;99: Moller JE, Sondergaard E, Poulsen SH, Egstrup K. Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode Doppler echocardiographic study. J Am Coll Cardiol 2000;36: Temporelli PL, Giannuzzi P, Nicolosi GL, Latini R, Franzosi MG, Gentile F, Tavazzi L, Maggioni AP. Doppler-derived mitral deceleration time as a strong prognostic marker of left ventricular remodeling and survival after acute myocardial infarction: results of the GISSI-3 echo substudy. J Am Coll Cardiol 2004;43: Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol 2000;36: Schiller NB, Shah PM, Crawford M, Demaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiogr 1989;2: Smart SC, Sawada S, Ryan T, Segar D, Atherton L, Berkovitz K, Bourdillon PD, Feigenbaum H. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993;88: Lang RM, Vignon P, Weinert L, Bednarz J, Korcarz C, Sandelski J, Koch R, Prater D, Mor-Avi V. Echocardiographic quantification of regional left ventricular wall motion with color kinesis. Circulation 1996;93: Mor-Avi V, Vignon P, Koch R, Weinert L, Garcia MJ, Spencer KT, Lang RM. Segmental analysis of color kinesis images: new method for quantification of the magnitude and timing of endocardial motion during left ventricular systole and diastole. Circulation 1997;95: Vignon P, Mor-Avi V, Weinert L, Koch R, Spencer KT, Lang RM. Quantitative evaluation of global and regional left ventricular diastolic function with color kinesis. Circulation 1998;97: Mor-Avi V, Spencer K, Gorcsan J, Demaria A, Kimball T, Monaghan M, Perez J, Sun JP, Weinert L, Bednarz J, et al. Normal values of regional left ventricular endocardial motion: multicenter color kinesis study. Am J Physiol Heart Circ Physiol 2000;279:H2464 H Garcia MJ, Thomas JD, Klein AL. New Doppler echocardiographic applications for the study of diastolic function. J Am Coll Cardiol 1998;32: Bolognese L, Neskovic AN, Parodi G, Cerisano G, Buonamici P, Santoro GM, Antoniucci D. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and longterm prognostic implications. Circulation 2002;106: Azevedo CF, Amado LC, Kraitchman DL, Gerber BL, Osman NF, Rochitte CE, Edvardsen T, Lima JA. 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19 A Multistate Comparison of Patient Characteristics, Outcomes, and Treatment Practices in Acute Myocardial Infarction Shadi S. Saleh, PhD, MPH*, Edward L. Hannan, PhD, and Larry Ting, MS The primary purpose of this study was to examine variations in patient characteristics, outcomes, and treatment practices in acute myocardial infarction (AMI) across 11 states. Data from 11 states were extracted from the Healthcare Cost and Utilization Project State Inpatient Dataset. Patients who had a primary diagnosis of AMI (International Classification of Diseases, Ninth Revision, Clinical Modification, code 410.x1) from 11 states were extracted from the Healthcare Cost and Utilization Project 1999 dataset. Bivariate comparisons were conducted to examine the characteristics, treatment practices, and outcomes of patients who had AMI. Multivariate regression models were used to examine the association between geographic location (and other factors) and the likelihood of in-hospital mortality, undergoing coronary artery bypass grafting (CABG), or percutaneous coronary interventions (PCIs). Results revealed considerable variations across states in practice patterns and treatment outcomes. New York had the highest average length of stay (8.2 days, p <0.01), rate of patients who had AMI being transferred (20.7%, p <0.01), and in-hospital case fatality rate (10.7%, p <0.01) and the lowest rate of alive discharges being routine (65.6%, p <0.01). PCI was performed 2 times as often as CABG for patients who had AMI (23.9% vs 11.3%, p <0.01), with patients who underwent CABG being transferred more often. Multivariate analyses showed that state of residence, age, female gender, transfer status, and number of co-morbidities were predictors of in-hospital mortality and the likelihood of undergoing CABG or PCI. In conclusion, large differences in practice patterns and treatment outcomes exist across states Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) In 2002, 40% of all deaths in the United States were attributed to cardiovascular disease, and close to 20% of these deaths ( 500,000 cases) were due to acute myocardial infarction (AMI). 1,2 One of the areas that has not been as extensively explored when examining AMI is geographic variation. Most investigations of the relation between geographic location and AMI outcomes have concentrated on the use of cardiac medications and procedures. 3 6 Studies that have examined international geographic variation in AMI outcomes have reported mixed results. Some have concluded that location is independently associated with mortality due to AMI, 6 8 whereas others have not been as conclusive. 9,10 A few single-state investigations of AMI outcomes have also been conducted. 11,12 To the best of our knowledge, only 1 study has examined statewide differences in treatment practices and outcomes for AMI, and that study was primarily aimed at examining percutaneous coronary intervention (PCI) outcomes among patients who had AMI. 13 This study examines variations The Department of Health Policy, Management and Behavior, School of Public Health, State University of New York, University at Albany, Rensselaer, New York. Manuscript received April 13, 2005; revised manuscript received and accepted June 22, * Corresponding author: Tel: ; fax: address: ssaleh@albany.edu (S. Saleh). in patient characteristics, outcomes, and treatment practices in 11 states. Methods Data source: The study used data extracted from the Agency for Health Research and Quality s national hospital discharge database, the Healthcare Cost and Utilization Project State Inpatient Databases. 14 The State Inpatient Databases contains all hospital discharge records from participating states. The states that were selected from State Inpatient Databases to be included in this study were Arizona, California, Colorado, Florida, Iowa, Maryland, New York, Oregon, South Carolina, Washington, and Wisconsin for The states were selected because of their geographic representation. All patients having code 410.x1 from the International Classification of Diseases, Ninth Revision, Clinical Modification as a principal diagnosis were included in the study. Patients who were discharged alive and stayed for 2 days were excluded from analysis. Study variables: The main independent variable in the study was geographic location (state). Other independent variables of major interest included demographic variables (age and gender), payer status (Medicaid vs other payers), /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

20 Coronary Artery Disease/Geographic Variation of AMI Outcomes and Treatment 1191 co-morbidities, 15 and in-hospital outcomes (length of stay and mortality). The main dependent variables were in-hospital mortality and treatment practices (use of PCI and coronary artery bypass grafting [CABG]). Statistical analysis: The age-adjusted rates of AMI were calculated using the age-specific total number of patients who were hospitalized with AMI (numerator). Rates were based on population estimates as of July 1, 1999 and were grouped into 10-year age intervals. The estimated United States population in 1999 was used as the standard population. 16 Bivariate analyses were conducted to examine differences in patients characteristics, treatment practices, outcomes, and transfer status by geographic location. The chisquare test (categorical variables) and analysis of variance were performed to determine whether these associations were statistically significant. Multivariate analyses were conducted using logistic regression models due to the binary nature of the outcome variables (in-hospital case fatality rate, CABG, and PCI). Independent variables in this analysis included geographic location (state), age, gender, numerous co-morbidities, and AMI site transfer status. Only co-morbidities that had a strong positive bivariate association with the outcome variable (p 0.2) were included in the analyses. The multivariate model included age as a categorical variable (with patients who were 55 years of age used as reference), gender (with male as reference), AMI sites (with subendocardial as reference), co-morbidities, and the 11 states using the state of Maryland as reference and then using the state of Iowa as reference in the effects coding. Results AMI practice patterns and treatment outcomes: Characteristics of patients who had AMI are presented in Table 1. Table 2 presents treatment practices and outcomes of AMI cases in the 11 states and for the total study population. Iowa had the highest in-hospital case fatality rate among transfer patients across the 11 states (6.9%), with Arizona having the lowest rate (5.0%). In contrast, New York had the highest in-hospital case fatality rate (13.0%) among patients who did not transfer and Colorado had the lowest rate (7.9%). CABG was performed in 11.3% of patients who had AMI. Arizona had the highest rate of CABG being performed on patients who had AMI (13.1%), and Oregon had the lowest (9.3%). In-hospital case fatality rate after CABG also varied across states, with 3 states (Iowa, Wisconsin, and Maryland) having the highest case fatality rate (5.2%) and South Carolina having the lowest (3.7%). Great variation was observed in the percentage of patients who had AMI, underwent CABG, and were transferred into the focal hospital from another short-term hospital. One-fifth of patients (21.6%) who had AMI in Iowa and underwent CABG were transfers compared with 49.9% in Maryland. A larger percentage of patients who had AMI underwent PCI (23.9%) rather than CABG, with Colorado having the highest rate (36.0%) and Maryland having the lowest (16.8%). In-hospital case fatality rate after PCI (1.8%) was lower than that of CABG (4.7%). Maryland had the highest case fatality rate for PCI (3.0%), whereas New York had the lowest (1.1%). The rate of patients who had AMI, underwent PCI, and were transferred varied greatly across the 11 states. The state with the highest rate, New York, had 3 times the rate of patients who underwent PCI and had transferred compared with the state with the lowest rate, Washington (43.9% vs 15.2%). Multivariate analyses: effect of geographic location on AMI mortality: The output from the multivariate logistic regression model is presented in Table 3. The results indicated that patients who lived in California (odds ratio 1.05, p 0.05), Maryland (odds ratio 1.11, p 0.05), (odds ratio 1.05, p 0.05), New York (odds ratio 1.37, p ), and South Carolina (odds ratio 1.26, p ) had significantly higher odds of dying compared with those who lived in the other study states. Conversely, patients who lived in Arizona (odds ratio 0.89, p 0.05), Colorado (odds ratio 0.82, p 0.001), Oregon (odds ratio 0.85, p 0.01), and Washington (odds ratio 0.88, p 0.01) were less likely to die during their hospital stay. Transfer status was also associated with a lower likelihood of in-hospital mortality (odds ratio 0.65, p ). Multivariate analyses: effect of geographic location on likelihood of CABG and PCI: The results of the multivariate analysis indicated that patients who lived in Arizona (odds ratio 1.20, p ), California (odds ratio 1.05, p 0.02), Florida (odds ratio 1.12, p ), and Wisconsin (odds ratio 1.22, p ) were more likely to undergo CABG than were patients who lived in other states. Conversely, patients who had AMI and lived New York (odds ratio 0.94, p 0.01) and Oregon (odds ratio 0.84, p 0.001) had a lower likelihood of undergoing CABG. Transfer status was strongly associated with having a CABG (odds ratio 3.2, p ). Geographic location was also strongly related to undergoing a PCI. Residing in Colorado (odds ratio 1.54, p ), Florida (odds ratio 1.12, p ), Iowa (odds ratio 1.48, p ), Washington (odds ratio 1.19, p ), and Wisconsin (odds ratio 1.16, p ) was associated with a higher likelihood of undergoing PCI. Conversely, patients who lived in California (odds ratio 0.87, p ), Maryland (odds ratio 0.01, p ), New York (odds ratio 0.66, p ), and Oregon (odds ratio 0.77, p ) had a lower likelihood of undergoing PCI compared with other states. As with CABG, transfer status was associated with the likelihood of undergoing PCI (odds ratio 1.87, p ).

21 Table 1 Selected characteristics of patients who had acute myocardial infarction by state, 1999 Characteristics* AZ (n 6,649) CA (n 37,826) CO (n 5,363) FL (n 35,053) IA (n 5,398) MD (n 7,133) NY (n 27,265) OR (n 5,021) SC (n 6,737) WA (n 7,493) WI (n 7,724) Total Population (n 151,662) Age-adjusted AMI cases/ ,000 Age (yrs) Mean % 31.5% 40.1% 28.8% 31.2% 32.5% 32.1% 33.9% 42.4% 36.3% 32.4% 32.3% % 24.6% 24.6% 25.2% 22.8% 23.7% 24.0% 24.2% 25.9% 23.1% 22.3% 24.5% % 28.3% 24.6% 29.2% 29.6% 28.4% 27.7% 27.7% 21.5% 27.0% 28.9% 27.9% % 15.5% 10.7% 16.7% 16.5% 15.5% 16.2% 14.1% 10.3% 13.6% 16.3% 15.3% Women 37.8% 41.1% 38.7% 40.8% 42.3% 45.2% 44.0% 37.8% 41.2% 37.4% 41.9% 41.3% Medicaid 6.3% 6.2% 1.8% 2.9% 1.8% 4.8% 7.8% 3.7% 3.4% 5.3% 1.8% 4.9% Co-morbidities Congestive heart failure 28.4% 35.7% 26.6% 38.8% 32.0% 41.1% 37.8% 30.9% 30.6% 30.2% 32.3% 35.5% Valve Disease 9.1% 11.3% 10.5% 17.4% 12.8% 17.9% 11.7% 10.0% 9.8% 11.3% 11.8% 12.9% Peripheral vascular 5.5% 7.0% 5.5% 8.7% 7.5% 8.5% 6.1% 5.3% 7.6% 6.4% 7.3% 7.1% disease Hypertension without 40.3% 41.2% 44.5% 42.0% 41.0% 44.0% 46.0% 38.6% 41.0% 38.3% 41.3% 42.2% complications Chronic pulmonary 20.1% 18.8% 19.0% 22.1% 19.8% 20.6% 16.7% 17.1% 17.8% 19.7% 16.1% 19.2% disease Diabetes without 21.1% 23.3% 18.5% 23.5% 22.4% 25.9% 25.6% 20.9% 25.6% 19.4% 20.8% 23.3% complications Diabetes with complications 4.0% 5.9% 3.9% 4.3% 3.6% 5.2% 4.6% 4.6% 4.1% 4.5% 4.7% 4.8% 1192 The American Journal of Cardiology ( * All characteristics were significantly different across states at p AZ Arizona; CA California; CO Colorado; FL Florida; IA Iowa; MD Maryland; NY New York; OR Oregon; SC South Carolina; WA Washington; WI Wisconsin.

22 Table 2 Acute myocardial infarction treatment practices and outcomes by state, 1999 Variable* AZ CA CO FL IA MD NY OR SC WA WI Total Population (n 151,662) Mean length of stay Transfer from another short-term facility 14.3% 16.2% 14.3% 13.4% 11.3% 16.0% 20.7% 15.8% 18.2% 11.5% 18.0% 16.0% In-hospital case fatality rate 8.3% 10.7% 7.6% 10.9% 10.1% 10.7% 11.4% 9.3% 10.4% 9.0% 10.2% 10.4% Transfer 5.0% 6.2% 5.7% 5.9% 6.9% 6.0% 5.4% 5.5% 5.5% 5.5% 5.7% 5.8% Nontransfer 8.9% 11.6% 7.9% 11.6% 10.5% 11.6% 13.0% 10.0% 11.5% 9.5% 11.2% 11.3% CABG Rate (among AMI patients) 13.1% 11.2% 10.7% 11.9% 9.6% 9.6% 11.0% 9.3% 12.4% 10.1% 12.9% 11.3% In-hospital mortality 5.0% 5.1% 5.1% 4.9% 5.2% 5.2% 4.0% 4.3% 3.7% 3.8% 5.2% 4.7% Transfer 27.9% 37.6% 22.4% 32.3% 21.6% 49.9% 48.1% 40.6% 33.5% 30.8% 32.1% 36.4% PCI Rate (among AMI patients) 27.3% 22.2% 36.0% 24.0% 31.0% 16.8% 19.6% 23.0% 27.0% 29.7% 28.8% 23.9% In-hospital mortality 1.7% 2.0% 1.6% 1.9% 2.3% 3.0% 1.1% 1.8% 1.5% 2.3% 2.1% 1.8% Transfer 21.9% 20.8% 18.7% 23.8% 16.2% 36.7% 43.9% 27.2% 28.9% 15.2% 27.3% 25.9% Discharge status (alive patients) Routine 79.6% 71.3% 78.7% 67.8% 72.6% 70.3% 65.6% 81.9% 83.2% 79.0% 73.8% 71.5% Skilled nursing facility 8.5% 4.2% 8.6% 11.7% 8.0% 9.3% 9.3% 7.3% 6.8% 10.7% 11.1% 8.5% Intermediate care facility 2.5% 8.2% 1.2% 1.0% 6.6% 6.3% 0.6% 1.1% 0.4% 0.6% 1.7% 3.2% Other type of facility 2.9% 0.7% 2.5% 4.4% 2.8% 3.7% 5.5% 1.8% 2.9% 2.0% 3.0% 3.1% Home health care 5.5% 12.2% 8.8% 14.3% 9.7% 9.5% 17.5% 7.3% 6.4% 7.2% 10.0% 12.2% Against medical advice 0.39% 0.9% 0.2% 0.8% 0.4% 0.8% 1.3% 0.4% 0.4% 0.4% 0.2% 0.8% Other 0.6% 2.6% 0.1% 0.0% 0.0% 0.0% 0.3% 0.1% 0.0% 0.1% 0.3% 0.8% * All characteristics were significantly different across states at p Differences were not significant. Abbreviations as in Table 1. Coronary Artery Disease/Geographic Variation of AMI Outcomes and Treatment 1193

23 1194 The American Journal of Cardiology ( Table 3 Results of logistic regression with in-hospital case fatality rate and likelihood of coronary artery bypass graft or percutaneous coronary interventions as outcomes Parameter/Effect In-Hospital CFR CABG as Procedure PCI as Procedure Odds Ratio p Value Odds Ratio p Value Odds Ratio p Value Women Age years years years years AZ CA CO FL IA MD NY OR SC WA WI Transfers Inferolateral wall Inferoposterior wall Other inferior wall Other lateral wall True posterior wall Other specified sites Unspecified sites Co-morbidities included congestive heart failure, cardiac arrest, valve disease, pulmonary circulatory disease, peripheral vascular disease, hypertension with complications, hypertension without complications, paralysis, other neurologic disease, chronic pulmonary disease, diabetes without complications, diabetes with complications, hypothyroidism, renal failure, liver disease, peptic ulcer, acquired immunodeficiency syndrome, lymphoma, malignant neoplasm, tumor, rheumatoid arthritis, coagulation, obesity, weight loss, fluid, electrolyte, and acid-base balance disorder, blood loss, iron deficiency anemia, alcohol abuse, drug abuse, psychoses, and depression. CFR case fatality rate; other abbreviations as in Table 1. Discussion This study examined geographic variations in patient characteristics, outcomes, and treatment practices across 11 states. Many studies have examined the effect of demographic variables, such as age, gender, and co-morbidities on AMI occurrences and outcomes and have evaluated treatment outcomes However, very few have conducted cross-state or international comparisons and some, like the European Heart Survey, have used different data collection methods. 25 Results from this study revealed significant geographic variations in AMI practice patterns and treatment outcomes. The in-hospital case fatality rate, which was 10.4% across all states, ranged from 7.6% in Oregon to 11.4% in New York. There are few studies with which to compare these results. In a study of coronary angioplasty (PCI) outcomes in 17 states from 1993 to 1994 using Healthcare Cost and Utilization Project data that included information on the subset of patients who underwent PCI and had preprocedural AMIs, Maynard et al 13 found that patients who had AMI and underwent PCI had a mean age of 62 years, that 33% were women, and that the hospital case fatality rate was 3.8%. Although that rate is much higher than the 1.8% rate reported in our study, it should be noted that the study by Maynard et al predated the introduction of stents and other advances in PCI between 1993 and In addition, PCI that should be used only in patients who have STelevation myocardial infarction and those who have non ST-elevation myocardial infarction and are at high risk currently may be used more liberally for low-risk patients who have non ST-elevation myocardial infarction. That will result in a lower case fatality rate. These data are limited because they do not allow the categorization of patients with ST-elevation myocardial infarction versus non ST-elevation myocardial infarction and high- versus low-risk patients. In 1996, the Pennsylvania Health Care Cost Containment Council reported on 38,764 patients who were hospitalized with AMI in The mortality rates for patients transferred in and not transferred in were 7.3% and 10.6%, respectively (compared with 5.8%, range 5.0 to 6.9, and 11.3%, range 7.9 to 13.0). A total of 8,049 patients (21.6%) were transferred in Pennsylvania compared with 16.0%

24 Coronary Artery Disease/Geographic Variation of AMI Outcomes and Treatment 1195 (range 11.3 to 20.7) across the 11 states in our study. 11 Another state that reports AMI outcomes is California. A recent report presented data on 128,509 patients who had AMI (1996 to 1998). 12 The results showed a 30-day mortality rate of 12.09% compared with an average of 10.4% (range 7.6 to 11.4) in the present study. Results of this study showed that California s crude in-hospital case fatality rate was 10.7%. Differences may be due to risk adjustment and the use of 30-day mortality rate compared with the inhospital case fatality rate. There are several possible reasons for the rather large differences across states in in-hospital case fatality rates in our study. First, differences may also be partly explained by the availability and utilization of procedures for treating AMI, most notably PCI. For example, in this study, the case fatality rate for patients who had AMI and underwent PCI was only 1.8% compared with a case fatality rate of 10.4% for all patients who had AMI. Although this difference is somewhat biased by the possibility that the very sickest patients may die before having a chance to undergo PCI, the advantage of PCI is apparent. Further, the percentage of patients who had AMI and underwent PCI varied considerably, from 16.8% in Maryland to 36.0% in Colorado. A second possible explanation for differences in adverse outcomes that cannot be detected through the use of administrative datasets is that there may be differences across states in the use of appropriate processes of care for treating patients who have AMI. For example, a study by Chen et al 26 found that patients who had AMI and were admitted to high-quality hospitals had a lower case fatality rate. This observation could be attributed to these high-quality hospitals providing better treatment for their newly admitted patients. For instance, they may give their patients blockers and aspirin in a timely manner. 26 Given this possibility, differences in AMI case fatality rate across states could be explained by hospitals in some states using some processes of care more often for their patients who are newly admitted for AMI than others. 27 Another difference across states that is noteworthy is in the rates of transfers of patients who had AMI from 1 hospital to another. The percentage of patients who were transferred to another hospital varied from 11.3% in Iowa to 20.7% in New York. We hypothesize that the presence of certificate-of-need criteria may have played a part in these differences. For example, New York has a small proportion of hospitals that is certified to perform cardiac procedures. This may explain why it had the highest rate of transfers among all 11 states. In contrast, states such as Colorado and Arizona, which repealed their certificates of need, had low rates of transfers. Another explanation is the geographic nature (rurality) of the states. States with large rural areas may have lower rates of transfers because patients are transferred only if they are stable enough to survive it. A good example among states examined in this study is Iowa, which had the lowest transfer rate across the 11 states. These 2 factors may have also played a role in the difference in in-hospital case fatality rate between patients who were transferred and those who were not. The results revealed that the mortality rate of patients who were transferred was higher than that of those who were not. That may have been a factor of certificate of need and rurality of certain states. The former results in patients who have AMI being transferred to hospitals that do not provide cardiac care, due to certificate-of-need restrictions; hence, the patient has to be transferred to another hospital that does provide cardiac care. Rurality effect is similar where hospitals that provide cardiac care may be scarce and far away. In these cases, patients will arrive at the host facility at a higher risk. In addition, a decision may be made at the originating hospital that a patient could not survive transfer, thus resulting in higher in-hospital case fatality rates for patients who are not transferred. Some additional limitations of the study merit consideration. Healthcare Cost and Utilization Project data do not contain comprehensive information on many potential risk factors that may be associated with mortality, such as heart rate and blood pressure at the time of admission. The data also lack information on the degree of severity of the coronary artery blockage, the amount of time that has elapsed between symptom onset and hospital arrival, and the amount of time that has elapsed between hospital arrival and treatment. All these factors limit this study s ability to provide strong evidence to enhance daily clinical care and improve AMI care logistics. In addition, these factors may be systematically different across states and may be associated with AMI case fatality rates. In addition, administrative data are subject to various coding anomalies. This creates a bias in assessing differences across states in patient co-morbidities unless the degree of undercoding is identical across states. We tried to eliminate differences among states in administrative databases by allowing only 10 secondary diagnoses (the minimum number used by any of the states in the study) to be considered. However, this does not account for any differences among states in the tendency to code all secondary diagnoses that are present, and we found that the mean number coded varied from 5.22 in New York to 6.10 in Florida. Future studies should examine whether there are interstate and interhospital differences in the manner in which patients who have AMI are treated, the degree of provider conformation to guidelines for PCI and CABG according to the American Heart Association/American College of Cardiology, and the extent to which those differences are related to short- and long-term outcomes. 1. Heart attack and angina statistics. Available at: americanheart.org/presenter.jhtml?identifier Accessed March 18, Spake A. Eyeing signs of trouble. U.S. News & World Report December 1, Pilote L, Califf RM, Sapp S, Miller DP, Mark DB, Weaver WD, Gore JM, Armstrong PW, Ohman EM, Topol EJ. Regional variation across the United States in the management of acute myocardial infarction.

25 1196 The American Journal of Cardiology ( GUSTO-1 Investigators. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. N Engl J Med 1995;333: Pilote L, Merrett P, Karp I, Alter D, Austin PC, Cox J, Johansen H, Ghali W, Tu JV. Cardiac procedures after an acute myocardial infarction across nine Canadian provinces. Can J Cardiol 2004;20: Weitzman S, Cooper L, Chambless L, Rosamond W, Clegg L, Marcucci G, Romm F, White A. Gender, racial, and geographic differences in the performance of cardiac diagnostic and therapeutic procedures for hospitalized acute myocardial infarction in four states. Am J Cardiol 1997;79: Giugliano RP, Llevadot J, Wilcox RG, Gurfinkel EP, McCabe CH, Charlesworth A, Thompson SL, Antman EM, Braunwald E. Geographic variation in patient and hospital characteristics, management, and clinical outcomes in ST-elevation myocardial infarction treated with fibrinolysis. Results from InTIME-II. Eur Heart J 2001;22: Domanski M, Antman EM, McKinlay S, Varshavsky S, Platonov P, Assmann SF, Norman J. Geographic variability in patient characteristics, treatment and outcome in an International Trial of Magnesium in acute myocardial infarction. Control Clin Trials 2004;25: Subramanian U, Weinberger M, Eckert GJ, L Italien GJ, Lapuerta P, Tierney W. Geographic variation in health care utilization and outcomes in veterans with acute myocardial infarction. J Gen Intern Med 2002;17: Pilote L, Saynina O, Lavoie F, McClellan M. Cardiac procedure use and outcomes in elderly patients with acute myocardial infarction in the United States and Quebec, Canada, 1988 to Med Care 2003;41: Van de Werf F, Topol EJ, Lee KL, Woodlief LH, Granger CB, Armstrong PW, Barbash GI, Hampton JR, Guerci A, Simes RJ. Variations in patient management and outcomes for acute myocardial infarction in the United States and other countries. Results from the GUSTO trial. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries. JAMA 1995;273: Focus on Heart Attack in Pennsylvania: Research Methods and Results. Harrisburg, PA: PA Health Care Cost Containment Council, Healthcare Quality and Analysis Division. Report on Heart Attack Outcomes in California , Volume 1: User s Guide. Sacramento: California Office of Statewide Health Planning and Development, Maynard C, Chapko MK, Every NR, Martin DC, Ritchie JL. Coronary angioplasty outcomes in the healthcare cost and utilization project, Am J Cardiol 1998;81: Healthcare Cost and Utilization Project: overview of HICUP. Available at: Accessed February 18, Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36: US Bureau of the Census, population division, Available at: Accessed January 22, Rich MW, Bosner MS, Chung MK, Shen J, McKenzie JP. Is age an independent predictor of early and late mortality in patients with acute myocardial infarction? Am J Med 1992;92: Greenland P, Reicher-Reiss H, Goldbourt U, Behar S. In-hospital and 1-year mortality in 1,524 women after myocardial infarction: comparison with 4,315 men. Circulation 1991;83: Naylor CD, Chen E. Population-wide mortality trends among patients hospitalized for acute myocardial infarction: the Ontario experience, 1981 to J Am Coll Cardiol 1994;24: Wilkinson P, Laji K, Ranjadayalan K, Parsons L, Timmis AD. Acute myocardial infarction in women: survival analysis in first six months. BMJ 1994;309: Chang WC, Kaul P, Westerhout CM, Graham MM, Fu Y, Chowdhury T, Armstrong PW. Impact of sex on long-term mortality from acute myocardial infarction vs. unstable angina. Arch Intern Med 2003;163: Every NR, Parsons LS, Hlatky M, Martin JS, Weaver WD. A comparison of thrombolytic therapy with primary coronary angioplasty for acute myocardial infarction. N Engl J Med 1996;335: Magid DJ, Calonge BN, Rumsfeld JS, Canto JG, Frederick PD, Every NR, Barron HV. Relation between hospital primary angioplasty volume and mortality for patients with acute MI treated with primary angioplasty vs thrombolytic therapy. JAMA 2000;284: McErlean ES. Thrombolytic therapy versus primary angioplasty in the treatment of acute myocardial infarction. J Cardiovasc Nurs 1999;13: European Society of Cardiology. Euro Heart Survey: Research Plan. Available at: Chen J, Radford MJ, Wang Y, Marciniak TA, Krumholz HM. Do America s best hospitals perform better for acute myocardial infarction? N Engl J Med 1999;340: Bradley EH, Herrin J, Mattera J, Holmboe ES, Wang Y, Frederick P, Roumanis SA, Radford MJ, Krumholz HM. Hospital-level performance improvement: beta-blocker use after acute myocardial infarction. Med Care 2004;42:

26 N-Terminal Pro-Brain Natriuretic Peptide and Tombstoning ST-Segment Elevation in Patients With Anterior Wall Acute Myocardial Infarction János Tomcsányi, MD, PhD,* András Marosi, MD, Béla Bózsik, MD, Miklós Somlói, MD, András Zsoldos, MD, Tibor Vecsey, MD, PhD, Hrisula Arabadzisz, MD, and Erzsébet Nagy, MD Tombstoning ST-segment elevation myocardial infarction (STEMI) has been associated with a poor prognosis ever since Wimalaratna s first description of this clinical entity, and the reasons for this are not fully understood. We studied 87 consecutive patients who had anterior STEMI (January 2004 to September 2004) to compare the form of STEMI, coronary anatomy, and initial N-terminus pro-brain natriuretic peptide (NT pro-bnp) level. Patients who had tombstoning STEMI had higher levels of NT pro-bnp despite significant differences in cardiac enzyme levels or extent of coronary disease. This finding suggests that, in addition to changing the shape of repolarization, decreased microcirculation plays a role in the development of increased wall tension. Increased wall tension in turn is the probable cause of higher NT pro-bnp levels and increased mortality Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Tombstoning ST-segment elevation (STE) denotes a unique subset of STE myocardial infarctions (STEMIs). Its clinical importance is based on the observation that the mortality rate of patients who have tombstoning STE significantly exceeds that of patients who have conventional STE. 1 The exact mechanisms that are responsible for the development of tombstoning STE are not known. One possible explanation is the presence of multivessel disease with poor collateral circulation and lower left ventricular ejection fraction. 2,3 No studies have been conducted on the relation between coronary anatomy and tombstoning STE in consecutive patients who have acute myocardial infarction. Brain natriuretic peptide (BNP) is released from the ventricles of the heart in response to increased wall tension. 4 BNP levels also increase after myocardial infarction and in unstable angina. 5 Pro-BNP is a proneurohormone that is synthesized by the ventricles of the heart and is enzymatically cleaved to BNP and the amino-terminal portion of the prohormone (N-terminus pro-bnp [NT pro-bnp]). BNP and NT pro-bnp levels were recently proved to be independent predictors of sudden and nonsudden death in patients who had acute coronary syndrome and myocardial infarction. 6,7 The goal of the present study was to compare the form of STEMI, coronary anatomy, and initial NT pro-bnp level in The Department of Cardiology, Polyclinic of the Hospitaller Brothers of St. John of God, Budapest, Hungary. Manuscript received February 8, 2005; revised manuscript received and accepted June 15, This work was supported by NSRF grant 1/001/2001 from the Széchenyi National Scientific Research Fund of Hungary, Budapest, Hungary. * Corresponding author: Tel/fax: address: tomcsanyi.janos@axelero.hu (J. Tomcsányi). consecutive patients who had acute anterior wall myocardial infarction. The study included 87 consecutive patients who were admitted to our institution with anterior STEMI between January and September Inclusion criteria consisted of chest pain that was 12 hours in duration and STE of 2 mm in leads V 1 to V 3 or 1 mm in other leads (as measured at the J point), and STE had to be present in 2 contiguous leads. Standard 12-lead electrocardiograms were recorded at a speed of 25 mm/s and an amplitude of 1 mv/10 mm. Exclusion criteria were left or right bundle branch block, pacemaker rhythm, Wolff-Parkinson-White syndrome, and left ventricular hypertrophy. The tombstoning pattern was identified according to modified criteria of Wimalaratna 1 : (1) the R wave is absent or its duration is 0.04 second with minimal amplitude; (2) the ST segment is convex upward and merges with the descending limb of the R wave or the ascending limb of the QS wave; (3) the peak of the convex ST segment is higher than whatever remains of the R wave; and (4) the convex ST segment merges with the ascending limb of the T wave. Patients were categorized as having tombstoning STE only or as having mixed-type or non-tombstoning STE. Baseline NT pro-bnp and creatine kinase values were obtained after admission to the hospital and before percutaneous coronary intervention. In vitro quantitative determination of NT pro-bnp levels in human serum samples was performed using an electrochemiluminescence immunoassay pro-bnp (Roche GmBH, Mannheim, Germany) method on an Elecsys 2010 analyzer (Roche). Mean hospital stay was 9 days. Of the 87 patients who were admitted with anterior STEMI, 23 (26%) had typical /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

27 1198 The American Journal of Cardiology ( Table I Patient characteristics (n 87) Clinical Characteristics and In-hospital Adverse Events With Tombstoning STEMI (n 23) Without Tombstoning STEMI (n 64) p Value Age (yrs) History of hypertension 12 (53%) 31 (48%) History of diabetes 6 (26%) 12 (18%) 0.55 Ejection fraction (%) or 3-VD 11 (48%) 35 (54%) CK (IU/I) CK-MB (IU/L) Death 3 (13%) 4 (6%) svt/vf 2 (9%) 4 (6%) HF 5 (22%) 9 (14%) Cardiogenic shock 2 (9%) 2 (3%) Open culprit artery 6 (26%) 22 (34%) Myocardial rupture 1 (4%) 0 (0%) LAD segment Unsuccessful PCI 5 (22%) 4 (6%) 0.05 TIMI frame count * TIMI myocardial perfusion grade * * Data are available for 20 patients. Data are available for 58 patients. CK creatine kinase; HF heart failure; LAD left anterior descending coronary artery; PCI percutaneous coronary intervention; svt sustained ventricular tachycardia; TIMI Thrombolysis In Myocardial Infarction; VD vessel disease; VF ventricular fibrillation. Figure 1. Baseline level of plasma pro-bnp in tombstoning and nontombstoning acute anterior wall myocardial infarctions. tombstoning STE. Clinical characteristics, coronary angiographic results, and relevant in-hospital events are listed in Table 1. There were no significant differences between groups with regard to age, diabetes, hypertension, left ventricular ejection fraction, and drug therapy (including the use of aspirin, statins, blockers, heparin, glycoprotein IIb/IIIa inhibitors, and angiotensin-converting enzyme inhibitors). NT pro-bnp values of samples that were taken simultaneously with the initial electrocardiogram are shown in Figure 1. The initial NT pro-bnp levels of patients who had tombstoning STEMI were 5 times higher than those of patients who had non-tombstoning STEMI. This difference was not associated with higher creatine kinase levels (as a marker of extent of myocardial damage) or more severe coronary artery disease. In-hospital complications and mortality rates tended to be much higher in the tombstoning group. The lack of statistical significance in this respect is due to the relatively small number of cases. The left anterior descending coronary artery was divided into proximal, middle, and distal segments. There were no statistically significant differences between groups with regard to the location of the culprit lesion. However, the frequency of unsuccessful revascularization, Thrombolysis In Myocardial Infarction frame count, and myocardial perfusion grade differed significantly. Tombstoning STEMI has been associated with a poor prognosis ever since Wilmalaratna s 1 first description of this clinical entity, but the reasons are not fully understood. Guo et al 2 hypothesized that this unique form of STEMI is evoked by the presence of stenosis in the proximal left anterior descending coronary artery that is aggravated by 3-vessel disease and a lack of collateral circulation. Our results showed that neither proximal left anterior descending coronary artery stenosis nor multivessel disease provided an explanation for the development of tombstoning STEMI. Nevertheless, in-hospital adverse event and mortality rates tended to be higher, although the difference did not reach statistical significance due to the small number of patients included in this homogenous group. However, the frequency of unsuccessful revascularization was significantly higher in the tombstoning group. Based on the higher Thrombolysis In Myocardial Infarction frame count and lower myocardial perfusion grade, we believe that tombstoning STEMI develops as a consequence of inadequate collateral circulation, and the higher mortality and adverse event rates noted in this group of patients may in part be the result of a higher rate of unsuccessful revascularization, which in turn is explained by the presence of more severe stenosis distal to the culprit lesion. Levels of BNP and NT pro-bnp begin to increase very early in the course of myocardial ischemia. 8,9 Patients who have tombstoning STEMI have higher levels of NT pro- BNP despite significant differences in cardiac enzyme blood levels or extent of coronary artery disease. This suggests that, in addition to changing the shape of repolarization, decreased microcirculation plays a role in the development of increased wall tension secondary to myocardial infarction. Increased wall tension in turn is the probable cause of higher NT pro-bnp levels and increased mortality, which were documented in the early hospital phase. This hypothesis is supported by a recent finding that adverse cardiac events after a myocardial infarction are predicted by pre-

28 Coronary Artery Disease/Acute Myocardial Infarction and Natriuretic Peptide 1199 served left ventricular function and baseline BNP level and not by echocardiographic left ventricular volumes Wimalaratna HS. Tombstoning of ST segment in acute myocardial infarction (letter). Lancet 1993;342: Guo XH, Yap YG, Chen LJ, Huang J. Correlation of coronary angiography with tombstoning electrocardiographic pattern in patients after acute myocardial infarction. Clin Cardiol 2000;23: Balci B, Yesildag O. Correlation between clinical findings and the tombstoning electrocardiographic pattern in patients with anterior wall acute myocardial infarction. Am J Cardiol 2003;92: Hunt PJ, Richards AM, Nicholls MG. Immunoreactive aminoterminal pro-brain natriuretic peptide (NT-PROBNP): a new marker of cardiac impairment. Clin Endicrinol 1997;47: Kettunen RV, Leppäluoto J, Jounela A. Plasma N-terminal atrial natriuretic peptide in acute myocardial infarction. Am Heart J 1994; 127: James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, Barnathan ES, Califf R, Topol EJ, Simoons ML, Wallentin L. N-terminal pro brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease. A Global Utilization of Strategies to Open Occluded Arteries (GUSTO)-IV substudy. Circulation 2003;108: Tapanainen JM, Lindgren KS, Mäkikallio TH, Voulteenaho O, Leppäluoto J, Huikuri HV. Natriuretic peptides as predictors of non-sudden and sudden cardiac death after acute myocardial infarction in the beta-blocking era. J Am Coll Cardiol 2004;43: Sabatine MS, Morrow DA, de Lemos JA, Omland T, Desai MY, Tanasijevic M, Hall C, McCabe CH, Braunwald E. Acute changes in circulating natriuretic peptide levels in relation to myocardial ischaemia. J Am Coll Cardiol 2004;44: Foote RS, Pearlman JD, Siegel AH, Yeo KTJ. Detection of exerciseinduced ischaemia by changes in B-type natriuretic peptides. JAm Coll Cardiol 2004;44: Otterstad JE, Sutton MGST, Froeland GS, Holme I, Skjaerpe T, Hall C. Prognostic value of two-dimensional echocardiography and N- terminal proatrial natriuretic peptide following an acute myocardial infarction. Eur Heart J 2002;23:

29 Impact of Bleeding Severity on Clinical Outcomes Among Patients With Acute Coronary Syndromes Sunil V. Rao, MD a, *, Kristi O Grady, MS a, Karen S. Pieper, MS a, Christopher B. Granger, MD a, L. Kristin Newby, MD, MHS a, Frans Van de Werf, MD b, Kenneth W. Mahaffey, MD a, Robert M. Califf, MD a, and Robert A. Harrington, MD a Bleeding is a complication of current therapies for acute coronary syndrome (ACS). No studies have examined the effect of bleeding events on clinical outcomes. We analyzed pooled data from 4 multicenter, randomized clinical trials of patients who had ACS (n 26,452) to determine an association between bleeding severity as measured by the GUSTO scale and 30-day and 6-month mortality rates using Cox proportional hazards modeling that incorporated bleeding as a time-dependent covariate. The analysis was repeated to examine procedure- and non procedure-related bleeding and after censoring at the time of coronary artery bypass grafting. Of all the patients included, 27.6% had >1 bleeding episode. Patients who bled were older and sicker at presentation than were those who did not bleed. Unadjusted rates of 30-day and 6-month mortality increased as bleeding severity increased. There were stepwise increases in the adjusted hazards of 30-day mortality (mild bleeding, hazard ratio [HR] 1.6, 95% confidence interval [CI] 1.3 to 1.9; moderate bleeding, HR 2.7, 95% CI l 2.3 to 3.4; severe bleeding, HR 10.6, 95% CI 8.3 to 13.6) and 6-month mortality (mild bleeding, HR 1.4, 95% CI 1.2 to 1.6; moderate bleeding, HR 2.1, 95% CI 1.8 to 2.4; severe bleeding, HR 7.5, 95% CI 6.1 to 9.3) as bleeding severity increased. Results were consistent after censoring for coronary artery bypass grafting and for procedureand non procedure-related bleeds. In conclusion, the GUSTO bleeding classification identifies patients who are at risk for short- and long-term adverse events. Therapies that minimize bleeding risk and maintain an anticoagulant effect may improve outcomes among patients who have ACS Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Current medical therapies for patients who have acute coronary syndromes (ACSs) focus on the coagulation cascade and on platelet inhibition. These, coupled with early use of cardiac catheterization and revascularization, 1 have decreased morbidity and mortality rates in patients who have acute ischemic heart disease but carry a risk for bleeding. Clinical trials of antithrombotic agents in patients who have non ST-segment elevation ACS have reported bleeding rates of 0.4% to 10%. 2 5 Although a few studies have found an association between bleeding and adverse outcomes, 6,7 an estimation of the true rate of bleeding among patients who have ACS and its association with mortality is hindered by variability in bleeding definitions. To standardize the definition of bleeding, the Global Use of Strategies To Open Occluded Coronary Arteries (GUSTO) investigators devised the GUSTO bleeding severity scale. 8 This definition is The a Duke Clinical Research Institute, Durham, North Carolina; and the b Universitaire Ziekenhuizen Leuven, Leuven, Belgium. Manuscript received February 2, 2005; revised manuscript received and accepted June 24, This analysis was supported by The Duke Clinical Research Institute, Durham, North Carolina. * Corresponding author: Tel: ; fax: address: sunil.rao@duke.edu (S.V. Rao). 1 of the most commonly used in clinical trials, but the true clinical effect of GUSTO bleeding complications has never been examined. In this study, we analyzed data from 4 international, multicenter, randomized trials that included patients who had non ST-segment elevation ACS to determine the association between bleeding severity and death or myocardial infarction (MI). Methods Patient population and treatments: Clinical data from the multicenter international GUSTO IIb, the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT), and the Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network (PARAGON) A and B trials were pooled. The details of the trials have been published elsewhere. 3 5,9,10 Briefly, GUSTO IIb randomized 12,142 patients who had ACS to intravenous heparin or hirudin. For this analysis, we included 8,011 patients from the GUSTO IIb who did not have persistent ST-segment elevation on the initial electrocardiogram. PURSUIT randomized 10,948 patients who had ACS but no persistent ST-segment elevation to eptifi /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

30 Coronary Artery Disease/Bleeding and Outcomes 1201 batide or placebo. PARAGON A and B randomized 2,282 and 5,225 patients who had ACS but no ST-segment elevation, respectively, to intravenous lamifiban or placebo. For the present study, analysis was limited to patients from the 4 trials who had complete data on bleeding occurrence. Concomitant treatment with aspirin (dose range 80 to 325 mg/day) was recommended by protocol in all 4 trials. Patients who were randomized in the PARAGON A trial could receive lamifiban, unfractionated heparin, or lamifiban and unfractionated heparin. The use of antithrombin agents was recommended in the PURSUIT and PARAGON B trials and was mandated by protocol in the GUSTO IIb trial. The use of other medications and procedures was at the discretion of the treating physicians in all 3 trials. Definitions and end points: BLEEDING: The GUSTO IIb and PURSUIT investigators used the GUSTO definition of bleeding, which classifies bleeding as mild, moderate, and severe or life-threatening. Severe or life-threatening bleeding is defined as intracranial hemorrhage or bleeding that causes hemodynamic compromise and requires intervention. Moderate bleeding is defined as bleeding that requires blood transfusion but does not result in hemodynamic compromise; mild bleeding is defined as bleeding that does not meet criteria for severe or moderate bleeding. The PARAGON investigators defined bleeding complications as major or life-threatening and intermediate. Major or life-threatening bleeding was defined as any intracranial hemorrhage or bleeding that led to hemodynamic compromise that required intervention. Intermediate bleeding was defined as bleeding that required transfusion or a decrease in hemoglobin of 5 g/dl (or a decrease 15% in hematocrit when hemoglobin was unavailable). To be consistent across trials, major or lifethreatening bleeding and intermediate bleeding from the PARAGON A and B trials were considered to be GUSTO severe and moderate bleeding, respectively. Data on the date, time, severity, and location (including unidentifiable) of each bleeding event were collected prospectively. For patients who developed 1 bleeding episode, only the most severe bleeding event was considered. END POINTS: The primary end point of the study was 30-day mortality. Secondary end points were an occurrence of the composite of 30-day death or myocardial infarction (MI) and 6-month mortality. MI was defined according to the protocol of each trial. The GUSTO IIb and PARAGON investigators defined MI as an increase in creatine kinase-mb (or total creatine kinase) to above the upper limit of normal or 2 times the previous value if it was increased at enrollment, and/or new significant Q waves in 2 contiguous electrocardiographic leads, in addition to appropriate signs and symptoms. The PURSUIT investigators defined MI as new chest pain and ST-segment elevation within 18 hours of enrollment, new or repeat creatine kinase-mb fraction increase above the upper limit of normal after 18 hours, and/or new Q waves in 2 contiguous electrocardiographic leads. Creatine kinase-mb increases 3 times the upper limit of normal after percutaneous coronary intervention and 5 times the upper limit of normal after coronary artery bypass grafting were also classified as MI. All death and MI events were adjudicated by an independent blinded events committee. Bleeding events were not adjudicated but were determined by the investigator. Statistical analysis: Patients were grouped according to presence or absence of a bleeding event. Patients who developed a bleeding event were further classified by the severity of the bleed based on the GUSTO scale. Baseline characteristics were compared using chi-square tests for categorical variables and nonparametric Kruskal-Wallis test for continuous variables. Baseline differences with p values 0.01 were considered statistically significant. Kaplan- Meier analysis was used to illustrate 30-day event-free survival for patients who had different degrees of bleeding severity. Survival curves were compared using the log-rank statistic. We compared unadjusted rates of the primary and secondary end points among patients who had no bleeding and those who had mild, moderate, and severe bleeding according to the GUSTO scale. Because bleeding events are postrandomization events that can influence and be influenced by in-hospital treatments (medications and procedures) and adverse events (e.g., MI), we performed Cox regression with bleeding as a time-dependent covariate to determine the adjusted hazard of the primary and secondary end points for each bleeding category relative to no bleeding. This technique minimizes confounding by considering only those bleeding events that transpired before the occurrence of the end points. 11 Variables that were entered into the regression were based on a comprehensive set of baseline variables from a validated model of outcome among patients who had non ST-segment elevation ACS 12 (c-index 0.81) and included patient characteristics, presenting signs and symptoms, and treatments, including blood transfusion. Because bleeding that was related to coronary artery bypass grafting might influence the outcome, we repeated the analysis with censoring at the time of coronary artery bypass grafting. Further, the use of procedures, such as cardiac catheterization, percutaneous coronary intervention, and coronary artery bypass grafting, can influence the incidence and severity of bleeding and outcome, so we repeated the analysis again after separating the population into those who underwent procedures during the hospitalization and those who did not. Procedure-related bleeds were defined as any bleeding event that occurred within 24 hours after cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass grafting. All analyses were performed with SAS 8.2 (SAS Institute, Cary, North Carolina). Ethics of protocol: The protocols of all the included trials complied with the Declaration of Helsinki, and institutional review boards of all participating institutions reviewed and approved the protocols. All enrolled patients gave written informed consent.

31 1202 The American Journal of Cardiology ( Table 1 Baseline characteristics of patients with varying degrees of GUSTO bleeding severity Characteristic Degree of Bleeding p Value None (n 19,151) Mild (n 4,393) Moderate (n 2,601) Severe (n 307) for Trend Demographic Median age (yrs) 63.8 (54.0, 71.3) 65.9 (56.5, 73.0) 68.0 (60.9, 74.0) 70.0 (61.4, 74.9) Women Median weight (kg) 77.0 (68.0, 87.0) 78.0 (68.0, 88.0) 74.3 (65.0, 85.0) 76.0 (65.0, 86.0) Medical history Diabetes mellitus Hypertension Hyperlipidemia Chronic renal insufficiency Previous stroke Previous coronary artery bypass grafting Previous congestive heart failure Current smoker Presenting characteristics Median systolic blood pressure (mm Hg) (120.0, 150.0) (120.0, 150.0) (120.0, 150.0) (120.0, 150.0) 0.76 Killip s class I In-hospital treatment Randomized to active treatment (experimental arm) Cardiac catheterization* Percutaneous coronary intervention* Coronary artery bypass grafting* Values are percentages or medians (25th, 75th percentiles). * Within 7 days of randomization. GUSTO Global Use of Strategies To Open Occluded Coronary Arteries. Table 2 Unadjusted rates and adjusted hazard ratios* of the primary and secondary end points by GUSTO bleeding severity Outcome Degree of Bleeding None Mild Moderate Severe Unadjusted rates (%) 30-d end points Death 549/19,110 (2.9%) 155/4,387 (3.5%) 154/2,599 (5.9%) 79/307 (25.7%) MI 1,412/19,110 (7.4%) 501/4,373 (11.5%) 605/2,591 (23.4%) 100/306 (32.7%) Death or MI 1,758/19,110 (9.3%) 572/4,372 (13.1%) 675/2,591 (26.1%) 151/306 (49.4%) 6-mo end point Death 983/18,886 (5.2%) 273/4,358 (6.3%) 253/2,566 (9.9%) 107/305 (35.1%) Adjusted hazard ratios (95% confidence intervals) 30-d end points Death ( ) 2.7 ( ) 10.6 ( ) Death or MI ( ) 3.3 ( ) 5.6 ( ) 6-mo end point Death ( ) 2.1 ( ) 7.5 ( ) * Hazard ratios were adjusted for age, gender, body weight, site of randomization, diabetes mellitus, smoking status, peripheral vascular disease, chest pain duration, Killip s class, MI at enrollment, heart rate, prerandomization medications, systolic blood pressure, and treatment assignment (active vs control). p Reference. Results Baseline characteristics: A total of 26,452 patients from the 4 trials had complete data on bleeding. Of these, 7,301 patients (27.6%) had 1 bleeding event during the index hospitalization. Proportions of patients who had mild, moderate, and severe bleeding were 16.6%, 9.8%, and 1.2%, respectively. Table 1 lists baseline characteristics of patients who had different bleeding severities. Patients who bled were older and had lower body weight than did those who did not bleed. In addition, proportions of women and

32 Coronary Artery Disease/Bleeding and Outcomes 1203 Figure 1. Kaplan-Meier estimates of 30-day survival among patients by GUSTO bleeding category: log-rank p values are for all 4 categories, 0.20 for no bleeding versus mild bleeding, for mild versus moderate bleeding, and for moderate versus severe bleeding. Table 3 Adjusted hazard ratios* for 30-day and 6-month death by procedure-related or non procedure-related GUSTO bleeding severity Outcome Degree of Bleeding None (reference) Mild Moderate Severe Procedure-related bleeds 30-d mortality ( ) 3.7 ( ) 16.5 ( ) 6-mo mortality ( ) 2.6 ( ) 10.5 ( ) Non procedure-related bleeds 30-d mortality ( ) 2.5 ( ) 10.9 ( ) 6-mo mortality ( ) 2.2 ( ) 8.7 ( ) * Hazard ratios were adjusted for age, gender, body weight, site of randomization, diabetes mellitus, smoking status, peripheral vascular disease, chest pain duration, Killip s class, MI at enrollment, heart rate, prerandomization medications, systolic blood pressure, and treatment assignment (active vs control). Abbreviation as in Table 1. patients who had cardiac risk factors increased as bleeding severity increased. In terms of in-hospital treatment, patients who had any bleed received active treatment (hirudin, eptifibatide, or lamifiban) and underwent invasive cardiac procedures more often than did patients who did not bleed. Outcomes: Table 2 presents the incidence of 30-day death, MI, and the composite end points and 6-month mortality by bleeding severity. There was a stepwise increase in the incidence of the end points by bleeding severity. Figure 1 shows the Kaplan-Meier curves of 30-day survival by bleeding severity. Survival decreased significantly as bleeding severity increased. After adjustment for potential confounders, there was a stepwise increase in the hazard for 30-day mortality, 30-day mortality or MI, and 6-month mortality by bleeding severity (Table 2). Addition of blood transfusion to the models did not significantly alter the results. In addition, results were nearly identical after censoring for coronary artery bypass grafting (data not shown). Because procedures influence not only the incidence of bleeding but also outcomes, we repeated the analysis after dividing the study population into those who underwent procedures (cardiac catheterization, percutaneous coronary intervention, or coronary artery bypass grafting) and those who did not. Of the study patients, 14,397 patients underwent 1 in-hospital procedure, and 288 (2.0%) developed a procedure-related bleeding event. The remaining 11,830 patients did not undergo an in-hospital procedure, and 434 (3.7%) developed a bleeding event. Table 3 lists the ad-

33 1204 The American Journal of Cardiology ( justed hazard ratios for 30-day and 6-month mortality for patients who had different degrees of procedure- or non procedure-related bleeding severity. Discussion The results of our study show that bleeding is a relatively common occurrence among patients who have non STsegment elevation ACS and that there is a stepwise increase in short- and long-term mortality with increasing bleeding severity. This association between bleeding and adverse outcomes persisted after adjustment for potential confounders, including blood transfusion, and after censoring for coronary artery bypass grafting. In addition, it was similar between procedure-related and non procedure-related bleeding. Although an association between severe (and perhaps even moderate) bleeding and death would be expected, it is surprising and concerning that mild bleeding was associated with a statistically significant increase in the adjusted hazard for death and death or MI. This suggests that mild bleeding events are not simply nuisance bleeds but are important clinical events that portend serious consequences. Although there have been several reports on the incidence and predictors of bleeding among patients who have ST-segment elevation MI, 13,14 there have been relatively few analyses that have examined bleeding issues among patients who have non ST-segment elevation ACS. Lenderink et al 15 determined the rates of bleeding events in the GUSTO IV- ACS trial. They used the Thrombolysis in Myocardial Infarction classification of bleeding 16 and found that the rates of Thrombolysis In Myocardial Infarction major and minor bleeding were 1.2% and 2.8%, respectively, but other outcomes were not examined. Berkowitz et al 17 evaluated the incidence of bleeding among patients who had non STsegment elevation ACS and were randomized in the Efficacy and Safety of Subcutaneous Enoxaparin in Non Qwave Coronary Events (ESSENCE) study. Major bleeding was defined as bleeding that resulted in death, transfusion of 2 U of blood, a decrease in hemoglobin of 3 g/dl, or hemorrhage in a retroperitoneal, intraocular, or intracranial location. Minor bleeding was defined as any clinically significant bleeding that did not qualify as major. Although the classification of bleeding events included some clinically important events such as death and transfusion, other important clinical outcomes (such as MI) were not specifically examined. Moscucci et al 6 reported on predictors of major bleeding from the Global Registry of Acute Coronary Events (GRACE) study. Major bleeding in this study was defined as life-threatening bleeding that required transfusion of 2 U of packed red cells or that led to an absolute hematocrit decrease of 10% or a subdural hematoma. The overall incidence of major bleeding was 3.9%. Among patients who had unstable angina and non ST-segment elevation MI, they found that advanced age, female gender, renal insufficiency, anticoagulant medications, and procedures were associated with major bleeding, and that major bleeding was associated with an adjusted odds ratio of 1.64 for in-hospital death. Although it is difficult to compare this study with ours directly because of the arbitrary bleeding definition used by Moscucci et al, 6 the rate of bleeding of similar severity was higher in our study. Our findings not only confirm the age, gender, and medical co-morbidity associations found by Moscucci et al 6 but also extend them by the use of a standard bleeding definition and the examination of outcomes that are associated with 3 levels of bleeding severity. As bleeding severity increased, the adjusted hazard for 30-day death and death or MI increased proportionately. It seems intuitive that severe bleeding, which includes intracranial hemorrhage, would be associated with increased mortality. However, it is less clear why mild, and perhaps moderate, bleeding would also be associated with adverse outcomes. The physiologic effects of hemorrhage may be a partial explanation. Experimental models and human studies of bleeding and hemorrhagic shock have found that there are increases in norepinephrine, angiotensin, endothelin-1, and vasopressin levels with various degrees of hemorrhage. 18,19 These neurohormones act to maintain blood pressure and regional blood flow to vital tissues but are also associated with adverse cardiac events. 20 Further, hemorrhagic shock appears to lead to upregulation of cellular adhesion molecules, such as P-selectin and vascular cell adhesion molecule-1, that have been associated with increased mortality in patients who have ACS. 21 At a microvascular level, bleeding may lead to impaired tissue oxygenation. Erythrocyte nitric oxide plays a central role in oxygen delivery. 22 Animal models of hypovolemic hemorrhagic shock have shown that lethal levels of bleeding lead to induction of nitric oxide synthase, which may help to maintain adequate nutritional blood supply to the tissues. 23 However, experimental studies also have indicated that norepinephrine leads to greater increases in cardiac output and blood pressure in animals that have hemorrhagic shock that are treated with nitric oxide synthase inhibitors. 24 This suggests that maintenance of adequate tissue perfusion in the setting of acute hemorrhage is a delicate balance between the neurohormonal axis that is designed to regulate regional blood flow and the nitric oxide system that functions to facilitate oxygen delivery. Although most of these studies were conducted in the setting of severe hemorrhage, mild and moderate bleeding may also lead to an imbalance between these homeostatic systems in certain patients. Although speculative, this imbalance may ultimately lead to an exacerbation of myocardial ischemia and increased mortality. This concept that some patients may be more vulnerable to bleeding and bleeding-related morbidity than others is supported by the finding of an association between certain genetic variants and recurrent MI plus bleeding events among patients who are treated with glycoprotein IIb/IIIa inhibitors. 25 There are some limitations to our analysis. First, 2 of the 4 trials included in the analysis (PURSUIT and GUSTO IIb)

34 Coronary Artery Disease/Bleeding and Outcomes 1205 used the GUSTO classification of bleeding complications, whereas the other 2 trials (PARAGON A and B) used a slightly modified definition. The modified definition differed from the GUSTO definition only in that a decrease in hemoglobin was added to the intermediate category, and there was no category that included mild bleeding. Although this theoretically would have decreased the statistical power to detect an association between mild bleeding and outcomes, we still were able to associate mild bleeding with a statistically significant increase in risk. Second, we did not examine the influence of activated partial thromboplastin times or activated clotting times on the incidence of bleeding and/or outcome. Previous studies have found that there is an optimum therapeutic range of these 2 parameters 26,27 that decreases bleeding and adverse outcomes, but this was not the purpose of our study. We sought to determine the overall incidence of bleeding of varying severity and determine its association with mortality. Third, we cannot make any firm recommendations with regard to treatment of bleeding beyond that which has been suggested by other investigators. 28 For all levels of bleeding, it appears that prevention through judicious dosing of antithrombotic therapy and careful observation may be the best strategy. Newer antithrombotic agents that allow for rapid reversal may provide a therapeutic option in patients who are at risk for bleeding complications. 29 Fourth, we could not explore the mechanisms that underlie the relation between bleeding and adverse outcomes. The level of detail that is required for such an analysis is not present in the clinical trials databases. Fifth, although we repeated the analysis using different methods, there may have been unmeasured confounders that accounted for the association between bleeding and adverse events. Sixth, the patients included in our study were participants in a clinical trial and therefore may not reflect the population of patients who have ACS and are encountered in clinical practice. The latter may include patients who have more co-morbidities and whose bleeding may lead to an even higher risk for death Cannon CP, Weintraub WS, Demopoulos LA, Vicari R, Frey MJ, Lakkis N, Neumann FJ, Robertson DH, DeLucca PT, DiBattiste PM, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344: Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998;338: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996;335: The PURSUIT Trial Investigators. Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes: Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. N Engl J Med 1998;339: The PARAGON B Investigators. Randomized, placebo-controlled trial of titrated intravenous lamifiban for acute coronary syndromes. Circulation 2002;105: Moscucci M, Fox KA, Cannon CP, Klein W, Lopez-Sendon J, Montalescot G, White K, Goldberg RJ. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003;24: Kinnaird TD, Stabile E, Mintz GS, Lee CW, Canos DA, Gevorkian N, Pinnow EE, Kent KM, Pichard AD, Satler LF, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol 2003; 92: The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 1993;329: Ferguson JJ, Kereiakes DJ, Adgey AA, Fox KA, Hillegass WB Jr, Pfisterer M, Vassanelli C. Safe use of platelet GP IIb/IIIa inhibitors. Am Heart J 1998;135:S77 S The PARAGON Investigators. International, randomized, controlled trial of lamifiban (a platelet glycoprotein IIb/IIIa inhibitor), heparin, or both in unstable angina: Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network. Circulation 1998;97: Fisher LD, Lin DY. Time-dependent covariates in the Cox proportionalhazards regression model. Annu Rev Public Health 1999;20: Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee KL, Akkerhuis KM, Harrington RA, Deckers JW, Armstrong PW, et al. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000; 101: Van de Werf F, Barron HV, Armstrong PW, Granger CB, Berioli S, Barbash G, Pehrsson K, Verheugt FW, Meyer J, Betriu A, et al. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-pa. Eur Heart J 2001;22: Berkowitz SD, Granger CB, Pieper KS, Lee KL, Gore JM, Simoons M, Armstrong PW, Topol EJ, Califf RM. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. Circulation 1997;95: Lenderink T, Boersma E, Ruzyllo W, Widimsky P, Ohman EM, Armstrong PW, Wallentin L, Simoons ML. Bleeding events with abciximab in acute coronary syndromes without early revascularization: an analysis of GUSTO IV-ACS. Am Heart J 2004;147: Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P. Thrombolysis In Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 1987;76: Berkowitz SD, Stinnett S, Cohen M, Fromell GJ, Bigonzi F. Prospective comparison of hemorrhagic complications after treatment with enoxaparin versus unfractionated heparin for unstable angina pectoris or non ST-segment elevation acute myocardial infarction. Am J Cardiol 2001;88: Francis RC, Hohne C, Kaczmarczyk G, Boemke W. Effect of angiotensin II and endothelin-1 receptor blockade on the haemodynamic and hormonal changes after acute blood loss and after retransfusion in conscious dogs. Acta Physiol Scand 2004;180: Ponchon P, Elghozi JL. Contribution of humoral systems to the recovery of blood pressure following severe haemorrhage. J Auton Pharmacol 1997;17: Ferrari R, Ceconi C, Curello S, Visioli O. The neuroendocrine and sympathetic nervous system in congestive heart failure. Eur Heart J 1998;19(suppl F):F45 F Mulvihill NT, Foley JB, Murphy RT, Curtin R, Crean PA, Walsh M. Risk stratification in unstable angina and non Q wave myocardial infarction using soluble cell adhesion molecules. Heart 2001;85: McMahon TJ, Moon RE, Luschinger BP, Carraway MS, Stone AE, Stolp BW, Gow AJ, Pawlowski JR, Watke P, Singel DJ, et al. Nitric oxide in the human respiratory cycle. Nat Med 2002;8:

35 1206 The American Journal of Cardiology ( 23. Tabrizchi R. Cardiovascular effects of noradrenaline in hypovolemic haemorrhage: role of inducible nitric oxide synthase. Eur J Pharmacol 1998;361: Mellander S, Bjornberg J, Ekelund U, Alm P. Cardiovascular regulation by endogenous nitric oxide is essential for survival after acute haemorrhage. Acta Physiol Scand 1997;160: Shields DC, Fitzgerald AP, O Neill PA, Muckian C, Kenny D, Moran B, Cannon CP, Byrne CE, Fitzgerald DJ. The contribution of genetic factors to thrombotic and bleeding outcomes in coronary patients randomised to IIb/IIIa antagonists. Pharmacogenomics J 2002;2: Gilchrist IC, Berkowitz SD, Thompson TD, Califf RM, Granger CB. Heparin dosing and outcome in acute coronary syndromes: the GUSTO- IIb experience. Global Use of Strategies to Open Occluded Coronary Arteries. Am Heart J 2002;144: Tolleson TR, O Shea JC, Bittl JA, Hillegass WB, Williams KA, Levine G, Harrington RA, Tcheng JE. Relationship between heparin anticoagulation and clinical outcomes in coronary stent intervention: observations from the ESPRIT trial. J Am Coll Cardiol 2003;41: de Bono DP, More RS. Prevention and management of bleeding complications after thrombolysis. Int J Cardiol 1993;38: Rusconi CP, Roberts JD, Pitoc GA, Nimjee SM, White RR, Quick G, Scardino E, Fay WP, Sullenger BA. Antidote-mediated control of an anticoagulant aptamer in vivo. Nat Biotechnol 2004;22: Lee PY, Alexander KP, Hammill BG, Pasquali SK, Peterson ED. Representation of elderly persons and women in published randomized trials of acute coronary syndromes. JAMA 2001;286:

36 Intensity of Lipid Lowering With Statins and Brachial Artery Vascular Endothelium Reactivity After Acute Coronary Syndromes (from the BRAVER Trial) Jocelyn Dupuis, MD, PhD a, *, Jean-Claude Tardif, MD a, Jean-Lucien Rouleau, MD a, Joseph Ricci, MD b, Malcolm Arnold, MD c, Eva Lonn, MD d, René Roux, MD e, Lawrence M. Title, MD f, Robert Amyot, MD g, Nickie Bonafede, MD h, Anna Woo, MD i, and Christopher P. Cannon, MD j The time course and differential effects of statin regimens on endothelial function after acute coronary syndromes (ACSs) are unknown and could contribute to the superiority of a more intense strategy. A subset of subjects who were enrolled in the PROVE IT-TIMI 22 trial (n 50) underwent evaluation of vascular reactivity by high-resolution brachial ultrasound. Endothelium-dependent flow-mediated dilation (FMD) and endothelium-independent sublingual nitroglycerin-mediated dilation (NMD) were measured at baseline and at 48 hours, 1 month, and 4 months after the initiation of 40 mg of pravastatin (n 26) or 80 mg of atorvastatin (n 24). After 4 months, low-density lipoprotein cholesterol was decreased by 32% in the atorvastatin group but was not different from baseline after ACS in the pravastatin group. C-reactive protein decreased similarly in the 2 groups. Brachial artery diameters at rest were similar in the 2 groups and at each time point of the trial. FMD and NMD increased significantly after 4 months by 27% and 24%, respectively (p <0.05), with no difference between groups. There was no correlation between the change in FMD and the change in lipids or C-reactive protein. In subjects who had received previous statin therapy (n 15), there was no significant variation in FMD (p 0.140) and NMD (p 0.129). In conclusion, initiation of statin therapy soon after ACS is associated with improvements in endothelium-dependent and independent vascular reactivities after 4 months Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) The a Research Center of the Montreal Heart Institute and the Department of Medicine of the University of Montreal, Montreal, Quebec, Canada; the b Scarborough Cardiology Research, Scarborough, Ontario, Canada; the c London Health Sciences Center, London, Ontario, Canada; the d Department of Medicine, McMaster University, Hamilton, Ontario, Canada; the e Bureau des Internistes de Drummondville, Drummondville, Quebec, Canada; the f Queen Elizabeth II Health Sciences Center, Halifax, Nova Scotia, Canada; the g Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada; the h Brampton Research Associates, Brampton, Ontario, Canada; the i Toronto General Hospital, Toronto, Ontario, Canada; and the j TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts. Manuscript received April 1, 2005; revised manuscript received and accepted June 16, * Corresponding author: Tel.: ; fax: address: jocelyn.dupuis@bellnet.ca (J. Dupuis). Compared with placebo, cholesterol lowering with 40 mg of pravastatin that is started soon after acute coronary syndromes (ACSs) improves endothelial function as measured from flow-mediated dilation (FMD) of the brachial artery in as little as 6 weeks. 1 Even if baseline endothelial function is increasingly recognized as a barometer of cardiovascular risk, it remains to be established whether variations in endothelial function after lifestyle modification or pharmacologic intervention can be used to gauge response to therapy or as a surrogate marker of events. 2 Although cholesterol lowering can rapidly improve endothelial function after ACSs, the time course of the improvement with statin therapy is unknown; more specifically, the effect of treatment intensity has not been evaluated. The Brachial Artery Vascular Endothelium Reactivity (BRAVER) study was designed as a substudy of the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial. It represented a distinctive opportunity to evaluate the time course of the BRAVER study after ACSs and compare the effects of intense therapy with 80 mg of atorvastatin with moderate intensity therapy with 40 mg of pravastatin. Methods Patient population and study sites: Patients who were hospitalized with ACSs and randomized into the PROVE IT-TIMI 22 trial were eligible for the substudy. Briefly, patients were included if they had myocardial infarction (with or without ST-segment elevation) or high-risk unstable angina within 10 days. Patients had to be in stable /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

37 1208 The American Journal of Cardiology ( condition and were enrolled after a percutaneous revascularization procedure, if 1 was planned. Total cholesterol level, measured at a local hospital within the first 24 hours after the onset of an ACS or up to 6 months previously, had to be 240 mg/dl (6.21 mmol/l). Patients who were receiving long-term lipid-lowering therapy at the time of their index ACS had to have a total cholesterol level 200 mg/dl (5.18 mmol/l) at the time of screening in the local hospital. In addition to the enrollment criteria listed in the main study protocol, pre- and post-menopausal women who were receiving hormone replacement therapy were also excluded from participation in the substudy because this therapy can interfere with serial evaluations of vascular reactivity. 3 All subjects gave written informed consent before inclusion into the substudy. They were randomized in a double-blind 2 2 factorial design to 80 mg of atorvastatin or 40 mg of pravastatin and to a 10-day course per month of the antibiotic gatifloxacin or placebo for a mean follow-up of 24 months. The trial was conducted in 9 participating Canadian centers. High-resolution ultrasound examination of the brachial artery was performed at baseline (before study drug initiation) and at day 2, day 30, and month 4. Images of the scanned brachial artery segments were evaluated and analyzed in a blinded manner by the core laboratory at the Montreal Heart Institute (Montreal, Quebec, Canada) by 1 of us (J.-C. Tardif). High-resolution brachial ultrasound study and analysis: Noninvasive examinations of brachial artery endothelial reactivity were performed in a quiet, dimly lit room. Subjects were studied in the fasting state and the morning dose of all medications with the exception of aspirin and clopidogrel was withheld. Subjects also had to refrain from tobacco use until after the procedure was performed. Subjects rested in a supine position for 10 minutes before the procedure was performed. A nontortuous segment of the brachial artery above the antecubital fossa was identified. The distance between the tip of the third finger and the transducer was noted to serve as an index of the transducer position for repeated examinations. Baseline imaging was performed by scanning the brachial artery in a longitudinal fashion. Depth and gain settings were optimized, and images were magnified in a viewing window. All images of the brachial artery were recorded on S-VHS tape. A blood pressure cuff was then inflated 30 mm Hg above the systolic pressure for 5 minutes. The cuff was then rapidly released and the artery was continuously imaged for 5 minutes. After an additional 5 minutes of recuperation, a new baseline imaging was performed followed by the administration of 0.4 mg of a sublingual nitroglycerin spray and continuous imaging for an additional 5 minutes. Percent FMD, which was measured 1 minute after cuff deflation, was used as an index of endothelium-dependent dilation, whereas percent nitroglycerin-mediated dilation (NMD), Table 1 Baseline clinical and biochemical characteristics Characteristics Pravastatin 40 mg (n 26) Atorvastatin 80 mg (n 24) Age (yrs) Men 22 (85%) 22 (92%) Gatifloxacin 10 (39%) 14 (58%) Diabetes mellitus 5 (19%) 5 (21%) Hypertension 13 (50%) 12 (50%) Current smoker 9 (35%) 9 (37%) Previous myocardial 6 (23%) 3 (12%) infarction Percutaneous coronary intervention Before index event 2 (8%) 0 For treatment of index event 14 (54%) 15 (62%) Coronary bypass before index 7 (27%) 1 (4%)* event Previous peripheral vascular 3 (11%) 1 (4%) disease Previous statin therapy 9 (35%) 6 (25%) Index event Unstable angina pectoris 5 (19%) 1 (4%) Myocardial infarction 7 (27%) 10 (42%) without ST elevation Myocardial infarction with 14 (54%) 13 (54%) ST elevation Total cholesterol (mg/dl) LDL cholesterol (mg/dl) * HDL cholesterol (mg/dl) Triglycerides (mg/dl) C-Reactive protein (mg/l), medium (interquartile range) 1.64 ( ) 0.80 ( ) Values are means SD, numbers of patients (percentages), or medians (interquartile ranges). *p 0.05 versus pravastatin. HDL high-density lipoprotein; LDL low-density lipoprotein. which was obtained 3 minutes after administration of nitroglycerin, represented endothelium-independent dilation. These procedures were repeated at day 2, day 30, and month 4 of the study. The mean diameter of the 20-mm brachial artery segment was analyzed using proprietary software by 2 independent technicians who were blinded to treatment allocation. Frames from 3 consecutive cardiac cycles were taken at the peak of the R wave and results were averaged. Using these methods and analysis, at the Montreal Heart Institute, the intra- and interobserver variabilities for brachial artery diameter determinations were and mm, respectively, and the variability for percent FMD performed on 2 separate days was %. Participating centers in the substudy previously demonstrated expertise in this technique or possessed expertise in ultrasound vascular imaging. To ensure homogeneity of the procedure, a technical video was provided by the core laboratory with a hands-on demonstration of the technique. A maximum of 2 technicians per center was allowed and the same technician was required to perform the serial exami-

38 Coronary Artery Disease/Statins in Acute Coronary Syndromes 1209 Figure 1. Plasma lipid profile and C-reactive protein levels measured at baseline and after 1 and 4 months of pravastatin therapy (open bars) or atorvastatin therapy (hatched bars). *p 0.05, p 0.01, and p versus baseline. Values are means SEM except for C-reactive protein, for which a box-and-whisker plot is shown with interquartile ranges. HDL high-density lipoprotein; LDL low-density lipoprotein. nations on a given patient. For quality control, each technician had to submit a test run that was performed in duplicate on the same subject on 2 separate days. A 5% relative variability in the measurement of basal brachial diameter was considered acceptable. For the combined test runs (n 12), the mean brachial artery diameters were mm on day 1 (mean SD) and mm on day 2, with an absolute difference of mm between the 2 measurements. For the same test runs at the time of reactive hyperemia, the mean brachial diameters were mm on day 1 and mm on day 2, with an absolute difference of mm between the 2 measurements. Statistical analysis: The Montreal Heart Institute and the TIMI investigators performed statistical analyses jointly. Baseline comparisons of clinical and biochemical parameters between the atorvastatin and pravastatin groups were performed by independent 2-tailed t tests or Wilcoxon s rank-sum tests for continuous variables and by Pearson s chi-square tests for noncontinuous variables. Serial measurements of lipid profile, C-reactive protein, and brachial ultrasound parameters were evaluated by repeated measures analysis of variance with between-group interactions for atorvastatin or pravastatin allocation and gatifloxacin or placebo allocation. When a significant interaction was found between visits or treatment allocations (p 0.05), patient comparisons were performed by paired or unpaired t tests, as appropriate. Because some patients who were randomized into this trial may have previously used statin therapy, the same analysis was performed without these patients to detect possible differences in outcome only in those patients who were newly initiated to statin therapy.

39 1210 The American Journal of Cardiology ( Figure 2. Brachial artery diameter measured by high-resolution ultrasound before FMD and NMD at baseline, 48 hours, 1 month, and 4 months of pravastatin therapy (white bars) or atorvastatin therapy (black bars). Values are means SEM. Correlations between the changes in lipids or C-reactive protein and changes in FMD and NMD were performed by linear regression analysis. Comparisons were considered statistically significant at a p value Results Clinical and biochemical characteristics of patients who were randomized to 40 mg of pravastatin (n 26) and those who were randomized to 80 mg of atorvastatin (n 24) are presented in Table 1. There were more previous coronary artery bypass surgeries in the pravastatin group. Baseline levels of low-density lipoprotein cholesterol were slightly lower in this group at mg/dl compared with mg/dl in the atorvastatin group (p 0.05). Proportions of patients who received gatifloxacin therapy and those who were on previous statin therapy were similar between groups. In the pravastatin group, there was no significant change in lipid profile over the 4 months of the trial except for a mild significant increase in high-density lipoprotein cholesterol after 4 months (p 0.05 vs baseline). In the atorvastatin group, levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides were significantly lower after 1 and 4 months of therapy. After 4 months, total cholesterol, low-density lipoprotein cholesterol, and triglycerides had decreased by 22%, 32%, and 28%, respectively (Figure 1). C-reactive protein decreased similarly in the 2 groups at 1 and 4 months. Baseline brachial artery diameter before the measurement of FMD and NMD was similar between groups and remained the same at all time points during the study (Figure 2). Endothelium-dependent FMD significantly increased after 4 months only and was similar in the 2 groups (Figure 3). FMD increased from 5.6% to 7.3% in the pravastatin group and from 6.4% to 7.9% in the atorvastatin group (p 0.01 for the 2 groups). Interestingly, endothelium-independent NMD also increased over the 4 months in the 2 groups without any significant difference. NMD increased from 10.2% to 12.4% in the pravastatin group (p 0.05) and from 8.6% to 11.0% in the atorvastatin group (p 0.01). When confined to patients who previously were not on statin therapy (n 35), the results of the analysis were similar, with improvements in FMD (p ) and NMD (p 0.009; Figure 3). When confined to patients who previously received statin therapy (n 15), there was no significant variation in FMD (p 0.140) and NMD (p 0.129; Figure 3). For the entire study population, there was no correlation between change in FMD and decreases in total cholesterol (r 0.09), low-density lipoprotein cholesterol (r 0.14), triglycerides (r 0.03), and C-reactive protein (r 0.32). There was also no correlation between change in NMD and lipids or C-reactive protein. There was no significant effect of gatifloxacin therapy on FMD or NMD. Discussion This study evaluated the time course of the improvement in endothelial function with statin therapy after ACSs. It is also the first comparison of the effects of intense and moderate lipid-lowering therapies on vascular reactivity in this patient population. The results confirm not only that endotheliumdependent vascular reactivity is improved by statins after ACSs but also that endothelium-independent vasodilation is ameliorated. The improvement became significant after 4 months and was equivalent for the 2 treatment strategies, with no apparent superiority of the more intense therapy. A good correlation has been demonstrated between endothelial function that is measured in the coronary and peripheral circulations using FMD. 4 The latter, less invasive technique has thus rapidly gained in popularity and is more suitable for serial evaluations. The Reduction of Cholesterol After Ischemia and Function of the Endothelium (RECIFE)

40 Coronary Artery Disease/Statins in Acute Coronary Syndromes 1211 Figure 3. (A to C) Time course of FMD and NMD in the pravastatin and atorvastatin groups. *p 0.05, p 0.01 versus baseline. Values are means SEM. NTG nitroglycerin. trail, which used FMD of the brachial artery, demonstrated that pravastatin therapy (40 mg/day) after ACSs can rapidly improve endothelial function in as little as 6 weeks, whereas placebo-treated subjects showed no improvement. 1 Except for patients who have coronary artery disease or ACSs, cerivastatin therapy has been shown to improve endothelium-dependent FMD after a few days, even after a single dose. 5,6 Other trials in subjects who had hypercholesterolemia demonstrated that atorvastatin and cerivastatin improved FMD after 2 weeks 7 and, using forearm plethysmog-

41 1212 The American Journal of Cardiology ( raphy, that simvastatin improved endothelium-dependent vasodilation to acetylcholine after 4 weeks. 8 In the present trial, serial evaluation time points were thus chosen at baseline, 48 hours, 1 month, and 4 months after randomization. We found a significant improvement in FMD after only 4 months of a magnitude comparable to that found in the RECIFE trial after 6 weeks. This result suggests that the improvement in endothelium-dependent dilation after ACSs occurs after 4 weeks to 4 months of statin therapy. In the coronary circulation, 2 weeks of statin therapy seems to be necessary; in subjects who had stable coronary artery disease, simvastatin did not improve endothelium-dependent dilation after 12 days but did so after 5-1/2 months. 9 However, the point in time when improvement in endothelial function becomes maximal is unknown and could not be resolved in the present trial. We also found improved endothelium-independent vasodilation to nitroglycerin that similarly became apparent after 4 months of therapy. This improvement in NMD was also comparable for the atorvastatin and pravastatin groups. In the RECIFE trial, pravastatin therapy for 6 weeks did not improve NMD. Many previous studies in other patient populations also showed no improvement in NMD with statin therapy alone. However, in another trial, addition of vitamin E to simvastatin was associated with improvements in NMD and FMD in men who had hypercholesterolemia. 10 The finding of improved endothelium-independent vascular reactivity has an important influence on the interpretation of an improvement in FMD. In the presence of improved NMD and FMD, it becomes particularly difficult to determine in what proportions selective modifications of endothelial and vascular smooth muscle biology have occurred. The ratio of FMD to NMD did not change between baseline ( , mean SD) and 4-month evaluations ( ) for the 2 groups combined or individually. However, this ratio is a very crude estimate that cannot be reliably used as an index of the proportion of endothelium-dependent dilation. The previous demonstration of selective improvement in endotheliumdependent FMD after 6 weeks in the RECIFE trial, 1 and the many studies that have demonstrated this selective improvement with statin therapy, suggest that at least part of the increase in FMD of the present study truly reflects improved endothelium biology. This could occur as a result of increased nitric oxide synthase expression 11 or decreased oxidative stress. 12 The mechanisms that led to the improvement in endothelium-independent dilation to sublingual nitroglycerin could also be related to decreased oxidative stress and, although highly speculative, increased smooth muscle sensitivity to nitric oxide. Direct in vitro effects on vascular smooth muscle cells through decreased protein prenylation suggest that statins can directly modify smooth muscle biology. 13 Some recent basic studies have challenged the dogma that NMD is specifically an endotheliumindependent response. Part of the in vitro response to nitroglycerin in isolated human vessels is modulated by endothelial potassium channels. 14 Further, there is in vitro evidence that nitroglycerin can activate the soluble guanylate cyclase pathway and induce vasorelaxation without intermediacy of the free radical nitric oxide. 15 The mechanisms that are responsible for the improved NMD with statins could therefore result from effects on the endothelium and the smooth muscle cells. In the present study, the power to detect a difference in FMD between baseline and 4 months was 82%. Based on the findings at 4 months, the power to detect a difference between the pravastatin and atorvastatin groups was only 11%. Although clearly underpowered to detect a difference between the 2 treatment strategies, our findings still contribute to the growing evidence that improvement in vascular reactivity with statin therapy is independent of the importance of lowering cholesterol. This is supported by the observed increase in FMD in the pravastatin group despite any significant lowering of low-density lipoprotein cholesterol and by the lack of correlation between lipid lowering and the change in FMD or NMD. We similarly found no correlation between cholesterol lowering and improvement in FMD with pravastatin in the RECIFE trial. 1 Atorvastatin therapy can also improve endothelial function in patients who have normocholesterolemia and smoke independent of changes in low-density lipoprotein cholesterol. 16 Whether the magnitude of this cholesterol-independent effect would truly be different between statins will require larger trials. The lack of improvement in FMD and NMD in subjects who previously used statin therapy, although few (n 15), further suggests that new statin initiation is needed for improved vascular reactivity after ACS. Acknowledgment: The investigators thank Marie Gagnon and Francine Poulin for expert technical assistance in analysis of brachial ultrasound examinations. 1. Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes. The RECIFE (Reduction of Cholesterol in Ischemia and Function of the Endothelium) trial. Circulation 1999;99: Cohn JN, Quyyumi AA, Hollenberg NK, Jamerson KA. Surrogate markers for cardiovascular disease: functional markers. Circulation 2004;109:IV31 IV Vita JA, Keaney JF Jr. Hormone replacement therapy and endothelial function: the exception that proves the rule? Arterioscler Thromb Vasc Biol 2001;21: Anderson TJ, Uehata A, Gerhard MD, Meredith IT, Knab S, Delagrange D, Lieberman EH, Ganz P, Creager MA, Yeung AC. Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 1995;26: Hashimoto M, Akita H. Cerivastatin, a hydroxymethylglutaryl coenzyme a reductase inhibitor, improves endothelial function in elderly diabetic patients within 3 days. Circulation 2002;105:E30 E Omori H, Nagashima H, Tsurumi Y, Takagi A, Ishizuka N, Hagiwara N, Kawana M, Kasanuki H. Direct in vivo evidence of a vascular statin: a single dose of cerivastatin rapidly increases vascular endothelial responsiveness in healthy normocholesterolaemic subjects. Br J Clin Pharmacol 2002;54:

42 Coronary Artery Disease/Statins in Acute Coronary Syndromes Sakabe K, Fukuda N, Wakayama K, Nada T, Shinohara H, Tamura Y. Time course differences for statin-induced pleiotropic effects in hypercholesterolemic patients. Int J Cardiol 2004;94: O Driscoll G, Green D, Taylor RR. Simvastatin, an HMG-coenzyme A reductase inhibitor, improves endothelial function within 1 month. Circulation 1997;95: Treasure CB, Klein JL, Weintraub WS, Talley JD, Stillabower ME, Kosinski AS, Zhang J, Boccuzzi SJ, Cedarholm JC, Alexander RW. Beneficial effects of cholesterol-lowering therapy on the coronary endothelium in patients with coronary artery disease. N Engl J Med 1995;332: Neunteufl T, Kostner K, Katzenschlager R, Zehetgruber M, Maurer G, Weidinger F. Additional benefit of vitamin E supplementation to simvastatin therapy on vasoreactivity of the brachial artery of hypercholesterolemic men. J Am Coll Cardiol 1998;32: Laufs U, La Fata V, Plutzky J, Liao K. Upregulation of endothelial nitric oxide synthase by HMG CoA reductase inhibitors. Circulation 1998;97: Davignon J, Jacob RF, Mason RP. The antioxidant effects of statins. Coron Artery Dis 2004;15: Guijarro C, Blanco-Colio LM, Ortego M, Alonso C, Ortiz A, Plaza JJ, Diaz C, Hernandez G, Egido J. 3-Hydroxy-3-methylglutaryl coenzyme A reductase and isoprenylation inhibitors induce apoptosis of vascular smooth muscle cells in culture. Circ Res 1998;83: Gruhn N, Boesgaard S, Eiberg J, Bang L, Thiis J, Schroeder TV, Aldershvile J. Effects of large conductance Ca(2 )-activated K( ) channels on nitroglycerin-mediated vasorelaxation in humans. Eur J Pharmacol 2002;446: Kleschyov AL, Oelze M, Daiber A, Huang Y, Mollnau H, Schulz E, Sydow K, Fichtlscherer B, Mulsch A, Munzel T. Does nitric oxide mediate the vasodilator activity of nitroglycerin? Circ Res 2003;93:E104 E Beckman JA, Liao JK, Hurley S, Garrett LA, Chui D, Mitra D, Creager MA. Atorvastatin restores endothelial function in normocholesterolemic smokers independent of changes in low-density lipoprotein. Circ Res 2004;95:

43 Frequency of Abdominal Aortic Aneurysm in Patients >60 Years of Age With Coronary Artery Disease Juraj Madaric, MD a,b, *, Ivan Vulev, MD a, Jozef Bartunek, MD, PhD b, Augustin Mistrik, MD a, Katia Verhamme, MD, PhD c, Bernard De Bruyne, MD, PhD b, and Igor Riecansky, MD, PhD a Using B-mode ultrasound, we studied the prevalence of abdominal aortic aneurysm (AAA; diameter >3 cm) and its predictive risk factors in 109 consecutive patients who were >60 years of age and had coronary artery disease (CAD). A group of 60 age-matched patients who did not have CAD served as controls. The prevalence of AAA was higher in the CAD group than in the control group (14%, 16 of 109, vs 3%, 2 of 60, p <0.05). By multivariate analysis, only smoking was strongly associated with AAA (odds ratio 4.86, 95% confidence interval 1.55 to 15.25). In contrast, presence of diabetes mellitus was negatively associated with AAA in univariate analysis (odds ratio 0.11, 95% confidence interval 0.01 to 0.83) and a strong trend of inverse association remained in multivariate analysis (odds ratio 0.12, 95% confidence interval 0.01 to 1.03). Thus, systematic screening can detect AAA in 1 of 7 patients who are >60 years of age and have CAD. AAA shares some, but not all, risk factors of atherosclerosis Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) The prevalence of abdominal aortic aneurysm (AAA) increases with age 1 and affects 5% of the population who are 50 years old. 2 It has been demonstrated that ultrasound examination is accurate in identifying and following patients who have AAA 3,4 and is favored as a screening method in subjects who are at high risk. 5,6 Although AAA is almost always associated with aortic atherosclerosis, the etiologic relation between atherosclerosis and aneurysms remains controversial. 2,7,8 Therefore, we studied the prevalence and predictive factors of AAA in patients who had coronary artery disease (CAD). We studied the prevalence of AAA in 109 consecutive patients (90 men) who were 60 years of age (mean 67) and had documented significant CAD. Significant CAD was defined as a narrowing 50% in diameter of the epicardial segment of the coronary artery by quantitative coronary angiography. Ultrasound study of the abdominal aorta was performed in B mode (5500 SONOS, 2.5-MHz transducer, Hewlett- Packard, Andover, Massachusetts) in transverse and longitudinal projections. The suprarenal aortic diameter was taken 1 cm distal to the origin of the superior mesenteric artery, just above the level of the renal arteries. The level of the infrarenal aortic diameter was measured at the site of the maximum aortic artery diameter below the renal arteries. The a Slovak Institute of Cardiovascular Diseases, Bratislava, Slovak Republic; and the b Cardiovascular Center and the c Department of Epidemiology, OLV-Clinic, Aalst, Belgium. Manuscript received March 21, 2005; revised manuscript received and accepted June 23, * Corresponding author: Tel: ; fax: address: jurmad@hotmail.com (J. Madaric). Presence of AAA was diagnosed when the aortic diameter was 3 cm. In addition, we studied the presence of AAA in 60 age-matched patients who did not have angiographic CAD. Severity of CAD and presence of systemic hypertension, hyperlipoproteinemia, smoking, diabetes mellitus (DM), peripheral arterial disease, and carotid atherosclerosis were recorded. All data are presented as mean SD for continuous data and as a ratio for categorical data. Gaussian distributions of data were tested by the Kolmogorov-Smirnov test. A nonpaired t test for continuous data and Pearson s chi-square test for categorical data were used to compare results between patients who had CAD and those who did not. Multivariate logistic regression analysis was used to study multiple risk factors for AAA among patients who had CAD. For all analyses, a p value 0.05 was considered statistically significant. All statistical analyses were performed with SPSS/PC 11.5 (SPSS, Inc., Chicago, Illinois). Table 1 lists baseline characteristics and prevalence of AAA in patients who had CAD and those who did not. There were no differences in baseline demographic and clinical characteristics. Prevalence of AAA was significantly higher in the CAD group than in the control group (14.7%, 16 of 109, vs 3.3%, 2 of 60, p 0.02). Five patients from the CAD group had an AAA 5 cm (4.6%). The average diameter of the suprarenal abdominal aorta was cm, and that of the normal infrarenal abdominal aorta was cm. In all patients who had AAA, aneurysms were of the infrarenal type. In 6 patients, aneurysms were partly thrombosed. No episodes of distal embolization were clinically detected. In 1 patient, an incipient rupture required urgent surgery. Eleven patients who had an /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

44 Coronary Artery Disease/Coronary Artery Disease and Abdominal Aortic Aneurysm 1215 Table 1 Baseline characteristics and prevalence of abdominal aortic aneurysm CAD Group (n 109) Control Group (n 60) p Value Age (yrs) Men 83% (90) 83% (50) 0.90 Prevalence of AAA 14.7% (16) 3.3% (2) 0.02 New cases of AAA 8.3% (9) 3.3% (2) 0.36 AAA 5 cm 4.6% (5) AAA 5 cm were followed further by ultrasonography. Three of 5 patients whose AAA was 5 cm were referred for open surgery; in 2 patients, endovascular stent-graft implantation was performed. Table 2 lists risk factors for AAA in patients who had CAD. In univariate analysis, smoking and the presence of arterial carotid stenosis were associated with an increased risk of AAA. The presence of DM was associated with a decreased risk of AAA. By multivariate analysis, age, gender, smoking, DM, and carotid stenosis were entered into the final model, and smoking emerged as an independent risk factor for AAA. Although not statistically significant, a strong trend of an inverse association of DM with the presence of AAA in the CAD group was maintained. The present study indicates that (1) prevalence of AAA is higher in patients who have CAD than in those who do not, and (2) smoking is associated with an increased risk of AAA. Several previous studies have addressed the relation between CAD and AAA. In patients who had known AAA, significant CAD was found in 33% of patients who were scheduled for surgical correction of the AAA. 9 However, the prevalence of AAA in patients who have known CAD is less clear. Thurmond and Semler 10 reported AAAs 3 cm in 1 of 5 patients who were referred to routine cardiology examinations. Likewise, Bergersen et al 11 found AAAs 3 cm in 13% and 5 cm in 5% of patients who were scheduled for elective coronary artery bypass surgery. Our data corroborate these finding and demonstrate an average prevalence of AAA in 1 of 7 patients who are 60 years of age and have significant CAD as detected by coronary angiography. A diagnosis of unknown AAA was established in 8% of patients who had CAD on angiography. These findings indicate that ultrasound screening of AAA in patients who have diagnosed CAD can increase detection of asymptomatic AAA. Such a selective screening is useful and beneficial, particularly in older men who smoke. This approach appears to be cost effective and compares favorably with the equivalent costs of screening for breast and cervical cancers. 12 In our study, smoking emerged as an independent risk factor for AAA. This is consistent with previous reports that demonstrated that smoking may be more strongly associated with AAA than with CAD 13 and is strongly associated with progression of AAA. 7 In this regard, increased plasma levels of matrix metalloproteinases-1, -2, -3, and -9 have been reported in patients who have AAA The mechanism underlying this association may be related to the effects of smoking on elastase activity and elastin degradation in the vessel wall media. 17 However, matrix metalloproteinase activity and matrix metalloproteinase-1, -2, and -9 content are decreased in vascular tissue of patients who have DM. In addition, DM is associated with modification and glycation of collagen and with resistance to metalloproteinase digestion. 16 These findings are supported by our observation of the negative relation between the incidence of DM and AAA in our patients who had CAD, which is in accord with a few other reports. 2,7 The absence of any significant relation between systemic hypertension and AAA in our study is consistent with the Cardiovascular Health Study 18 or the Oxford Screening Study. 19 Likewise, expansion of AAA does not appear to be related to the presence of hypertension. 7 This contradicts the general clinical belief that hypertension is etiologically linked to AAA and reflects more the clinical practice in which patients who have hypertension are more likely to be examined for aneurysm due to an increased abdomen pulsation secondary to hypertension. Similar to other investigators, we did not find a higher incidence of hyperlipidemia in patients who had AAA or a higher incidence of peripheral artery disease. Together, these findings suggest that the risk factors for AAA may Table 2 Risk factors for abdominal aortic aneurysm in patients with coronary artery disease univariate analysis and adjustment for other covariates CAD with AAA (n 16) CAD without AAA (n 93) OR (95% CI) Adjusted OR* (95% CI) Age (yrs) ( ) Men 13 (81%) 77 (83%) 1.11 ( ) Hypertension 15 (93.8%) 79 (85.0%) 2.66 ( ) Smoking 11 (68.8%) 29 (31.2%) 4.85 ( ) ( ) Hyperlipoproteinaemia 9 (56.3%) 60 (64.5%) 0.71 ( ) DM 1 (6.3%) 36 (38.7%) 0.11 ( ) 0.12 ( ) Carotid stenosis 9 (56.3%) 26 (27.9%) 3.11 ( ) 2.69 ( ) Peripheral artery disease 5 (31.3%) 12 (12.9%) 3.07 ( ) * Age, gender, smoking, DM, and carotid stenosis were entered into the final model. CI confidence interval; OR odds ratio.

45 1216 The American Journal of Cardiology ( differ from those associated with atherosclerosis and that atherosclerosis alone cannot causally explain AAA. 1. Bickerstaff LK, Hollier LH, Van Peenan HJ. Abdominal aortic aneurysms: the changing natural history. J Vasc Surg 1984;1: Lederle FA, Johnson FR, Wilson SE, Chute EP, Littooy FN, Bandyk D, Krupski WC, Barone GW, Acher CW, Ballard DJ. Prevalence and associations of abdominal aortic aneurysm detected through screening. Aneurysm Detection and Management (ADAM) Veterans Affairs Cooperative Study Group. Ann Intern Med 1997;126: Lee TY, Korn P, Heller JA, Kilaru S, Beavers FP, Bush HL, Kent KC. The cost-effectiveness of a quick-screen program for abdominal aortic aneurysms. Surgery 2002;132: The United Kingdom Small Aneurysm Trial Participants. Mortality results for randomised controlled trial of early elective surgery or ultrasonographic surveillance for small abdominal aortic aneurysms. Lancet 1998;352: Kent KC, Zwolak RM, Jaff MR, Hollenbeck ST, Thompson RW, Schermerhorn ML, Sicard GA, Riles TS, Cronenwett JL. Screening for abdominal aortic aneurysm: a consensus statement. J Vasc Surg 2004; 39: The Multicentre Aneurysm Screening Study Group. The Multicentre Aneurysm Screening Study (MASS) into the effect of abdominal aortic aneurysm screening on mortality in men: a randomised controlled trial. Lancet 2002;360: Brady AR, Thompson SG, Fowkes, GR, Greenhalgh RM, Powell JT. Abdominal aortic aneurysm expansion. Risk factors and time intervals for surveillance. Circulation 2004;110: Blanchard JF, Aarmenian HK, Friesen PP. Risk factors for abdominal aortic aneurysm: results of a case-control study. Am J Epidemiol 2000;151: Hertzer NR, Beven EG, Young JR, O Hara PJ, Ruschhaupt WF III, Graor RA, Dewolfe VG, Maljovec LC. Coronary artery disease in peripheral vascular patients: a classification of 1000 coronary angiograms and results of surgical management. Ann Surg 1984;199: Thurmond AS, Semler HJ. Abdominal aortic aneurysm: incidence in a population at risk. J Cardiovasc Surg 1986;27: Bergersen L, Kiernan MS, McFarlane G, Case TH, Ricci MA. Prevalence of abdominal aortic aneurysms in patients undergoing coronary artery bypass. Ann Vasc Surg 1998;12: Wilmink AB, Quick CR, Hubbard CS, Day NE. Effectiveness and cost of screening for abdominal aortic aneurysm: results of a population screening program. J Vasc Surg 2003;38: Reed D, Reed C, Stemmermann G, Hayashi T. Are aortic aneurysms caused by atherosclerosis? Circulation 1992;85: Sangiorgi G, D Averio R, Mauriello A, Bondio M, Pontillo M, Castelvecchio S, Trimarchi S, Tolva V, Nano G, Rampoldi V, et al. Plasma levels of metalloproteinases-3 and -9 as markers of successful abdominal aortic aneursm exlusion after endovascular graft treatment. Circulation 2001;104(suppl I):I-288 I Longo GM, Xiong W, Greiner TC, Zhao Y, Fiotti N, Baxter BT. Matrix metalloproteinases 2 and 9 work in concert to produce aortic aneurysms. J Clin Invest 2002;110: Portik-Dobos V, Anstadt MP, Hutchinson J, Bannan M, Ergul A. Evidence for a matrix metalloproteinase induction/activation system in arterial vasculature and decreased synthesis and activity in diabetes. Diabetes 2002;51: Murphy EA, Danna-Lopes D, Sarfati I, Rao SK, Cohen JR. Nicotinestimulated elastase activity release by neutrophils in patients with abdominal aortic aneurysms. Ann Vasc Surg 1998;12: Alcorn HG, Wolfson SK Jr, Sutton-Tyrrell K, Kuller LH, O Leary D. Risk factors for abdominal aortic aneurysms in older adults enrolled in the Cardiovascular Health Study. Arterioscler Thromb Vasc Biol 1996; 16: Collin J, Walton J, Araujo L, Lindsell D. Oxford screening programme for abdominal aortic aneurysm in men aged 65 to 74 years. Lancet 1988;2:

46 Gender Differences in Carotid Intima-Media Thickness in Patients With Suspected Coronary Artery Disease Anna Kablak-Ziembicka, MD, PhD a, *, Tadeusz Przewlocki, MD, PhD a, Wieslawa Tracz, MD, PhD a, Piotr Pieniazek, MD, PhD a, Piotr Musialek, MD, DPhil a, and Andrzej Sokolowski, MSc, PhD b Selecting patients who have suspected coronary artery disease (CAD) for coronary angiography remains difficult in some subgroups (e.g., women have often atypical symptoms and false-positive findings on noninvasive tests). This study evaluated gender differences and the clinical value of carotid intima-media thickness (IMT) in predicting CAD. We evaluated 558 patients who had symptoms and underwent coronary angiography: 91 women ( years of age) had CAD (>1 lesion with a decrease >50% in luminal diameter of a coronary artery), 29 women ( years of age) did not have CAD, 372 men ( years of age) had CAD, and 66 men ( years of age) did not have CAD. Maximal IMT was assessed bilaterally at the common carotid, bulb, and internal carotid arteries and expressed as mean IMT for each patient. Among patients who did not have CAD, women had lower mean IMT values than men ( vs , p < 0.001). This gender difference was not seen in patients who had CAD ( vs , p 0.92). Among women and men, those with CAD had larger IMT values than those without CAD. Multivariable regression analysis showed that age, CAD, hypertension, smoking, and diabetes had the strongest effect on IMT values in women and men. Receiver-operator characteristic analysis showed that women had a significantly lower IMT threshold for likelihood of CAD (p < 0.001) and that a mean IMT of mm was highly predictive of concomitant CAD (sensitivity 79%, specificity 90%, positive predictive value 96%); for men, the mean IMT threshold was mm (sensitivity 66%, specificity 74%, positive predictive value 93%). In conclusion, carotid IMT assessment may be a valuable tool in selecting patients for coronary angiography to predict the likelihood of CAD. This particularly concerns women in whom sensitivity and specificity of mean IMT are high Elsevier Inc. All rights reserved. (Am J Cardiol ;96: ) Assessment of carotid intima-media thickness (IMT) has a well-recognized value in diagnosing atherosclerosis. 1 3 IMT measurement has been shown to be useful in detection of coronary artery disease (CAD). 4 However, IMT is related to many variables, such as age, atherosclerosis risk factors, and environmental and genetic determinants. 5 7 Previous studies have indicated that men have larger carotid IMT values than women We hypothesized that gender-adjusted IMT might be useful in evaluating the likelihood of CAD (as proved by catheterization). The purpose of this study was to establish the power of carotid IMT in predicting CAD in women and in men. The a Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University; and the b Cracow University of Economics, Krakow, Poland. Manuscript received March 21, 2005; revised manuscript received and accepted June 20, * Corresponding author: Tel: ; fax: address: kablakziembicka@op.pl (A. Kablak-Ziembicka). Methods We evaluated 558 consecutive patients (120 women and 438 men) who had suspected CAD. Coronary angiography (COROSCOP, Siemens, AG, Munich, Germany, using Quantcor QCA 2.0 for quantitative coronary analysis) was performed in all patients because of stated chest pain and/or a positive result on treadmill testing. Patients who had 1 lesion with a decrease of 50% in luminal diameter within the main branches of the coronary arteries were considered to have significant CAD. High-resolution B-mode, color Doppler, and pulse-wave Doppler ultrasound of 2 carotid arteries was performed in a standard fashion with an ALOKA 5500 ultrasound machine (ALOKA 5500 SSD, ALOKA Co, Tokyo, Japan) that was fitted with a 5- to 10-MHz linear array transducer. After locating carotid arteries by transverse scans, the probe was rotated 90 to obtain and record a longitudinal image of the anterior and posterior walls. Maximal IMT (including plaques) was measured at the near and far walls of the /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

47 1218 The American Journal of Cardiology ( Table 1 Clinical characteristics of the respective groups Variable Group IA (n 91) Group IB (n 29) p Value* Group IIA (n 372) Group IIB (n 66) p Value* Age (yrs) Hypertension 68 (74.7%) 23 (79.3%) (60.7%) 34 (51.5%) Cigarette smoking 34 (37.4%) 3 (10.3%) (71.5%) 33 (50.0%) Diabetes mellitus 17 (18.7%) 1 (3.4%) (20.7%) 7 (10.6%) Obesity (body mass index 30 kg/m 2 ) 18 (19.8%) 7 (24.1%) (20.2%) 18 (27.3%) Hyperlipidemia 79 (86.8%) 18 (62.1%) (87.4%) 43 (65.2%) Symptoms in CCS (II IV) 85 (93.4%) 24 (82.8%) (94.9%) 64 (97.0%) Positive treadmill test (%) 73 (84.9%) 22 (75.9%) (77.5%) 36 (54.5%) * Chi-square test. Exercise testing was performed in 73 of 91 women in group IA and 258 of 372 men in group IIA; the other subjects did not perform testing due to contraindications (Leriche s syndrome, artificial joints, or unstable angina). CCS Canadian Cardiovascular Society. Table 2 Mean values of maximal intima-media thickness measured at the selected sites of carotid arteries* with post hoc comparison test (Tukey) IMT (mm) Group IA (n 91) Group IB (n 29) p Value Group IIA (n 372) Group IIB (n 66) p Value c-imt ( ) ( ) ( ) ( ) b-imt ( ) ( ) ( ) ( ) i-imt ( ) ( ) ( ) ( ) m-imt ( ) ( ) ( ) ( ) Values are means SD (95% confidence interval). * Analyis of variance, p Tukey s test. b-imt bifurcation IMT; c-imt common carotid IMT; i-imt internal carotid IMT; m-imt mean IMT. common carotid, bifurcation, and internal carotid arteries and expressed as a mean aggregate value (mean IMT). All scans were obtained by 1 experienced sonographer before angiography. Results were analyzed separately for women (group I) and men (group II). Group IA consisted of 91 women ( years of age, range 42 to 77) who had angiographically confirmed CAD. Group IB consisted of 29 women ( years of age, range 46 to 68) who had no significant lesions on coronary angiography. Group IIA consisted of 372 men ( years of age, range 30 to 84) who had angiographically confirmed CAD. Group IIB consisted of 66 men ( years of age, range 27 to 73) who had no significant lesions on coronary angiography. The distribution of classic major cardiovascular risk factors was assessed between women who had CAD and women who did not and men who had CAD and men who did not with Pearson s chi-square test. Differences in mean IMT values were analyzed with 1-way analysis of variance for the 4 groups and then verified with a post hoc test (Tukey s test for multiple comparisons of means). Receiveroperator characteristic curves for mean IMT were constructed to establish the best IMT cut-off point that determined the highest probabilities of CAD for men and women separately. For these cut-off points, the positive and negative predictive values, sensitivity, and specificity were calculated to determine the discriminating power of mean IMT in the detection of CAD in women and men. Further, the relative risk of CAD and the odds ratio were calculated with Koopman s test. Multivariable stepwise regression analysis was performed to establish which variables (including age, gender, hypertension, type 2 diabetes mellitus, hyperlipidemia, CAD, obesity, and cigarette smoking) had the strongest effect on IMT values in group IA versus IB and group IIA versus IIB, respectively. Statistica 5.5 (Stat Soft, Inc., Tulsa, Oklaham) was used for statistical analyses. Values were considered statistically significant at a p value Results Clinical characteristics of the study groups are presented in Table 1. There were no differences between groups IA and IB (women) with regard to age (p 0.083) and body mass index (p 0.615). However, women who had CAD more often had hypertension (p 0.003), hyperlipidemia (p 0.003), diabetes (p 0.045), and smoked cigarettes (p 0.006). Groups IIA and IIB (men) were homogenous with regard to body mass index (p 0.193) and prevalence of hypertension (p 0.159) but differed significantly with regard to age (p

48 Coronary Artery Disease/Gender-Adjusted IMT in Coronary Disease 1219 Figure 1. IMT values for women (group IB) and men (group IIB) who did not have CAD. b-imt bifurcation IMT; c-imt common carotid IMT; i-imt internal carotid IMT; m-imt mean IMT. Figure 2. IMT values for women (group IA) and men (group IIA) who had angiographically confirmed CAD. Abbreviations as in Figure 1. Table 3 Multiple regression model for mean intima-media thickness (adjusted R ) in women* Variable (n 120) Regression Coefficient SE p Value Intercept Age 0.009/year Obesity Cigarette smoking Diabetes type 2 Hypertension CAD * Model shows strong influence of CAD, diabetes, and age on mean IMT. Table 4 Multiple regression model for mean intima-media thickness (adjusted R ) in men* Variable (n 438) Regression Coefficient SE p Value Intercept Age 0.013/year Hyperlipidemia Cigarette smoking Diabetes type 2 Hypertension CAD * Model shows strong influence of CAD, diabetes, and age on mean IMT.

49 1220 The American Journal of Cardiology ( Discussion Figure 3. Receiver-operator characteristic discriminating curves for women (dashed line) and men (dotted line) ), frequency of hyperlipidemia (p 0.001), cigarette smoking (p 0.001), and type 2 diabetes (p 0.055). Respective IMT values were significantly greater in women and men who had CAD compared with women and men who did not (Table 2). Comparison of IMT values between men and women showed that men who did not have CAD did have significantly higher IMT values than did women who did not have CAD (Figure 1). However, the difference in IMT was not statistically significant between men and women who had CAD (Figure 2). In men and women, multivariable regression analyses that were performed separately for each gender showed that CAD, age, hypertension, smoking, and diabetes had a significant effect on IMT values (Tables 3 and 4). Obesity was found to be an important factor in women (p ) but not in men. The opposite was seen with hyperlipidemia, which was an independent risk factor in men only (p ). Receiver-operator characteristic curves showed that the optimal mean IMT cut-off value for women who had suspected CAD was significantly lower than that in men (p 0.001; Figure 3). The mean IMT value of mm was strongly predictive of concomitant CAD in women (sensitivity 79.1%, specificity 89.7%, positive predictive value 96%, and negative predictive value 58%). For men, the optimal cut-off point was established at mm (sensitivity 66.4%, specificity 74.2%, positive predictive value 93%, and negative predictive value 28%). In women, the relative risk of CAD for a mean IMT of mm was increased 7.65-fold; in men, the risk of CAD for a mean IMT value of mm increased 2.58-fold (Table 5). Our data show that carotid IMT is strongly related to angiographically proved CAD. This may have a role in the selection of some patients for invasive evaluation, particularly women, in whom routine noninvasive tests may be misleading. Previously published large-cohort studies have indicated that carotid IMT is smaller in women than in men This observation is consistent with our findings in patients who had normal coronary arteries (Figure 1). One possible explanation of this phenomenon might be that IMT increases with age more slowly in women than in men. 10,14 Moreover, in subjects who are 65 years of age, gender differences in the increased common carotid IMT can no longer be detected. 15 We found that gender differences in IMT disappeared in patients who had CAD (Figure 2). This phenomenon may be related to an acceleration of the atherosclerotic process in postmenopausal women. 16,17 A recent study found lower IMT values and less plaque formation in carotid arteries in premenopausal women than in postmenopausal women. 16 The IMT value was strictly related to prevalence of risk factors in pre- and postmenopausal women We found previously that IMT increases markedly in subjects who have multiple risk factors. 19 This is consistent with the Framingham Study, which indicated a synergistic effect of multiple risk factors on morbidity and mortality from CAD. 20,21 In men and women, CAD, diabetes, and age had the strongest effect on IMT (Tables 3 and 4). Our data indicate that obesity is an important determinant of IMT in women but not in men, which may be related to differences in fat distribution, whereas hyperlipidemia is independently correlated with IMT only in men. Diagnosis of CAD is currently based on different noninvasive examinations, such as electrocardiography, treadmill testing, stress echocardiography, or perfusion scintigraphy. Some of these have limited sensitivity and the others are expensive This is particularly true for some specific subgroups of patients; true recognition of significant CAD remains challenging in women due to atypical symptoms and often false-positive results from treadmill testing and perfusion scintigraphy. 27 Our present study confirmed the limited value of treadmill testing in women (Table 1). Thus, there is still a need for an inexpensive, easily accessible test that would indicate Table 5 Data obtained from receiver-operating characteristic (ROC) analysis performed for women and for men separately Mean IMT Optimal Cut-off Point for CAD (mm) ROC Area Wilcoxon s estimate (95% CI) p Value Relative Risk of CAD OR Sensitivity (%) Specificity (%) PPV (%) NPV (%) Women ( ) Men ( ) CI confidence interval; NPV negative predictive value; OR odds ratio; PPV positive predictive value.

50 Coronary Artery Disease/Gender-Adjusted IMT in Coronary Disease 1221 the likelihood of CAD with reasonably high sensitivity and specificity. 28,29 We found that IMT shows a strong correlation with probability of CAD. The IMT value cannot be used as a sole indicator of CAD but needs to be considered in the panel of studies that is requested in women who are considered candidates for coronary angiography. Measurement of carotid IMT is inexpensive and relatively easy and has been shown to have low intraand interobserver variabilities. 30 Previous work by us and others has indicated a significant correlation between angiographically documented CAD and IMT or the presence of plaque formation in carotid arteries as assessed with ultrasonography. 2,4,16,27,28 In the present study, we evaluated the diagnostic value of carotid ultrasonography separately for men and women because the prognostic influence of IMT on the likelihood of CAD may differ between genders. We found that the threshold IMT value in women is significantly lower than that in men; moreover, it has higher accuracy in predicting the likelihood of CAD in women (Figure 3). Further, the correlation of IMT with CAD is stronger than that of a positive finding from treadmill testing with CAD in women. The IMT cut-off point, set at 1.07 mm in women and 1.15 mm in men, has a high positive predictive value in women and men. However, this value shows higher specificity and sensitivity in women than in men (Table 5). Further, the relative risk of CAD in women whose mean IMT value is 1.07 mm is more than sevenfold higher compared with women whose mean IMT value is below that threshold. This finding is potentially important because true recognition of CAD in some women remains problematic. Thus, particularly in those who have atypical angina, ambiguous results from traditional noninvasive tests, and low cardiovascular risk, carotid IMT evaluation may have an important role in selecting patients who require invasive assessment Kasliwal RR, Bansal M, Bhargava K, Gupta H, Tandon S, Agrawal V. Carotid intima-media thickness and brachial-ankle pulse wave velocity in patients with and without coronary artery disease. Indian Heart J 2004;56: Adams MR, Nakagomi A, Keech A. Carotid intima-media thickness is only weakly correlated with the extent and severity of coronary artery disease. Circulation 1995;92: Craven TE, Ryu JE, Espeland MA. Evaluation of the association between carotid artery atherosclerosis and coronary artery stenosis. Circulation 1990;82: Kablak-Ziembicka A, Tracz W, Przewlocki T, Pieniazek P, Sokolowski A, Konieczynska M. Association of increased carotid intima-media thickness with the extent of coronary artery disease. Heart 2004;90: Davis PH, Dawson JD, Riley WA, Lauer RM. Carotid intimal-media thickness is related to cardiovascular risk factors measured from childhood through middle age. The Muscatine Study. Circulation 2001; 104: Zannad F, Sass C, Visvikis S. Environmental and genetic determinants of intima-media thickness of the carotid artery. Clin Exp Pharmacol Physiol 2001;28: Salonen R, Salonen JT. Determinants of carotid intima-media thickness: a population based ultrasonography study in Eastern Finnish men. J Intern Med 1991;229: Cuspidi C, Ambrosioni E, Mancia G, Pessina AC, Trimarco B, Zanchetti A. Role of echocardiography and carotid ultrasonography in stratifying risk in patients with essential hypertension: the assessment of Prognostic Risk Observational Survey. J Hypertens 2002;20: Riley WA. Carotid intima-media thickness: risk assessment and scanning protocol. Eur Heart J 2002;23: Heiss G, Sharett AR, Barnes R, Chambles LE, Szklo M, Alzola C, and the ARIC Investigators. Carotid atherosclerosis measured by B-mode ultrasound in populations: association with cardiovascular risk factors in the ARIC study. Am J Epidemiol 1991;134: Held C, Hjemdahl P, Eriksson SV, Bjorkander I, Forslund L, Rehnquist N. Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris. Eur Heart J 2001;22: Wei M, Gonzalez C, Haffner SM, O Leary DH, Stern MP. Ultrasonographically assessed maximum carotid artery wall thickness in Mexico City residents and Mexican Americans living in San Antonio, Texas. Association with diabetes and cardiovascular risk factors. Arterioscler Thromb Vasc Biol 1996;16: Sun Y, Lin CH, Lu CJ, Yip PK, Chen RC. Carotid atherosclerosis, intima media thickness and risk factors an analysis of 1781 asymptomatic subjects in Taiwan. Atherosclerosis 2002;164: Howard G, Burke GL, Evans GW, Crouse JR III, Riley W, Arnett D, de Lacy R, Heiss G. Relationship of intima-media thickness among sites within the carotid artery as evaluated by B-mode ultrasound. Stroke 1994;25: O Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL, Wolfson SK Jr. Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. N Engl J Med 1999;340: Sutton-Tyrrell K, Lassila HC, Meilahn E, Bunker C, Matthews KA, Kuller LH. Carotid atherosclerosis in premenopausal and postmenopausal women and its association with risk factors measured after menopause. Stroke 1998;29: Lassila HC, Sutton-Tyrrell K, Matthews KA, Wolfson SK, Kuller HL. Prevalence and determinants of carotid atherosclerosis in healthy postmenopausal women. Stroke 1997;28: Stensland-Bugge E, Bonaa KH, Joakimsen O, Njolstad I. Sex differences in the relationship of risk factors to subclinical atherosclerosis measured 15 years later. The Tromso Study. Stroke 2000;31: Kablak-Ziembicka A, Przewlocki T, Kostkiewicz M, Pieniazek P, Mura A, Podolec P, Tracz W. Relationship between carotid intimamedia thickness, atherosclerosis risk factors and angiography findings in patients with coronary artery disease. Przegl Lek 2003;60: Kannel WB. Contributions of the Framingham Study to the conquest of coronary artery disease. Am J Cardiol 1988;62: Lawlor DA, Ebrahim S, Whincup P, Sterne J, Papacosta O, Wannamethee G, Dhanjil S, Griffin M, Nicolaides AN, Davey Smith G. Sex differences in body fat distribution and carotid intima-media thickness: cross sectional survey using data from the Br regional heart study. J Epidemiol Community Health 2004;58: de Michele M, Panico S, Ianuzzi A, Celentano E, Ciardullo AV, Galasso R, Sacchetti L, Zarrilli F, Bond MG, Rubba P. Association of obesity and central fat distribution with carotid artery wall thickening in middle-aged women. Stroke 2002;33: Rexrode KM, Carey VJ, Hennekens CH, Walters EE, Colditz GA, Stampfer MJ, Willett WC, Manson JE. Abdominal adiposity and coronary heart disease in women. JAMA 1998;280: Calvert AF, Ayres B, Ilicic V, Dunn B. True sensitivity of cardiac exercise testing. Med J Aust 1984;140: Iliceto S, Galiuto L, Marangelli V, Rizzon P. Clinical use of stress echocardiography: factors affecting diagnostic accuracy. Eur Heart J 1994;15:

51 1222 The American Journal of Cardiology ( 26. Hill J, Timmis A. Exercise tolerance testing. BMJ 2002;324: Nowak J, Nilson T, Sylven C, Jogestrand T. Potential of carotid ultrasonography in the diagnosis of coronary artery disease: a comparison with exercise test and variance ECG. Stroke 1998;29: Crouse JR, Craven TE, Hagaman AP, Bond MG. Association of coronary disease with segment-specific intimal-media thickening of the extracranial carotid artery. Circulation 1995;92: Wofford JL, Kahl FR, Howard GR, McKinney WM, Toole JF, Crouse JR III. Relation of extent of extracranial carotid artery atherosclerosis as measured by B-mode ultrasound to the extent of coronary atherosclerosis. Arterioscler Thromb 1991;11: Tang R, Hennig M, Bond MG, Hollweck R, Mancia G, Zanchetti A; ELSA Investigators. Quality control of B-mode ultrasonic measurement of carotid artery intima-media thickness: the European Lacidipine Study on Atherosclerosis. J Hypertens 2005;23:

52 Gender-Based Differences in Brachial Artery Flow-Mediated Vasodilation as an Indicator of Significant Coronary Artery Disease Ayan R. Patel, MD a, *, Jeffrey T. Kuvin, MD a, Kathleen A. Sliney, RN a, William M. Rand, PhD b, Jessica C. Chiang, MA a, James E. Udelson, MD a, Natesa G. Pandian, MD a, and Richard H. Karas, MD, PhD c Ultrasound of the brachial artery is widely used to assess endothelial function, but whether brachial artery flow-mediated vasodilation (FMD) differs between women and men who have coronary artery disease (CAD) has not been examined. To investigate gender-based differences in brachial artery FMD as an indicator of significant CAD, FMD was measured in women and men outpatients who had CAD (coronary stenosis >50%, n 64) and those who did not have significant CAD (n 145). FMD in women who had CAD (n 33, %) was higher than that in similarly aged men who had CAD (n 31, %; p 0.008). The FMD cutpoint that maximized sensitivity with least effect on specificity for screening CAD was 15% (91% sensitivity, 25% specificity) in women but 10% (90% sensitivity, 43% specificity) in men. If the cutpoint as defined in men were used to evaluate women, brachial artery ultrasound would fail to diagnose 42% of women who do not have significant CAD; thus, a higher FMD cutpoint is required to optimize the sensitivity of FMD for identifying women who have significant CAD compared with similarly aged men. In studies using FMD to evaluate cardiovascular risk, different standards should be applied for women and men Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Most studies of brachial artery flow-mediated vasodilation (FMD) in patients who are at risk for coronary artery disease (CAD) have included predominantly men, 1 3 and normal and abnormal values of FMD in women have not been established. Although brachial artery FMD has been used widely as an end point in clinical research studies, the effect of a subject s gender on this measurement has not been evaluated. There are important gender differences in the development of CAD that suggest that the pathophysiology of CAD in women may differ from that in men. 4 Further, previous studies have reported that estrogen may have acute and long-term effects on vascular endothelial function, thus raising the possibility that FMD in women may differ from that in men Therefore, data with regard to FMD in men may not be applicable to women. This study compared the characteristics of FMD as an indicator of clinically significant CAD in women and men. The a Division of Cardiology, Department of Medicine, the b Department of Biostatistics, and the c Molecular Cardiology Research Institute, Tufts New England Medical Center, Boston, Massachusetts. Manuscript received March 25, 2005; revised manuscript received and accepted June 14, Dr. Patel was supported by the Pfizer/Society for Women s Health. Dr. Karas was supported by the American Heart Association. * Corresponding author: Tel: ; fax: address: apatel@tufts-nemc.org (A.R. Patel). The study was approved by the institutional review board of Tufts New England Medical Center (Boston, Massachusetts). Written informed consent was obtained from all study participants. Two-hundred nine consecutive outpatients (141 women and 68 men) who were referred for cardiovascular evaluation were enrolled in the study. Subjects who underwent sestamibi myocardial perfusion stress testing and had no evidence of ischemia or infarct were classified as being free of significant CAD. Subjects were considered to have CAD if they had angiographic evidence of 50% coronary stenosis or had any degree of fixed or reversible myocardial perfusion defects that was confirmed by angiography. Myocardial perfusion scans were analyzed by readers who were blinded to the results of brachial artery imaging. Brachial artery ultrasound imaging was performed in all patients using a 12-MHz linear array transducer (General Electric, Vingmed System Five, Horten, Norway) as previously described. 1,11 All subjects were instructed to fast for 8 hours before testing and to abstain from smoking on the day of testing. Baseline longitudinal axis images of the brachial artery were obtained at rest. Maximal end-diastolic diameter was measured as the distance between the anterior and posterior intima-blood interface. Measurement of the arterial diameter was made manually with ultrasonic calipers by taking the average of 5 evenly spaced measurements within a 5-cm segment of the vessel. Reactive hyperemia was induced by inflating a sphygmomanometer cuff that was placed above the antecubital fossa to suprasystolic pressure. After 5 minutes of occlusion, the cuff was deflated, and the vessel was imaged continuously for 1 minute after cuff deflation. The presence of reactive hyperemia was /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

53 1224 The American Journal of Cardiology ( Table 1 Baseline characteristics of subjects evaluated for coronary artery disease Variable CAD No Yes Women (n 108) Men* (n 37) Women (n 33) Men (n 31) Age (yrs) Diabetes mellitus 6 (6%) 4 (11%) 14 (42%) 7 (23%) Hypertension 44 (41%) 11 (30%) 23 (70%) 18 (58%) Smoker 8 (7%) 5 (14%) 2 (6%) 4 (13%) Hyperlipidemia 48 (44%) 12 (32%) 26 (79%) 27 (87%) Aspirin use 3 (3%) 4 (11%) 24 (73%) 21 (68%) -Blocker use 10 (9%) 2 (5%) 21 (64%) 24 (77%) Calcium channel 11 (10%) 3 (8%) 12 (36%) 6 (19%) blocker use ACE inhibitor or 17 (16%) 6 (16%) 13 (39%) 17 (55%) angiotensin receptor blocker use Nitrate use 7 (6%) 0 (0%) 8 (24%) 6 (19%) Lipid-lowering drug use 25 (22%) 7 (19%) 25 (76%) 27 (87%) *p NS compared with women who had no CAD for all variables. p NS compared with women who had CAD for all variables. ACE angiotensin-converting enzyme. confirmed by pulse-wave Doppler interrogation of arterial flow. Measurements of the brachial artery diameter during reactive hyperemia were obtained 60 seconds after cuff deflation. FMD was calculated as the percent increase in brachial artery diameter during reactive hyperemia compared with baseline. Measurements were made by observers who were blinded to the clinical data. Reproducibility analysis in our laboratory has demonstrated that the mean values for intra- and interobserver variabilities for percent change in diameter are 1.9% and 2.8%, respectively. Baseline characteristics of women and men were compared using 2-sample t test for continuous variables and chi-square or Fisher s exact test to compare prevalence of baseline cardiac risk factors and medications (Sigmastat 2.03, SPSS, Inc., Chicago, Illinois). Analysis of the sensitivity and specificity of FMD to screen CAD was performed (MedCalc 7.4, MedCalc Software, Mariakerke Belgium). Unless otherwise indicated, data are presented as mean SEM. Findings were considered statistically significant at a p value Baseline characteristics of subjects who were evaluated for CAD are listed in Table 1. Among the postmenopausal women who were evaluated for CAD (n 128), 32 subjects (25%) were on hormone replacement therapy (HRT). Within the group of postmenopausal women who had CAD (n 31), there was no difference in FMD between those who used HRT (n 15, FMD %) and those who did not (n 16, FMD %, p NS). Among the postmenopausal women who were free of perfusion defects on stress testing (n 97), there was also no difference in FMD between those who used HRT (n 17, FMD %) and who who did not (n 80, FMD , p NS). The characteristics of FMD as a tool to identify patients Figure 1. Mean FMD in women who had significant CAD (hatched bar) compared with that in men who had significant CAD (black bar). who have clinically significant CAD were assessed in the population of men and women. Mean FMD was significantly higher in women who had CAD than in similarly aged men who had CAD (Figure 1). Similar to previously reported observations, FMD had a high sensitivity but low specificity for identification of patients who had CAD. 1 Analysis of the sensitivity and specificity of FMD to identify men who had significant CAD demonstrated that a FMD cutpoint of 10% provided the best sensitivity with least effect on specificity (Figure 2), a finding that is consistent with previously published observations. 1,12 In contrast, similar analysis in women of comparable age demonstrated that a FMD cutpoint of 15% was required to achieve the same sensitivity for identification of women who had significant CAD (Figure 3). If the FMD cutpoint of 10% as defined in men was used for women, the sensitivity would decrease to 58%. Thus, if the FMD cutpoint of 10% as Figure 2. Distribution of FMD values in men who had CAD versus those in men who had negative results on stress tests. The FMD cutpoint that optimized the sensitivity (Sens) for identifying patients who had clinically significant CAD with the least effect on specificity (Spec) was 10%.

54 Coronary Artery Disease/Gender Differences in Flow-Mediated Vasodilation 1225 Figure 3. Distribution of FMD values in women who had CAD versus those in women who had negative results on stress tests. The FMD cutpoint that optimized the sensitivity for identifying patients who had clinically significant CAD with the least effect on specificity was 15%. If a FMD cutpoint of 10% were applied to women, then the sensitivity would decrease substantially. Abbreviations as in Figure 2. defined in men were applied to women, 42% of women who had known significant CAD would not be diagnosed. The results of this study indicate that, when appropriate gender-specific cutpoints are applied, FMD has a high sensitivity but a low specificity as an indicator of clinically significant CAD in men and women. This low specificity is likely due to the well-established observation that the presence of atherosclerotic risk factors can cause vascular endothelial dysfunction, even in the absence of established CAD. 13,14 The optimal cutpoint of 10% in men is consistent with previously reported findings in a population of predominantly men. 1 However, although most men who have CAD have a FMD 10%, a substantial number of women who have significant CAD have a FMD 10%. Thus, compared with similarly aged men, a higher FMD cutpoint is required to optimize the sensitivity of FMD for identifying women who are at risk for significant CAD. These findings indicate that FMD requires gender-specific standards for determining normal and abnormal values, just as genderspecific standards have been employed for other testing modalities (e.g., electron-beam computed tomography). 15,16 Given the increasingly widespread use of endothelial function testing as an end point in clinical research studies, these gender-based differences have important implications for studies using flow-mediated vasodilation to evaluate atherosclerotic risk. There are several limitations of this study that warrant comment. Although all subjects who were classified as having significant CAD had angiographically documented disease, not all subjects who presented negative findings on perfusion scans underwent angiography. Because some subjects who presented negative findings on perfusion imaging did not undergo coronary angiography, CAD may have been missed in subjects who had a negative finding on myocardial perfusion scans. However, because the sensitivity of myocardial perfusion testing is 90%, 17 the number of potential false-negative results on stress tests is small and unlikely to have significantly altered the results of the study. Further, this limitation of potentially misclassifying a small number of subjects who had false-negative findings on stress tests would tend to have the effect of decreasing the mean FMD in the non-cad group but would not affect the observation that women who have significant (angiographically proved) CAD have a higher FMD than do comparable men. The use of stress myocardial perfusion testing as a comparator test allows for evaluation of brachial artery testing as a screening tool in a large population with low to intermediate cardiovascular risk, in whom noninvasive testing is indicated. An additional potential limitation of this study design is that vasodilator medications were not withheld before measurement of brachial artery ultrasound testing. However, previously published work has indicated that continuation of vasodilator therapy does not significantly influence FMD. 18 In addition, there were no significant differences between women and men in terms of vasodilator use; thus, the observed differences in FMD are unlikely to have been affected by the continuation of vasodilator therapy. Nitroglycerin-mediated vasodilation was not evaluated in this study; hence, the association between endotheliumindependent vasodilation and CAD cannot be determined. Because there is variability across laboratories in the technical aspects of performing brachial artery ultrasound, the cutpoints discussed in this study may not apply to centers that use differing methodologies. 19 Upper arm cuff occlusion was used in this study because it induces a larger FMD response compared with lower-arm occlusion and may therefore provide a greater degree of separation between subjects who have normal values and those who have abnormal values. 20 Acknowledgment: The investigators thank Louise Postell, RT(N), and the Nuclear Cardiology Laboratory staff for assistance with the conduction of this study. 1. Kuvin JT, Patel AR, Sliney KA, Pandian NG, Rand WM, Udelson JE, Karas RH. Peripheral vascular endothelial function testing as a noninvasive indicator of coronary artery disease. J Am Coll Cardiol 2001;38: Gokce N, Keaney JF, Hunter LM, Watkins MT, Nedeljkovic ZS, Menzoian JO, Vita JA. Predictive value of noninvasively determined endothelial dysfunction for long-term cardiovascular events in patients with peripheral vascular disease. J Am Coll Cardiol 2003;41: Schroeder S, Enderle MD, Ossen R, Meisner C, Baumbach A, Pfohl M, Herdeg C, Oberhoff M, Haering HU, Karsch KR. Noninvasive determination of endothelium-mediated vasodilation as a screening test for coronary artery disease: pilot study to assess the predictive value in comparison with angina pectoris, exercise electrocardiography, and myocardial perfusion imaging. Am Heart J 1999;138:

55 1226 The American Journal of Cardiology ( 4. Mosca L, Appel LJ, Benjamin EJ, Berra K, Chandra-Strobos N, Fabunmi RP, Grady D, Haan CK, Hayes SN, Judelson DR, et al. Evidence-based guidelines for cardiovascular disease prevention in women. Circulation 2004;109: Hashimoto M, Akishita M, Eto M, Ishigawa M, Kozaki K, Toba K, Sagara Y, Taketani Y, Orimo H, Ouchi Y. Modulation of endotheliumdependent flow-mediated vasodilation of the brachial artery by sex and menstrual cycle. Circulation 1995;92: Lieberman EH, Gerhard MD, Uehata, Walsh BW, Selwyn AP, Ganz P, Yeung AC, Creager MA. Estrogen improves endothelium-dependent flow-mediated vasodilation in postmenopausal women. Ann Intern Med 1994;121: Gerhard M, Walsh BW, Tawakol A. Estradiol therapy combined with progesterone and endothelium-dependent vasodilation in postmenopausal women. Circulation 1998;98: Bush DE, Jones CE, Bass KM, Walters GK, Bruza JM, Ouyang P. Estrogen replacement reverses endothelial dysfunction in postmenopausal women. Am J Med 1998;104: Koh KK, Jin DK, Yang SH, Lee SK, Hwang HY, Kang MH, Kim W, Kim DS, Choic IS, Shin EK. Vascular effects of synthetic or natural progestogen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001;103: Koh KK, Cardillo C, Bui MN, Hathaway L, Csabo G, Waclawiw MA, Panza JA, Cannon RO. Vascular effects of estrogen and cholesterollowering therapies in hypercholesterolemic postmenopausal women. Circulation 1999;99: Patel AR, Kuvin JT, Pandian NG, Smith JJ, Udelson JE, Mendelsohn ME, Konstam MA, Karas RH. Heart failure etiology affects peripheral vascular endothelial function after cardiac transplantation. J Am Coll Cardiol 2001;37: Neunteufl T, Heher S, Katzenschlager R, Wolfl G, Kostner K, Maurer G, Weidinger F. Late prognostic value of flow-mediated dilation in the brachial artery of patients with chest pain. Am J Cardiol 2000;86: Vita JA, Treasure CB, Nabel EG. Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease. Circulation 1990;81: Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. JAm Coll Cardiol 1994;24: Hoff JA, Chomka EV, Kraenik AJ, Daviglus M, Rich S, Kondos GT. Age and gender distributions of coronary artery calcium detected by electron bean tomography in 35,246 adults. Am J Cardiol 2001;87: Raggi P, Callister TQ, Cooil B, He ZX, Lippolis NJ, Russo DJ, Zelinger A, Mahmarian JJ. Identification of patients at increased risk of first unheralded acute myocardial infarction by electron-beam computed tomography. Circulation 2000;101: Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, Berman DS, O Gara PT, Carabello BA, Russell RO Jr, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (ACC/AHA/ASNC committee to revise the 1995 guidelines for the clinical use of radionuclide imaging). Available at: fulltext.pdf. Accessed August 18, Gokce N, Holbrook M, Hunter LM, Palmisano J, Vigalox E, Keaney JK, Vita JA. Acute effects of vasoactive drug treatment on brachial artery reactivity. J Am Coll Cardiol 2002;40: Kuvin JT, Patel AR, Karas RH. Need for standardization of noninvasive assessment of vascular endothelial function. Am Heart J 2001; 141: Vogel RA, Corretti MC, Plotnick GD. A comparison of brachial artery flow-mediated vasodilation using upper and lower arm arterial occlusion in subjects with and without coronary risk factors. Clin Cardiol 2000;23:

56 Outcome in Patients Transferred for Percutaneous Coronary Intervention (A National Registry of Myocardial Infarction 2/3/4 Analysis) David M. Shavelle, MD a, *, M. Leila Rasouli, MD a, Paul Frederick, MPH, MBA b, C. Michael Gibson, MS, MD c, and William J. French, MD a, for the National Registry of Myocardial Infarction Investigators Hospital transfer is associated with delays in performance of primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction. Given the limited number of interventional centers in the United States, the transfer of patients is widely practiced. We compared the outcome of patients who were transferred for primary PCI and determined whether prolonged door-to-balloon times were associated with increased mortality. Patients who presented within 12 hours with STsegment elevation myocardial infarction and underwent transfer for primary PCI were identified from the National Registry of Myocardial Infarction database (NRMI databases 2, 3, and 4, n 7,133). The short-term outcome of those who received early (<2 hours) was compared with that of those who received delayed primary PCI (>2 hours) using multivariate logistic regression analyses and propensity score methods. The door-to-balloon time for the early PCI group compared with the delayed PCI group was versus minutes, respectively (p <0.0001). The early PCI group had less recurrent ischemia and angina (5.8% vs 10.1%, p <0.001), less cardiogenic shock (5.1% vs 8.9%, p <0.001), and shorter length of hospital stay ( vs days, p <0.001). In-hospital mortality was lower for the early PCI group than for the delayed PCI group (2.7% vs 6.2%, p <0.001; entire cohort 5.7%). Comparison of patients matched on propensity score (n 993) showed that mortality was lower in the early than in the delayed PCI group (2.6% vs 4.6%, p 0.014, c-statistic 0.67). In conclusion, <4% of patients who received PCI were treated within the recommended guideline of <120 minutes by the American College of Cardiology/American Heart Association. Door-to-balloon times <2 hours in patients who undergo transfer for PCI is associated with a significant decrease in short-term mortality, which suggests that efforts must be made to decrease transfer delays Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Although many hospitals without on-site percutaneous coronary intervention (PCI) capabilities transfer patients who have ST-segment elevation myocardial infarction (MI), robust real-world data for this approach are lacking because large numbers of unselected patients who are treated at community hospitals have not been studied. 1 6 We hypothesized that prolonged door-to-balloon times among patients who had ST-segment elevation MI and were transferred for primary PCI would be associated with increased mortality. The a Division of Cardiology, Harbor-UCLA Medical Center, Torrance, California; the b Ovation Research Group, Seattle, Washington; and the c TIMI Study Group, Boston, Massachusetts. Manuscript received March 11, 2005; revised manuscript received and accepted June 20, The National Registry of Myocardial Infarction is supported by Genentech, South San Francisco, California. * Corresponding author: Tel: ; fax: address: dshavelle@hotmail.com (D.M. Shavelle). Methods Study population: Patients who participated in the National Registry of Myocardial Infarction (NRMI) 2, 3 and 4 databases, had ST-segment elevation MI or left bundle branch block on initial electrocardiogram, presented within 12 hours of symptom onset with no contraindications to fibrinolytic therapy, and who were transferred to receive primary PCI were included (n 7,133; Figure 1). NRMI 2, 3, and 4 databases included information on 1,799,785 patients that was collected from 1,900 hospitals from 1994 to Patients were excluded from this study if they (1) had cardiogenic shock, (2) did not receive primary PCI, and (3) were not transferred to undergo primary PCI. Patients who received primary PCI were classified as those who received primary PCI within or 2 hours (door-to-balloon time 2 hours; early group) and those who received primary PCI after 2 hours (door-to-balloon time 2 hours; delayed group). Baseline demographic and presentation data included age, gender, race, medical history, time from the door to the /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

57 1228 The American Journal of Cardiology ( Figure 1. Flow diagram of study group. initial electrocardiogram (minutes), door-to-balloon time (minutes; from initial hospital), Killip s class, Air Primary Angioplasty in MI high risk, Thrombolysis In Myocardial Infarction high risk, initial heart rate, initial systolic and diastolic blood pressures, medications received within 24 hours (intravenous heparin, low-molecular-weight heparin, angiotensin-converting enzyme inhibitors, antiplatelet therapy, aspirin, blockers, calcium channel blocker, statin, glycoprotein IIb/IIIa inhibitors, and direct thrombin inhibitor), and electrocardiographic location of MI. Study variables: The main predictor variable was early primary PCI, with delay primary PCI as the reference group. Independent variables included demographics, medical history, hospital characteristics, clinical findings at presentation, cardiac medications administered within 24 hours of presentation, and diagnostic and therapeutic interventions. The primary outcome variable was in-hospital mortality rate. Continuous variables were broken down into categories: age ( 65, 65 to 74, and 75 years old), systolic blood pressure ( 90, 90 to 119, and 120 mm Hg), pulse ( 100, 100 beats/min, and missing), and ejection fraction ( 40%, 40%, and missing). Statistical analysis: Univariate and multivariate analyses were performed for those in the early and delayed primary PCI groups to determine whether delays in treatment are associated with higher in-hospital mortality. For continuous variables, comparisons between groups were analyzed for statistical significance by Student s t test. Pearson s chi-square test was used to evaluate differences for discrete variables. Unadjusted odds ratios and 95% confidence intervals were used to measure univariate associations between the predictor variable and in-hospital mortality and are presented with their p values. Because of baseline differences between groups (early vs delayed PCI group), the propensity score was used. 7 The propensity score was determined for each patient and represents the probability that a patient will receive early primary PCI. For matched-pair analysis, differences between matched pairs were evaluated using the signed rank test for continuous data and McNemar s test for binary data. Prospective variables that correlated with delay status and were used for propensity scores included age (as a continuous variable), race, gender, payer type, medical history, prehospital delay, Killip s class, pulse and systolic blood pressures (as continuous variables), anterior/septal MI, chest pain, urbanity, discharge year, acute MI volume, and census region. The adequacy of the model was assessed with the c-statistic, which is equivalent to the area under a receiver-operator characteristic curve. Forward logistic regression modeling was used to determine the association between door-to-balloon time and inhospital mortality rate at successive blocks that represented categories of covariates. Demographics, medical history, hospital characteristics, clinical presentation, medications, diagnostic procedures, procedures received, and propensity score were used in a logistic regression model. Adjusted odds ratios and 95% confidence intervals for each independent variable were determined. All analyses were 2-tailed, with clinical significance defined as a p value SAS 8.2 (SAS Institute, Cary, North Carolina) was used for all statistical analyses. Results From a registry population of 1,799,785 individuals, 7,133 patients met the inclusion criteria and were included in this study (Figure 1). From this group, 1,062 patients (15%) received early primary PCI ( 2 hours) and 6,071 patients (85%) received delayed primary PCI. There were significant baseline differences between these treatment groups (Table 1). Patients who underwent early primary PCI were younger (59 vs 62 years, p 0.001), more likely to be men (76% vs 68%, p 0.001), more likely to be smokers (45% vs 39%, p 0.001), and less likely to have diabetes mellitus (15% vs 20%, p 0.001) and hypertension (38% vs 49%, p 0.001). Patients in the early primary PCI group had fewer previous MIs (13% vs 17%, p 0.003), previous coronary bypass surgeries (2.9% vs 6.5%, p 0.001), and previous coronary angioplasties (9.8% vs 13%, p 0.007). Patients in the early primary PCI group had their first electrocardiogram obtained sooner (7.6 vs 13.3 minutes, p 0.001), had shorter door-toballoon times (98.6 vs 264 minutes, p 0.001), and had less severe congestive heart failure at presentation (Killip s class II/III, 5.8% vs 11.1%, p 0.001). In addition, patients in the early primary PCI group had lower risk features at presentation (Thrombolysis In Myocardial Infarction high risk 58% vs 69%, p 0.001) and were more likely to have an inferior MI (61% vs 52%, p 0.001) compared with patients in the delayed primary PCI group, who were more likely to have an anterior MI (41% vs 36%, p 0.002). Medical therapy within the first 24 hours after admission was more aggressive in the early primary PCI group than in

58 Coronary Artery Disease/Transfer for Primary Percutaneous Coronary Intervention 1229 Table 1 Baseline characteristics of the early and delayed primary percutaneous coronary intervention groups Characteristic Early Primary PCI Group (n 1,062) Delayed Primary PCI Group (n 6,071) p Value Age (yrs) Men 803 (75.6%) 4,145 (68.3%) Women 259 (24.4%) 1,926 (31.7%) Medical history Hypertension 407 (38.3%) 2,978 (49.1%) MI 141 (13.3%) 1,029 (16.9%) Congestive heart failure 15 (1.4%) 205 (3.4%) Coronary bypass 31 (2.9%) 394 (6.5%) Diabetes mellitus 159 (15.0%) 1,246 (20.5%) Smoker 482 (45.4%) 2,360 (38.9%) Hypercholesterolemia 333 (31.4%) 1,984 (32.7%) Previous coronary angioplasty 104 (9.8%) 775 (12.8%) Chronic renal insufficiency 18 (2.5%) 98 (2.6%) Presentation Door to electrocardiogram (min) Door to balloon (min) Killip s class I 982 (94.2%) 5,261 (88.9%) Killip s class II/III 61 (5.8%) 654 (11.1%) PAMI high-risk* 1,059 (99.7%) 6,024 (99.3%) TIMI high risk 617 (58.1%) 4,167 (68.6%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse (beats/min) Medications within 24 h Intravenous heparin 957 (90.1%) 5,461 (90.0%) Low-molecular-weight heparin 49 (6.7%) 399 (10.5%) Angiotensin-converting enzyme inhibitor 305 (28.7%) 1,554 (25.6%) Antiplatelet therapy 682 (64.2%) 3,114 (51.3%) Aspirin 1,001 (94.3%) 5,500 (90.6%) Blocker (intravenous, oral) 708 (66.7%) 3,725 (61.4%) Calcium channel blocker 93 (8.8%) 530 (8.7%) Statin 144 (35.7%) 650 (33.6%) Glycoprotein IIb/IIIa inhibitor 537 (73.7%) 2,557 (67.6%) MI location based on electrocardiogram Anterior/septal 382 (36.0%) 2,495 (41.1%) Inferior/posterior 751 (70.7%) 3,620 (59.6%) Lateral 193 (18.2%) 1,057 (17.4%) Right ventricular 15 (1.4%) 120 (1.9%) Values are means SD or numbers of patients (percentages). * PAMI high risk consists of age 70 years, anterior MI, systolic blood pressure 100 mm Hg, or pulse 100 beats/min. TIMI high risk consists of age 70 years, previous MI, Killip s class 2, 3, or 4, anterior MI, heart rate 100 beats/min, and systolic blood pressure 100 mm Hg. Data from NRMI 4. Data from NRMI 3 and 4. PAMI Primary Angioplasty in MI; TIMI Thrombolysis In Myocardial Infarction. the delayed primary PCI group. Antiplatelet therapy (64% vs 51%, p 0.001), aspirin (94% vs 91%, p 0.001), blockers (67% vs 62%, p 0.001), and glycoprotein IIb/ IIIa inhibitors (74% vs 68%, p 0.001) were used more frequently in those patients who received early primary PCI compared with those who received delayed primary PCI. Procedures, complications, and clinical outcomes of the early and delayed primary PCI groups are presented in Table 2. The prevalence of stroke was similar between groups (0.9% vs 0.8%, p 0.87), but there was a trend toward more bleeding that required intervention in the delayed PCI group (6.7% vs 9.4%, p 0.089) compared with the early primary PCI group. Recurrent ischemia or angina (5.8% vs 10.1%, p 0.001), congestive heart failure (7.7% vs 12.4%, p 0.001), and cardiogenic shock (5.1% vs 8.9%, p 0.001) were present less often in the early than in the delayed primary PCI group. There were no differences between treatment groups in terms of ventricular tachycardia/ ventricular fibrillation (12.4% vs 12.5%, p 0.92) and recurrent MI (1.0% vs 1.5%, p 0.20). Length of hospital stay (4.4 vs 5.4 days, p 0.001) and in-hospital mortality rate (2.7% vs 6.2%, p 0.001) were significantly lower in the early than in the delayed primary PCI group. Propensity score: Clinical outcomes of the 2 patient groups matched on the basis of propensity score are pre-

59 1230 The American Journal of Cardiology ( Table 2 Procedures, complications, and clinical outcomes of early and delayed primary percutaneous coronary intervention groups Early Primary PCI Group (n 1,062) Delayed Primary PCI Group (n 6,071) p Value Initial Reperfusion Strategy PCI with stent* 311 (42.7%) 1,656 (43.8%) PCI without stent 418 (57.3%) 2,126 (56.2%) Other procedures Coronary angiography 233 (21.9%) 1,748 (28.8%) Coronary angioplasty (not primary)* 31 (4.3%) 236 (6.2%) PCI with stent* 28 (90.3%) 188 (79.7%) PCI without stent 3 (9.7%) 48 (20.3%) Coronary bypass (excluding immediate) 50 (4.7%) 276 (4.5%) Intra-aortic balloon pump 104 (9.8%) 900 (14.8%) Echocardiography 398 (37.5%) 2,371 (39.1%) Pacemaker 77 (7.3%) 518 (8.5%) Stress test 31 (2.9%) 226 (3.7%) Nuclear imaging 5 (1.2%) 29 (1.5%) Right heart catheterization 9 (2.2%) 90 (4.7%) Complication Stroke 9 (0.9%) 49 (0.8%) Bleeding (requiring intervention) 27 (6.7%) 181 (9.4%) Major bleeding 42 (4.0%) 375 (6.2%) Recurrent ischemia or angina 62 (5.8%) 613 (10.1%) Recurrent MI 11 (1.0%) 94 (1.5%) Congestive heart failure 82 (7.7%) 751 (12.4%) Shock 54 (5.1%) 542 (8.9%) Ventricular tachycardia/ventricular fibrillation 132 (12.4%) 761 (12.5%) Hypotension requiring intervention 253 (23.8%) 1,425 (23.5%) Death 29 (2.7%) 375 (6.2%) Length of stay * Data from NRMI 3 and 4. Data from NRMI 4 only. sented in Table 3. Stroke, bleeding that required intervention, major bleeding, congestive heart failure, recurrent MI, and ventricular tachycardia/ventricular fibrillation occurred equally in the 2 treatment groups. Significantly fewer patients in the early primary PCI group had recurrent ischemia or angina (6% vs 10.3%, p 0.001), shock (4.9% vs 7.5%, p 0.020), and death (2.6% vs 4.6%, p 0.014) compared with those in the delayed primary PCI group. Door-to-balloon times: For the entire study cohort (n 7,133), the door-to-balloon time was minutes (mean SD), with a range of 30 to 1,425 (Figure 2). Approximately 15% of the entire study cohort had a doorto-balloon time of 120 minutes. The early primary PCI group had a door-to-balloon time of minutes compared with for the delayed primary PCI group. Among the 15% of patients whose door-to-balloon times were 120 minutes, 4% had times 90 minutes and the remaining 11% had times of 90 to 120 minutes. Discussion Although many hospitals without on-site PCI capabilities are currently transferring patients who have ST-elevation MI for primary PCI, real-world or registry data that support such a broad policy are lacking because large numbers of unselected patients who have acute MI and are treated at community hospitals have not yet been systematically characterized. The present study demonstrates that (1) only 15% of patients who are transferred for primary PCI have a door-to-balloon time 2 hours, (2) transferred patients who were lower risk are more likely to undergo primary PCI within 2 hours, and (3) door-to-balloon times 2 hours are associated with improved clinical outcome including lower mortality rate. These observations have significant implications for hospitals that routinely transfer patients who have acute MI for primary PCI and suggest that expanded efforts are needed to decrease transfer delays. The finding that most patients did not receive therapy within the time frame suggested by guidelines of the American College of Cardiology/American Heart Association (door-to-balloon time 120 minutes) indicates that further educational and quality improvement initiatives are needed. 8 Several recent randomized trials have evaluated patients who have acute MI and were transferred to undergo primary PCI The Air Primary Angioplasty in MI (Air PAMI) study found that patients who were transferred for primary PCI had a shorter hospital stay, less ischemia, and a trend toward lower major adverse cardiac events at 1 month compared with patients who received on-site thrombolysis. 9

60 Coronary Artery Disease/Transfer for Primary Percutaneous Coronary Intervention 1231 Table 3 Procedures, complications, and clinical outcomes of the early and delayed primary percutaneous coronary intervention groups using propensity score analysis Early Primary PCI Group (n 993) Delayed Primary PCI Group (n 993) p Value Initial reperfusion strategy PCI with stent* 299 (43.4%) 326 (47.4%) PCI without stent* 390 (56.6%) 380 (55.2%) Other procedures Coronary angiography 82 (11.9%) 124 (18.1%) Coronary angioplasty (not primary)* 30 (4.4%) 48 (5.2%) PCI with stent* 27 (90.0%) 37 (77.1%) PCI without stent* 3 (10.0%) 11 (22.9%) Coronary bypass 47 (4.7%) 43 (4.3%) Intra-aortic balloon pump 92 (9.3%) 117 (11.8%) Echocardiography 372 (37.5%) 366 (36.9%) Pacemaker 72 (7.3%) 83 (8.4%) Stress test 27 (2.7%) 37 (3.7%) Nuclear imaging 4 (1.1%) 6 (1.6%) Right heart catheterization 8 (2.1%) 121 (2.9%) Complication Stroke 8 (0.8%) 7 (0.7%) Bleeding (requiring intervention) 24 (6.4%) 35 (9.4%) Major bleeding 38 (3.8%) 46 (4.7%) Recurrent ischemia or angina 60 (6.0%) 109 (11.0%) Recurrent MI 9 (0.9%) 16 (1.6%) Congestive heart failure 74 (7.4%) 97 (9.8%) Shock 49 (4.9%) 74 (7.5%) Ventricular tachycardia/ventricular fibrillation 119 (12.0%) 116 (11.7%) Hypotension requiring intervention 231 (23.2%) 247 (24.9%) Death 26 (2.6%) 46 (4.6%) Length of Stay (days) * Data from NRMI 3 and 4 (matched early n 689, delayed n 689). Data from NRMI 4 only (matched early n 374, delayed n 374). However, this study included only patients who had highrisk MI features, including advanced age ( 70 years), anterior MI location, and Killip s class II or III. The Danish Multicenter Randomized Trial on Thrombolytic Therapy Versus Acute Coronary Angioplasty in Acute Myocardial Infarction (DANAMI-2) trial was halted prematurely because of a 40% relative decrease in the primary composite Figure 2. Door to balloon times for the entire study group. Approximately 15% of the study group had door to balloon times 120 minutes. end point of death, disabling stroke, or reinfarction for patients who received primary PCI versus thrombolytic therapy. 10 The composite end point was primarily driven by decreased rates of reinfarction. Seventy-three percent of patients who received PCI also required a transfer to dedicated invasive treatment centers and therefore had an average of 1 hour longer to reperfusion compared with those who underwent thrombolysis. In patients who presented 3 hours from symptom onset, the PRimary Angioplasty in patients transferred from General community hospitals to specialized PTCA Units with or without Emergency thrombolysis (PRAGUE-2) trial found a survival advantage for those who were transferred for primary PCI compared with those who received thrombolysis. 11 Further, a recent metaanalysis of 3,750 patients that included data from the AIR- PAMI, DANAMI-2, PRAGUE-2 trials, and 3 other randomized trials found that primary PCI was superior to on-site thrombolysis. 12 Previous studies that used the NRMI database found that the presence of co-morbid conditions, absence of chest pain at presentation, delayed presentation, and hospital presentation during off-hours were associated with longer door-to-balloon times. 3,13 The present study indicates that decreasing door-to-balloon times in the transfer cohort is important and achieving a door-toballoon time 2 hours decreases mortality.

61 1232 The American Journal of Cardiology ( The NRMI database includes information from 1,400 participating hospitals throughout the United States. Inherent to this are issues that are related to the observational nature of the data, the lack of randomization to the early and delayed treatment groups, and significant baseline differences among treated patients. We attempted to account for baseline differences using multivariate logistic regression analysis and propensity score methods. Patients who received early primary PCI were younger, less often had a cardiac history, and were less ill at the time of presentation compared with those who received delayed primary PCI. Despite the use of these statistical tools, the observed survival benefit of the early primary PCI group may be attributable in part to these differences. Most data (98%) that were obtained for the present analysis were submitted by hospitals with interventional capabilities and on-site cardiac surgery. Therefore, this study is not able to address the issue of performance of primary PCI at centers without on-site cardiac surgery. Only in-hospital data are available from the NRMI database and it remains unclear whether patients in the early primary PCI group would maintain a survival advantage during longterm follow-up. 1. Grines C, Patel A, Zijlstra F, Weaver WD, Granger C, Simes RJ. Primary coronary angioplasty compared with intravenous thrombolytic therapy for acute myocardial infarction: six-month follow up and analysis of individual patient data from randomized trials. Am Heart J 2003;145: Grines CL. Should thrombolysis or primary angioplasty be the treatment of choice for acute myocardial infarction? Primary angioplasty the strategy of choice. N Engl J Med 1996;335: Angeja BG, Gibson CM, Chin R, Frederick PD, Every NR, Ross AM, Stone GW, Barron HV. Predictors of door-to-balloon delay in primary angioplasty. Am J Cardiol 2002;89: Margheri M, Meucci F, Falai M, Comeglio M, Giglioli C, Chechi T, Bandini F, Fantini A, Idini R, Gensini GF. Transferring patients for direct coronary angioplasty: a retrospective analysis of 135 unselected patients with acute myocardial infarction. Ital Heart J 2001;2: Brodie BR, Stuckey TD, Hansen CJ, VerSteeg D, Muncy D, Pulsipher M, Gupta N. Effect of treatment delay on outcomes in patients with acute myocardial infarction transferred from community hospitals for primary percutaneous coronary intervention. Am J Cardiol 2002;89: Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol 2003;92: Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127: Ryan TJ, Antman EM, Brooks NH, Califf RM, Hillis LD, Hiratzka LF, Rapaport E, Riegel B, Russell RO, Smith EE III, et al Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). JAm Coll Cardiol 1999;34: Grines CL, Westerhausen DR Jr, Grines LL, Hanlon JT, Logemann TL, Niemela M, Weaver WD, Graham M, Boura J, O Neill WW, Balestrini C. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction: the Air Primary Angioplasty in Myocardial Infarction study. J Am Coll Cardiol 2002;39: Moon JC, Kalra PR, Coats AJ. DANAMI-2: is primary angioplasty superior to thrombolysis in acute MI when the patient has to be transferred to an invasive centre? Int J Cardiol 2002;85: Widimsky P, Budesinsky T, Vorac D, Groch L, Zelizko M, Aschermann M, Branny M, St asek J, Formanek P. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial PRAGUE-2. Eur Heart J 2003;2: Dalby M, Bouzamondo A, Lechat P, Montalescot G. Transfer for primary angioplasty versus immediate thrombolysis in acute myocardial infarction: a meta-analysis. Circulation 2003;108: Nallamothu BK, Bates ER, Herrin J, Wang Y, Bradley EH, Krumholz, for the NRMI Investigators. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation 2005;111:

62 Relation of Terminal QRS Distortion to Left Ventricular Functional Recovery and Remodeling in Acute Myocardial Infarction Treated With Primary Angioplasty Riccardo Bigi, MD a,b, *, Antonio Mafrici, MD a, Paola Colombo, MD a, Dario Gregori, MA, PhD c, Elena Corrada, MD a, Antonia Alberti, MD a, Annamaria De Biase, MD a, Pedro Silva Orrego, MD a, Cesare Fiorentini, MD b, and Silvio Klugmann, MD a The association between admission electrocardiogram and 6-month change in left ventricular function and volume was assessed in 200 patients who had acute myocardial infarction that was treated with primary percutaneous coronary intervention. Logistic regression analysis indicated peak creatine phosphokinase-mb, number of Q-wave leads, QRS interval distortion, wall motion score index, and angiographic Thrombolysis In Myocardial Infarction flow grade as predictors of no functional recovery and QRS interval distortion and Thrombolysis In Myocardial Infarction flow grade as predictors of left ventricular remodeling Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Despite the known association between initial ST-segment alterations and final size of an acute myocardial infarction (AMI), the value of the admission electrocardiogram in predicting the evolution of left ventricular (LV) function remains undefined. We sought to clarify the association between admission electrocardiogram and evolutionary changes of LV function in patients who had extensive AMI that was treated with percutaneous coronary intervention (PCI). The study population consisted of 200 patients who underwent primary PCI because of first ST-segment elevation AMI at Niguarda Hospital (Milan, Italy) and were consecutively selected on the basis of the following criteria: (1) ST-segment elevation 0.2 mv in 4 contiguous leads; (2) achievement of Thrombolysis in Myocardial Infarction trial flow grade 3 within 12 hours of symptom onset; (3) no left bundle branch block or paced rhythm; (4) Thrombolysis In Myocardial Infarction grade flow 3 before PCI; and (5) no major cardiovascular complications and/or further revascularization procedures within 6 months of the index PCI. Infarction was anterior in 130 patients (65%), inferior in 40 (20%), and lateral in 30 (15%); the right ventricle was involved in 14 patients (7%). All patients received unfractionated heparin and aspirin, and 30 (12%) were treated with platelet glycoprotein IIb/IIIa inhibitors before PCI. In case of stenting, which was applied in 190 patients (95%), aspirin plus ticlopidine or clopidogrel was administered The a A. De Gasperis Foundation, Cardiothoracic Department, Niguarda Cà Granda Hospital; and the b Cardiology Unit, Department of Medicine and Surgery, University School of Medicine, Milan; and the c Department of Public Health and Microbiology, University of Turin, Turin, Italy. Manuscript received March 3, 2005; revised manuscript received and accepted June 22, *Corresponding author: Tel: ; fax: address: riccardo.bigi@unimi.it (R. Bigi). for 1 month after hospital discharge. Standard postdischarge therapy included blockers, angiotensin-converting enzyme inhibitors, and aspirin. Statins were used to achieve low-density lipoprotein cholesterol levels 2.6 mmol/l. Angiograms were analyzed by 2 experienced observers; discrepancies were resolved by consensus. Percent luminal diameter stenosis was determined according to the caliper technique. Multivessel disease was defined as the presence of 70% luminal diameter obstruction in 1 major epicardial vessel. Contrast flow through the epicardial vessel was graded according to the standard Thrombolysis In Myocardial Infarction trial flow scale. 1 Echocardiographic measurements were obtained 24 hours after PCI, at hospital discharge, and at 6-month follow-up. LV volumes were echocardiographically assessed using the modified Simpson s rule and used to derive the ejection fraction according to standard calculations. Wall motion was semi-quantitatively evaluated with a 16-segment 4-point scoring modality. 2 A wall motion score index was calculated by adding the numeric value that was assigned to each segment and divided by the number of visualized segments. Admission electrocardiograms were analyzed by the same physician (PC) who was unaware of the study aim. The following electrocardiographic variables were considered: (1) number of leads with 0.2-mm ST-segment elevation; (2) number of pathologic Q waves; (3) maximal ST-segment elevation; and (4) QRS interval distortion, defined as the emergence of the J point at 50% of the R-wave amplitude that was measured from the isoelectric line in case of an initial qr pattern or as absence of S waves in case of an Rs pattern, as previously described. 3 Intraobserver agreement in diagnosing QRS interval distortion was 98%. Functional recovery and remodeling of the left ventricle /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

63 1234 The American Journal of Cardiology ( Table 1 Characteristics of patients with and without functional recovery No recovery (n 91) Recovery (n 103) Combined (n 194) OR (95% CI) Age (yrs) 59 (53, 68) 57 (47, 66) 59 (50, 67) 1.49 ( ) Women 18 (20%) 18 (17%) 36 (19%) 1.16 ( ) Hypertension 42 (46%) 37 (36%) 79 (41%) 1.53 ( ) Diabetes 13 (14%) 15 (15%) 28 (14%) 0.99 ( ) Symptom-to-balloon time (min) 222 ( ) 210 ( ) 220 ( ) 1.07 ( ) Peak creatine phosphokinase ( g/ml) 3,432 (1,718 5,467) 2,297 (1,393 3,485) 2,776 (1,461 4,868) 1.31 ( ) Peak creatine phosphokinase-mb ( g/ml) 250 ( ) 202 ( ) 225 ( ) 1.56 ( ) Killip s class II 67 (74%) 79 (77%) 146 (76%) 0.97 ( ) Killip s class II III 24 (26%) 24 (23%) 48 (24%) 1.11 ( ) Primary ventricular fibrillation 18 (20%) 24 (23%) 42 (22%) 0.88 ( ) Mechanical ventilatory support 11 (12%) 7 (7%) 18 (9%) 1.88 ( ) Intra-aortic balloon pumping 18 (20%) 7 (7%) 18 (9%) 1.08 ( ) Admission electrocardiogram ST-elevation lead number 6 (5 7.75) 5 (4 7) 5.5 (4 7) 1.69 ( ) Maximal ST elevation (mv) 0.8 ( ) 0.7 ( ) 0.7 ( ) 1.23 ( ) Q-wave number 2 (0 3) 1 (0 2) 1 (0 3) 1.69 ( ) QRS interval distortion 58 (64%) 32 (31%) 90 (46%) 3.84 ( ) 24-h echocardiogram End-diastolic volume 111 ( ) 106 (99 113) 108 ( ) 1.44 ( ) End-systolic volume 65 (37 87) 62 (35 84) 63 (36 85) 1.11 ( ) Ejection fraction 45 (38 55) 52 (46 57) 49 (42 57) 1.04 ( ) Wall motion score index 1.87 ( ) 1.75 ( ) 1.81 ( ) 1.75 ( ) Admission coronary angiogram Multivessel disease 5 (5%) 15 (15%) 20 (11%) 0.95 ( ) TIMI flow grade 0 74 (82%) 63 (62%) 137 (71%) 2.56 ( ) Continuous variables are presented as medians (first and third quartiles). Categorical variables are presented as absolute numbers (percentages). Univariate OR (95% CIs): Values refer to the effect of an interquartile difference for continuous variables and to the category with the highest observed frequency for categorical variables. CI confidence interval; OR odds ratio; TIMI Thrombolysis In Myocardial Infarction. Table 2 Multivariate predictors of no functional recovery and left ventricular remodeling Variable OR (95% CI) No functional recovery 0.80 ( )* Q-wave number 1.96 ( ) QRS interval distortion 3.70 ( ) Peak creatine phosphokinase-mb 1.72 ( ) Wall motion score index 3.03 ( ) TIMI flow grade ( ) Remodeling 0.73 ( ) QRS distorsion 2.84 ( ) TIMI flow grade ( ) * Area under the receiver operating characteristic curve of probability function. Abbreviations as in Table 1. were defined as an ejection fraction increase 10% and an end-diastolic LV volume increase 15%, respectively, at follow-up compared with predischarge evaluation. Continuous variables are presented as medians with corresponding interquartile differences. Categorical variables are presented as absolute numbers with corresponding percentages. Univariate odds ratios refer to the effect of an interquartile difference for continuous variables and to the category with the highest observed frequency for categorical variables. The patient effect of clinical, electrocardiographic, echocardiographic, and angiographic variables to predict LV functional recovery and remodeling was assessed by univariate and multivariate analyses using a stepwise logistic regression model. At each step, a significance of 0.1 was required for a variable to be entered into the model. Nonlinearity was formally assessed by Wald s test to compare higher order models with those that included only linear terms. In case of nonlinearity, a restricted cubic spline was used to model a nonlinear effect of the covariate. The selection criterion was the Akaike Information Criterion that was applied backward for each model. Models were cross-validated by bootstrap technique. Multivariate odds ratios are presented with 95% confidence intervals. Accuracy of the probability function as defined by the multivariate predictors in each subject was evaluated by the area under the receiver-operating characteristic curve method. Statistical significance was indicated by p S-plus (release 2000, Insightful Corporation, Seattle, Washington) statistical package and Harrell s Design and Hmisc libraries ( Hmisc) were used for analysis. Follow-up echocardiographic evaluation was not available in 6 patients (3%); thus the analysis refers to 194 patients. Of these, 103 (54%) showed recovery of LV function, whereas 91 (46%) did not. There was no significant

64 Coronary Artery Disease/ECG in AMI Treated With Angioplasty 1235 difference in the use of blockers (78% vs 80%), angiotensin-converting enzyme inhibitors (77% vs 75%), aspirin (87% vs 89%), and statins (49% vs 46%) between groups. Characteristics of the study population according to the occurrence of functional recovery are presented in Table 1. Among electrocardiographic variables, number of leads with ST-segment elevation and/or pathologic Q wave and presence of QRS interval distortion were inversely and significantly associated with failure to improve LV function. After adjusting for clinical, echocardiographic, and angiographic covariates, peak creatine phosphokinase-mb, number of pathologic Q waves, QRS interval distortion, wall motion score index, and angiographic Thrombolysis In Myocardial Infarction flow grade independently predicted the absence of functional recovery (Table 2). The correlation between QRS interval distortion and functional recovery is shown in Figure 1. At predischarge evaluation, functional recovery was similar in patients who had QRS interval distortion and those who did not; conversely, the absence of QRS interval distortion was associated with significantly greater improvement of ejection fraction and wall motion score index at 6-month evaluation. QRS interval distortion and Thrombolysis In Myocardial Infarction flow grade 0 were multivariate predictors of LV remodeling. Patients who had QRS interval distortion showed a significant increase in end-diastolic volume, indicating unfavorable LV remodeling at 6-month evaluation compared with those who did not have QRS interval distortion (Figure 2). Figure 1. Changes in ejection fraction and wall motion score index (WMSI) according to the presence/absence of QRS interval distortion (QRSD) on an admission electrocardiogram. *p Figure 2. Change in LV end-diastolic volume ( LVEDV) according to the presence/absence of QRS interval distortion on an admission electrocardiogram. Other abbreviation as in Figure 1. The results of the present study demonstrate that the admission electrocardiogram retains independent value in predicting LV functional recovery and remodeling in patients who have extensive AMI that is treated with primary PCI. Among electrocardiographic variables, the terminal QRS interval distortion is the most powerful predictor of persistent LV dysfunction. Infarct size, 4 LV filling pattern, 5 heart failure on admission, 6 and blood flow in the culprit vessel 7 have been identified as major predictors of LV dysfunction and unfavorable remodeling after primary PCI. The electrocardiogram has been used to estimate infarct size, 8,9 evaluate the patency of the infarct-related artery after reperfusion therapy, 10,11 and assess prognosis. 12,13 Moreover, it has been correlated with the presence and location of wall motion abnormalities 14,15 and myocardial perfusion. 16 Evolutionary changes in the T wave were found to predict postinfarct ventricular remodeling 17 in the Third Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico (GISSI-3) Echo Substudy that included low-risk patients who had only a 72% incidence of reperfusion therapy. Recently, QRS interval distortion has been suggested as a marker of increased in-hospital mortality 3 and long-term prognosis in patients who have AMI that is treated with thrombolytic therapy 18 or short-term outcome after primary PCI. 19 Our results expand these observations by demonstrating a strong association between QRS interval distortion and persistence of LV dysfunction in patients who undergo primary PCI. This association is independent of established prognostic determinants and may represent the pathophysiologic substrate of the unfavorable prognostic significance of QRS interval distortion that has been reported in previous studies. The presence of QRS interval distortion has been demonstrated to correlate with a larger infarct, 18 likely indicating profound ischemia, in the absence of myocardial

65 1236 The American Journal of Cardiology ( protection at the time of coronary occlusion. This hypothesis is supported by the finding of a greater incidence of no-reflow phenomenon after emergency PCI in patients who have QRS interval distortion compared with those who do not. 19,20 In addition, collateral flow may decrease myocardial ischemia and in turn prevent QRS interval distortion during AMI, as suggested by the major role of pressurederived fractional collateral flow index in the occurrence of QRS interval distortion. Thus, a larger infarct and an inability to achieve a complete reperfusion of the ischemic tissue despite successful recanalization of the culprit vessel can provide a pathophysiologic basis to explain remodeling and persistent dysfunction of the left ventricle. Patients who presented with major complications or underwent further revascularization during the 6-month follow-up were excluded; thus, this study deals with a selective group of patients that is not representative of the general postinfarction population. In addition, because corrected Thrombolysis In Myocardial Infarction frame count and myocardial blush grade were not available in all patients, no causal correlation was possible between QRS interval distortion and status of coronary microcirculation. 1. TIMI Study Group. The Thrombolysis In Myocardial Infarction (TIMI) trial. N Engl J Med 1985;312: Schiller NB, Shah PM, Crawford M. Recommendations for quantification of the left ventricle by two dimensional echocardiography: American Society of Echocardiography Committee on Standard Subcommittee. J Am Soc Echocardiogr 1989;2: Birnbaum Y, Herz I, Scalovsky S. Prognostic significance of the admission electrocardiogram in acute myocardial infarction. J Am Coll Cardiol 1996;27: Jeremy RW, Allman KC, Bautowich G, Harris PJ. Pattens of left ventricular dilatation during six months after myocardial infarction. J Am Coll Cardiol 1989;13: Cerisano G, Bolognese L, Carrabba N, Buonamici P, Santoro GM, Antoniucci D, Santini A, Moschi G, Fazzini PF. Doppler-derived mitral deceleration time: an early strong predictor of left ventricular remodeling after reperfused anterior acute myocardial infarction. Circulation 1999;87: Neskovic AN, Otasevic B, Bojic M, Popovic AD. Association between Killip class on admission and left ventricular dilatation after myocardial infarction: a closer look into an old clinical classification. Am Heart J 1999;137: Jeremy RW, Hackworthy RA, Bautowich G, Hutton BF, Harris PJ. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol 1987;9: Yusuf S, Lopez R, Maddison A, Maw P, Ray N, McMillan S, Sleight P. Value of electrocardiogram in predicting and estimating infarct size in man. Br Heart J 1979;42: Wagner GS, Freye CJ, Palmeri ST, Roark SF, Stack NC, Ideker RE, Harrel FE Jr, Selvester RH. Evaluation of a QRS scoring system for estimating myocardial infarct size. I. Specificity and observer agreement. Circulation 1982;65: Richardson SG, Morton P, Murtagh JG, Scott ME, O Keeffe DB. Relation of coronary arterial patency and left ventricular function to electrocardiographic changes after streptokinase treatment during acute myocardial infarction. Am J Cardiol 1988;61: de Lemos JA, Antman EM, Giugliano RP, McCabe CH, Murphy SA, Van de Werfe F, Gibbson CM, Braunwald E. ST-segment resolution and infarct-related artery patency and flow after thrombolytic therapy. Thrombolysis in Myocardial Infarction (TIMI) 14 Investigators. Am J Cardiol 2000;85: Mauri F, Maggioni AP, Franzosi MG, De Vita C, Santoro E, Santoro L, Giannuzzi P, Tognoni G. A simple electrocardiographic predictor of the outcome of patients with acute myocardial infarction treated with a thrombolytic agent. A Gruppo Italiano per lo Studio della Sopravvivenza nell Infarto Miocardico (GISSI-2)-derived analysis. J Am Coll Cardiol 1994;24: Schroder R, Dissmann R, Bruggemann T, Wegscheider K, Linderer T, Tebbe U, Neuhaus KL. Extent of early ST segment elevation resolution: a simple but strong predictor of outcome in patients with acute myocardial infarction. J Am Coll Cardiol 1994;24: Arkin BM, Hueter DC, Ryan TJ. Predictive value of electrocardiographic patterns in localizing left ventricular asynergy in coronary artery disease. Am Heart J 1979;97: Arvan S, Varat MA. Persistent ST-segment elevation and left ventricular wall abnormalities: a 2-dimensional echocardiographic study. Am J Cardiol 1984;53: Santoro GM, Valenti R, Buonamici P, Bolognese L, Cerisano G, Moschi G, Trapani M, Antoniucci D, Fazzini PF. Relation between ST segment changes and myocardial perfusion evaluated by myocardial contrast echocardiography in patients with acute myocardial infarction treated with direct angioplasty. Am J Cardiol 1998;82: Bosimini E, Giannuzzi P, Temporelli PL. Electrocardiographic evolutionary changes and left ventricular remodeling after acute myocardial infarction. Results of the GISSI-3 Echo Substudy. J Am Coll Cardiol 2000;35: Birnbaum Y, Kloner R, Sclarowsky S, Cannon CP, McCabe CH, Davis VG, Zaret BL, Wackers FJ, Braunwald E. Distortion of the terminal portion of the QRS on the admission electrocardiogram in acute myocardial infarction and the correlation with infarct size and long-term prognosis (Thrombolysis in Myocardial Infarction 4 Trial). Am J Cardiol 1996;78: Cheol Whan L, Myeong-Ki H, Hyun Suk Y, Si-Wan C, Jae-Joong K, Seong-Wook P, Seung-Yung P. Determinants and prognostic implications of terminal QRS complex distortion in patients treated with primary angioplasty for acute myocardial infarction. Am J Cardiol 2001;88: Mager A, Sclarowsky S, Herz I, Zlotikamien B, Strasberg B, Birnbaum Y. QRS complex distortion predicts no reflow after emergency angioplasty in patients with acute myocardial infarction. Coron Artery Dis 1998;9:

66 Impact of Intravascular Ultrasound Lesion Characteristics on Neointimal Hyperplasia Following Sirolimus-Eluting Stent Implantation Hideaki Kaneda, MD, PhD a, Tomomi Koizumi, MD, PhD a, Junya Ako, MD a, Mitsuyasu Terashima, MD a, Yoshihiro Morino, MD a, Yasuhiro Honda, MD a, Paul G. Yock, MD a, Martin B. Leon, MD b, Jeffrey W. Moses, MD b, and Peter J. Fitzgerald, MD, PhD a, *, for the SIRIUS Investigators The effect of lesion characteristics on neointimal hyperplasia after sirolimus-eluting stent implantation was examined in 45 patients who underwent successful preinterventional intravascular ultrasound. There were no differences in neointimal hyperplasia between the moderate/severe calcified lesion group (calcium arc >120 ) and the non/mild calcified lesion group or between the positive vessel remodeling group (external elastic membrane area at the minimal lumen area site larger than that at the proximal reference site) and negative vessel remodeling group. No correlation between preinterventional plaque burden and neointimal hyperplasia was found. In patients who have coronary artery disease, sirolimus-eluting stents continue to demonstrate striking suppression of neointimal proliferation, irrespective of lesion characteristics previously associated with greater restenotic risk Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Several studies have shown that lesion characteristics that are detected by intravascular ultrasound (IVUS), such as calcified plaque, 1,2 vessel remodeling, 3,4 and plaque burden 5 10 affect acute and long-term outcomes after bare metal stent implantation. Recently, sirolimus-eluting stents have shown a significant decrease in angiographic and clinical restenosis compared with bare metal stents. 11,12 However, it has not been fully elucidated whether such lesion characteristics affect the efficacy of this new technology. The a Center for Research in Cardiovascular Interventions, Stanford University, Stanford, California; and b Columbia University, New York, New York. Manuscript received March 28, 2005; revised manuscript received and accepted June 24, * Corresponding author: Tel: ; fax: address: ivus@crci.stanford.edu (P.J. Fitzgerald). This study represents an IVUS substudy of the Sirolimuscoated Bx Velocity Stent in the Treatment of Patients With De Novo Coronary Artery Lesions (SIRIUS) trial, the prospective, randomized, double-blind, placebo-controlled, multicenter clinical trial that compared the safety and feasibility of the sirolimus-coated Bx Velocity stent (Cordis, Miami Lakes, Florida) compared with that of the Bx Velocity uncoated control stent in the prevention of in-stent restenosis. The rationale and design of SIRIUS trial have been presented elsewhere. 12 IVUS was performed before and immediately after stent implantation and at 8 months using a 3.2Fr 30-MHz or 2.9Fr 40-MHz single-element mechanical ultrasound catheter (Boston Scientific, Natick, Massachusetts). Per protocol, intracoronary nitroglycerin was injected before image acquisition, with motorized pull-back devices (0.5 mm/s) being used during most IVUS data acquisitions. All IVUS images were recorded on s-vhs videotape for off-line analysis. An independent core laboratory at Stanford University Medical Center (Stanford, California) reviewed all ultrasound images. Quantitative IVUS analysis was performed using commercially available planimetry software (Tape- Measure, EchoPlaque, Indec Systems, Mountain View, California) according to previously validated and published protocols. 13 Lumen, stent, and external elastic membrane (EEM) areas were manually traced before and immediately after stenting (after the final adjunctive balloon inflation) and at follow-up. On preinterventional images, minimal lumen area cross section and proximal reference cross section were chosen according to previous reports. 14,15 Preinterventional plaque burden was measured as plaque (EEM minus lumen) area divided by EEM area at minimal lumen area cross section. 5 Residual plaque burden was measured as underlying plaque area (outside stent) divided by EEM area after stent implantation. 16 Percent neointimal area was defined as neointimal (stent minus lumen) area divided by stent area at minimal lumen area cross section. Lesions were classified as having no or mild calcification (calcium arc 120 ) or as having moderate or severe calcification (calcium arc 120 ) at the tightest cross section at preintervention. 2 Positive remodeling was defined as a lesion EEM that was larger than the proximal reference EEM. 3 Statistical analyses were performed with StatView 5.0 (SAS Institute, Cary, North Carolina). Continuous variables are presented as mean SD. For comparisons of continuous variables, 2-tailed unpaired Student s t test or analysis of variance was used. A p value 0.05 was considered statistically significant /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

67 1238 The American Journal of Cardiology ( Table 1 Baseline characteristics (moderate/severe calcified vs non/mild calcified lesions) Moderate/Severe Calcified (n 13) Non/Mild Calcified (n 32) p Value Age (yrs) Men 8 (62%) 23 (72%) 0.50 Diabetes mellitus 5 (38%) 8 (25%) 0.47 Hypertension 9 (69%) 22 (69%) 0.99 Hyperlipidemia 6 (46%) 26 (81%) 0.03 Smoking 3 (23%) 8 (25%) 0.99 Maximum balloon pressure (atm) Lesion length (mm) Reference vessel diameter (mm) Preintervention minimal lumen area (mm 2 ) Stent area at minimal lumen area (mm 2 ) Acute lumen gain (mm 2 ) Values are means SD or numbers of patients (percentages). Forty-five patients who underwent successful preinterventional IVUS and sirolimus-coated Bx Velocity stent implantation were enrolled in this IVUS substudy from among patients in the overall SIRIUS population. Of these, 31 were men and 14 were women (61 11 years of age, range 33 to 80). Baseline clinical characteristics were diabetes mellitus (n 13, 29%), hypertension (n 31, 69%), dyslipidemia (n 32, 71%), and current smoking (n 11, 24%). Baseline characteristics were similar between moderate/ severe calcified and non/mild calcified groups (Table 1). Although lesion calcification seemed to affect stent expansion, sirolimus-eluting stents suppressed neointimal hyperplasia (IH) efficiently in moderate/severe calcified and non/ mild calcified lesions (Table 1, Figure 1), resulting in similar target lesion revascularization rates (8% in moderate/severe calcified lesions vs 6% in non/mild calcified lesions). Baseline characteristics were similar between the positive and nonpositive remodeling groups except lesion length (Table 2). Follow-up percent IH area was not significantly different between groups (Figure 1). Target lesion revascularization ratio (8% vs 6%) was not significantly different between positive and nonpositive remodeling groups. Mean preinterventional plaque burden was 79 9%. Mean residual plaque burden was 50 9%. A lack of significant correlation between preinterventional plaque burden (R 0.028) or residual plaque burden (R 0.316) and percent neointimal area was found (Figure 2). Figure 1. (A) Percent neointimal area in moderate/severe calcified lesions (white bar) and non-mild calcified lesions (black bar). Neointimal area was defined as stent minus lumen area, and percent neointimal area as neointimal area divided by stent area. Data are mean SD. (B) Percent neointimal area in positive remodeling lesions (white bar) and nonpositive remodeling lesions (black bar). In this study population, lesion characteristics, such as calcification, preinterventional remodeling, or plaque burden did not appear to affect efficacy after sirolimus-eluting stent implantation. The treatment effect of sirolimus in decreasing restenosis remained constant, irrespective of lesion characteristics. Several IVUS studies have shown that lesion calcification affects acute outcomes after bare metal stent implantation that result in incomplete and/or asymmetrical expansion. 1,2 Although current generation sirolimus-eluting stents have mechanical properties similar to those of bare metal stents and minimum stent area is 1 of the strongest predictors of restenosis, these unfavorable results may also affect long-term outcomes after sirolimus-eluting stent implantation. Other concerns are that various plaque types may differ in drug

68 Coronary Artery Disease/Impact of Lesion Characteristics on SES 1239 Table 2 Baseline characteristics (positive remodeling vs nonpositive remodeling lesions) Positive Remodeling (n 24) Nonpositive Remodeling (n 17) p Value Age (yrs) Men 15 (63%) 12 (71%) 0.74 Diabetes mellitus 7 (29%) 4 (24%) 0.74 Hypertension 18 (75%) 11 (65%) 0.50 Hyperlipidemia 18 (75%) 11 (65%) 0.50 Smoking 6 (24%) 4 (25%) 0.99 Maximum balloon pressure (atm) Lesion length (mm) Reference vessel diameter (mm) Preintervention minimal lumen area (mm 2 ) Stent area at minimal lumen area (mm 2 ) Acute lumen gain (mm 2 ) Values are means SD or numbers of patients (percentages). Figure 2. Correlation between preinterventional plaque burden (A) or residual plaque burden (B) and percent neointimal area. Preinterventional plaque burden was measured as plaque (EEM minus lumen) area divided by EEM area at minimal lumen area cross section. Residual plaque burden was measured as underlying plaque area (outside stent) divided by EEM area after stent implantation. Percent neointimal area was defined as neointimal (stent minus lumen) area divided by stent area. absorption rate and that lesion calcification may affect homogenous drug diffusion/concentration and contribute to potential stent asymmetry. However, despite less optimal acute results in calcified lesions, this study demonstrated that sirolimus-eluting stents suppress IH effectively and that lesion calcification does not significantly affect the efficacy of sirolimus-eluting stents in the prevention of restenosis. Several IVUS studies have shown that preinterventional vessel remodeling (EEM areas at lesion site vs those at reference site) is related to long-term outcomes after bare metal stent implantation. Most studies have shown that positive remodeling lesions have poor outcomes (more frequent target lesion/vessel revascularization or more IH at follow-up), 3,17 whereas 1 study has reported a contrary result. 4 Moreover, positive remodeling lesions have shown larger follow-up IH volume after paclitaxel-coated stent implantation. 18 Although the exact mechanisms remain unclear, the investigators suggested that positive remodeling lesions are related to unstable patients who have poor clinical outcomes, further suggesting that unstable plaques seem to be associated with higher biologic activity and proliferative potential. In this substudy, sirolimus-eluting stents were found to suppress IH effectively, irrespective of vessel remodeling. Similar to vessel remodeling, most IVUS studies have shown that plaque burden affects long-term outcomes after bare metal stent implantation, 5 10 whereas some studies have shown controversial results. 16,19,20 In general, greater plaque burden at preintervention, postintervention, or follow-up is associated with larger IH or poor angiographic outcome at

69 1240 The American Journal of Cardiology ( follow-up. Atherosclerotic plaque serves as a source for cells and growth factors involved in the restenotic process, and greater plaque burden is also related to unstable patients/ plaques. Nonetheless, sirolimus-eluting stents suppressed IH effectively, irrespective of residual plaque burden in this cohort. First, this study is based on a relatively small sample, raising the possibility of selection bias. Preinterventional IVUS was not mandated in the SIRIUS protocol. Second, follow-up was limited to 8 months and therefore may not predict subsequent findings or relations identified in this dataset. Third, present IVUS capabilities to determine plaque type are limited, although IVUS is the most sensitive in vivo method for the detection of coronary calcium. In addition, severely calcified lesions were excluded in the SIRIUS trial. Because currently used or developed drug-eluting stents have significantly different properties in terms of drug and delivery platform (stent design and polymer), further studies are needed to examine whether lesion characteristics affect neointimal tissue growth after a different kind of drug-eluting stent implantation. Acknowledgment: The investigators thank Heidi N. Bonneau, RN, MS, for expert review of this report. Appendix Investigators and Institutions in the SIRIUS IVUS Substudy: Donald Baim, Brigham and Women s Hospital; Ted Bass, University of Florida Health Science Center; Charles Brown, Fuqua Heart Center, Piedmont Hospital; Michael Cleman, Yale Univerisity School of Medicine; Tim Fischell, Borgess Medical Center; David R. Holmes, St. Mary s Hospital; Jeffrey W. Moses, Lenox Hill Hospital; Igor Palacios, Massachusetts General Hospital; Emerson Perin, Texas Heart Institute; Mark Reisman, Swedish Heart Hospital; David Roberts, Sutter Memorial General Hospital; Lowell Satler, Washington Hospital Center; Charles Simonton, Sanger Clinic; Rob Wilensky, Hospital of the University of Pennsylvania; David O. Williams, Rhode Island Hospital; Shing Chiu Wong, New York Presbyterian Hospital Cornell; Alan Yeung, Stanford Medical Center. 1. Albrecht D, Kaspers S, Fussl R, Hopp HW, Sechtem U. Coronary plaque morphology affects stent deployment: assessment by intracoronary ultrasound. Catheter Cardiovasc Diagn 1996;38: von Birgelen C, Mintz GS, Bose D, Baumgart D, Haude M, Wieneke H, Neumann T, Brinkhoff J, Jasper M, Erbel R. Impact of moderate lesion calcium on mechanisms of coronary stenting as assessed with three-dimensional intravascular ultrasound in vivo. Am J Cardiol 2003;92: Endo A, Hirayama H, Yoshida O, Arakawa T, Akima T, Yamada T, Nanasato M. Arterial remodeling influences the development of intimal hyperplasia after stent implantation. J Am Coll Cardiol 2001;37: Hong MK, Park SW, Lee CW, Kim JJ, Park SJ. Preintervention arterial remodeling as a predictor of intimal hyperplasia after intracoronary stenting: a serial intravascular ultrasound study. Clin Cardiol 2002;25: Hoffmann R, Mintz GS, Mehran R, Pichard AD, Kent KM, Satler LF, Popma JJ, Wu H, Leon MB. Intravascular ultrasound predictors of angiographic restenosis in lesions treated with Palmaz-Schatz stents. J Am Coll Cardiol 1998;31: Prati F, Di Mario C, Moussa I, Reimers B, Mallus MT, Parma A, Lioy E, Colombo A. In-stent neointimal proliferation correlates with the amount of residual plaque burden outside the stent: an intravascular ultrasound study. Circulation 1999;99: Shiran A, Weissman NJ, Leiboff B, Kent KM, Pichard A, Satler LF, Wu H, Leon MB, Mintz GS. Effect of preintervention plaque burden on subsequent intimal hyperplasia in stented coronary artery lesions. Am J Cardiol 2000;86: Koyama J, Owa M, Sakurai S, Shimada H, Hikita H, Higashikata T, Ikeda S. Relation between vascular morphologic changes during stent implantation and the magnitude of in-stent neointimal hyperplasia. Am J Cardiol 2000;86: Hibi K, Suzuki T, Honda Y, Hayase M, Bonneau HN, Yock PG, Yeung AC, Fitzgerald PJ. Quantitative and spatial relation of baseline atherosclerotic plaque burden and subsequent in-stent neointimal proliferation as determined by intravascular ultrasound. Am J Cardiol 2002;90: Alfonso F, Garcia P, Pimentel G, Hernandez R, Sabate M, Escaned J, Banuelos C, Fernandez C, Macaya C. Predictors and implications of residual plaque burden after coronary stenting: an intravascular ultrasound study. Am Heart J 2003;145: Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, et al. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, et al. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: Morino Y, Kaneda H, Fox T, Takagi A, Hassan AH, Bonan R, Crocker I, Lansky AJ, Laskey WK, Suntharalingam M, et al. Delivered dose and vascular response after beta-radiation for in-stent restenosis: retrospective dosimetry and volumetric intravascular ultrasound analysis. Circulation 2002;106: Mintz GS, Kent KM, Pichard AD, Satler LF, Popma JJ, Leon MB. Contribution of inadequate arterial remodeling to the development of focal coronary artery stenoses. An intravascular ultrasound study. Circulation 1997;95: Mintz GS, Painter JA, Pichard AD, Kent KM, Satler LF, Popma JJ, Chuang YC, Bucher TA, Sokolowicz LE, Leon MB. Atherosclerosis in angiographically normal coronary artery reference segments: an intravascular ultrasound study with clinical correlations. J Am Coll Cardiol 1995;25: Tanabe K, Serruys PW, Degertekin M, Guagliumi G, Grube E, Chan C, Munzel T, Belardi J, Ruzyllo W, Bilodeau L, et al. Chronic arterial responses to polymer-controlled paclitaxel-eluting stents: comparison with bare metal stents by serial intravascular ultrasound analyses: data from the randomized TAXUS-II trial. Circulation 2004;109: Wexberg P, Gyongyosi M, Sperker W, Kiss K, Yang P, Hassan A, Pasterkamp G, Glogar D. Pre-existing arterial remodeling is associated with in-hospital and late adverse cardiac events after coronary interventions in patients with stable angina pectoris. J Am Coll Cardiol 2000;36: Mintz GS, Tinana A, Hong MK, Lee CW, Kim JJ, Fearnot NE, Park SW, Park SJ, Weissman NJ. Impact of preinterventional arterial remodeling on neointimal hyperplasia after implantation of (non-poly-

70 Coronary Artery Disease/Impact of Lesion Characteristics on SES 1241 mer encapsulated) paclitaxel-coated stents: a serial volumetric intravascular ultrasound analysis from the ASian Paclitaxel-Eluting Stent Clinical Trial (ASPECT). Circulation 2003;108: Hong MK, Park SW, Lee CW, Kim YH, Song JM, Kang DH, Song JK, Kim JJ, Park SJ. Relation between residual plaque burden after stenting and six-month angiographic restenosis. Am J Cardiol 2002; 89: Casserly IP, Aronow HD, Schoenhagen P, Tsutsui H, Popovich J, Goormastic M, Popma JJ, Nissen SE, Tuzcu EM. Relationship between residual atheroma burden and neointimal growth in patients undergoing stenting: analysis of the atherectomy before MULTI- LINK improves lumen gain and clinical outcomes trial intravascular ultrasound substudy. J Am Coll Cardiol 2002;40:

71 Impact of Coronary Culprit Lesion Calcium in Patients Undergoing Paclitaxel-Eluting Stent Implantation (a TAXUS-IV Sub Study) Issam Moussa, MD a, *, Stephen G. Ellis, MD b, Michael Jones, MD c, Dean J. Kereiakes, MD d, Daniel McMartin, MD e, Barry Rutherford, MD f, Roxana Mehran, MD a, Michael Collins, MD a, Martin B. Leon, MD a, Jeffrey J. Popma, MD g, Mary E. Russell, MD h, and Gregg W. Stone, MD a Randomized clinical trials have shown that paclitaxel-eluting stents significantly reduce restenosis after percutaneous coronary intervention. The impact of lesion calcification on the efficacy of paclitaxel-eluting stents is unknown. In the TAXUS-IV trial, 1,314 patients who underwent percutaneous coronary intervention were randomly assigned to a bare-metal or paclitaxel-eluting stent. By core laboratory analysis, 247 lesions (19%) were moderately or severely calcified. At the 9-month angiographic follow-up examination, the paclitaxel-eluting stent had significantly reduced the amount of late loss compared with the control stent ( vs mm, p 0.015) within the analysis segment in the calcific lesions. The analysis segment restenosis rate was similar in patients with calcified and noncalcified lesions after paclitaxel-eluting stent implantation (7.5% vs 8.0%, respectively; p 1.0). The rate of ischemia-driven target lesion revascularization (TLR) at 1 year was reduced by 56% in patients with calcified lesions (11.9% vs 5.1%, p 0.09) and by 75% in noncalcified lesions (15.7% vs 4.3%, p <0.0001). By interaction testing, the efficacy of the paclitaxel-eluting stent in reducing TLR at 1 year was similar in the calcified and noncalcified lesions (p 0.30). Moreover, by multivariate analysis, implantation of the paclitaxel-eluting stent was a powerful independent predictor of freedom from TLR, with similar hazard ratios for efficacy in calcified and noncalcified lesions (0.30 and 0.26, respectively). In conclusion, implantation of paclitaxel-eluting stents in patients with de novo coronary lesions significantly reduced restenosis in patients with and without calcified lesions Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) The TAXUS-IV trial was a prospective, double-blind, randomized, multicenter study that examined the safety and efficacy of the polymer-based paclitaxel-eluting stent in a broad cross section of patients with coronary artery disease. 1 The aim of this subanalysis was to examine the impact of lesion calcium on clinical and angiographic outcomes after paclitaxel-eluting stent implantation. a Cardiovascular Research Foundation and Columbia University Medical Center, New York, New York; b Cleveland Clinic Foundation, Cleveland, Ohio; c Central Baptist Hospital, Lexington, Kentucky; d Christ Hospital, Cincinnati, Ohio; e Jewish Hospital Heart and Lung Institute, Louisville, Kentucky; f Mid-American Heart Institute, Kansas City, Missouri; g Brigham and Women s Hospital, Boston, Massachusetts; h Boston Scientific Corporation, Natick, Massachusetts. Manuscript received January 20, 2005; revised manuscript received and accepted June 20, This study was supported by Boston Scientific Corporation, Natick, Massachusetts, under a Food and Drug Administration investigational device exemption. * Corresponding author: Tel: ; fax: address: im2132@columbia.edu (I. Moussa). Methods Study population and protocol: The TAXUS-IV study protocol and entry criteria have been previously described. 1 In brief, angiographic eligibility for inclusion required a single de novo lesion in a native coronary artery with a reference vessel diameter by visual estimate of 2.5 to 3.75 mm and a lesion length of 10 to 28 mm that could be covered by a single study stent. Patients were excluded if the operator considered that moderate or severe lesion calcification was present that might hinder stent expansion. Patients were also excluded if directional or rotational coronary atherectomy, laser, or cutting balloon was required before stent implantation. Of the 1,314 enrolled patients, 662 were assigned to receive either the slow rate release, polymer-based paclitaxel-eluting stent (TAXUS stent, Boston Scientific, Natick, Massachusetts) and 652 were assigned to receive a visually indistinguishable bare-metal Boston Scientific Express stent. Telephone randomization was stratified according to the presence or absence of medically treated diabetes mellitus and vessel size ( 3.0 vs 3.0 mm). Clinical follow-up was scheduled at 1, 4, and /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

72 Coronary Artery Disease/Calcium and Paclitaxel-Eluting Stent Outcomes 1243 Table 1 Baseline clinical characteristics of patients with calcified and noncalcified lesions according to treatment assignment Variable Calcified Coronary Lesion Yes No TAXUS (n 121) Control (n 126) p Value TAXUS (n 539) Control (n 524) p Value Age (yrs) Men 73.6% 69.8% % 72.9% 0.58 Current smoker 23.1% 17.1% % 21.3% 0.27 Diabetes mellitus 21.5% 21.4% % 25.8% 0.89 Insulin 9.2% 10.3% % 7.8% 0.75 Oral 12.3% 11.1% % 18.0% 0.39 Hypertension 62% 62.6% % 71.3% 0.63 Hyperlipedemia 58.7% 65.9% % 66.5% 0.65 Previous coronary bypass 9.9% 9.5% % 9.9% 1.0 Previous myocardial infarction 32.2% 27.0% % 30.5% 0.95 Table 2 Quantitative angiographic analysis for patients with calcified and noncalcified lesions according to treatment assignment Variable Calcified Coronary Lesions Yes No TAXUS (n 121) Control (n 126) p Value TAXUS (n 539) Control (n 524) p Value Baseline Reference vessel diameter (mm) Minimal luminal diameter (mm) Diameter stenosis (%) Lesion length (mm) Postprocedure In stent Minimal luminal diameter (mm) Diameter stenosis (%) In segment Minimal luminal diameter (mm) Diameter stenosis (%) months and yearly thereafter for 5 years. The latest follow-up was at 1 year and formed the basis of the present analysis. The principal clinical end points for the TAXUS-IV trial have been previously reported and defined. All major adverse cardiac events were reviewed and adjudicated by an independent committee whose members were unaware of the treatment allocation. Angiographic analysis: Angiographic follow-up was scheduled at 9 months in a prespecified subset of 732 patients. An independent analysis of all baseline and follow-up angiograms was performed at an angiographic core laboratory by a technician who was unaware of the clinical outcomes, using validated quantitative methods. 2 By qualitative assessment of the angiograms at the core angiographic laboratory, calcification was defined as readily apparent densities seen within the artery wall and site of lesion as an x-ray absorbing mass, and were classified as none/mild, moderate (densities noted only during the cardiac cycle before contrast injection, or severe radiopacities noted without cardiac motion before contrast injection generally involving both sides of the arterial wall). Quantitative measures were reported separately within the stent, within 5 mm proximal and distal to each edge and over the entire segment that was analyzed (the analysis segment ). Data management and statistical analysis: For the purpose of this analysis, the study population was divided into 2 groups, those whose lesions were moderately or severely calcified (hereafter called calcified, and those whose lesions had little to no calcification, noncalcified ). The outcomes of patients who underwent stent implantation with calcified versus noncalcified lesions were compared as a function of stent assignment. Categorical variables were compared using Fisher s exact test. Continuous variables are presented as means SDs and were compared using the Wilcoxon 2-sample test. The time to event estimates were created using Kaplan-Meier methods and compared using the log-rank test. The influence of baseline clinical and angiographic features, treatment assignment, and procedural

73 1244 The American Journal of Cardiology ( Table 3 Procedural variables for patients with calcified and noncalcified lesions according to treatment assignment Variable Calcified Coronary Lesions Yes No TAXUS (n 121) Control (n 126) p Value TAXUS (n 539) Control (n 524) p Value Stent number Stent length (mm) Stent length/lesion length ratio 1.53 (1.26, 2.17) 1.57 (1.23, 2.10) (1.30, 2.05) 1.60 (1.29, 2.11) 0.86 Maximal stent diameter (mm) Balloon/artery ratio Maximal balloon pressure (atm) Failure to deliver 5.8% 2.4% % 1.1% 0.54 Glycoprotein IIb/IIIa inhibitors 64.5% 55.6% % 57.3% 0.71 Table 4 Nine-month angiographic analysis for calcified and noncalcified lesions according to treatment assignment Variable Calcified Coronary Lesions Yes No TAXUS (n 73) Control (n 76) p Value TAXUS (n 301) Control (n 280) p Value Angiographic follow-up 73% 79% % 74% 0.17 In-stent Minimal luminal diameter (mm) Diameter stenosis (%) Late loss (mm) Inlesion Minimal luminal diameter (mm) Diameter stenosis (%) Late loss (mm) variables on the rate of target lesion revascularization (TLR) was evaluated using Cox proportional hazards regression analysis. The specific variables entered into the models were randomization arm, age, female gender, current smoker, any diabetes, left anterior descending artery location, previous myocardial infarction, hypertension, hyperlipidemia, left ventricular ejection fraction, unstable angina, number of study stents, bailout stent used, total stent length, maximum device pressure, maximum device diameter, balloon/artery ratio, stent/lesion length ratio, creatinine clearance, ostial location, bend 45, tortuosity, calcification, lesion length, baseline reference vessel diameter, and baseline minimal luminal diameter. The interaction between the presence of calcium and treatment assignment with respect to the angiographic and clinical outcomes was evaluated using the Breslow-Day test for homogeneity. All p values are 2-sided. Results Films were available for core laboratory assessment of the extent of calcification in 1,310 of 1,314 randomized patients (99.7%). Moderate or severe calcification was present in 247 lesions (18.9%), including 203 moderately calcified (15.4%) and 44 severely calcified lesions (3.5%). Moderate or severe calcification was present in 121 of 660 lesions (18.2%) randomized to receive the paclitaxel-eluting stent and 126 of 650 lesions (19.4%) randomized to receive the bare metal control stent (p 0.67). Baseline characteristics: Compared with patients without calcified lesions, those with calcified lesions were older ( vs years, p 0.01) and had a higher prevalence of insulin-dependent diabetes (10.0% vs 7.6%, p 0.05), but were less likely to have hypertension (62.3% vs 72.0%, p 0.004). Calcified lesions were longer ( vs mm, p 0.02), located in larger vessels ( vs mm, p 0.004), were more often in the left anterior descending artery (46.6% vs 39.7%, p 0.05), and were more frequently American College of Cardiology/American Heart Association lesion complexity class B2 or C (85.8% vs 46.1%, p ). Patients with calcified lesions assigned to the TAXUS versus bare metal control stent had similar clinical characteristics and similar baseline vessel size and lesion length.

74 Coronary Artery Disease/Calcium and Paclitaxel-Eluting Stent Outcomes 1245 Table 5 Angiographic restenosis: frequency, location, and pattern Variable Calcified Coronary Lesions Yes No TAXUS (n 53) Control (n 60) p Value TAXUS (n 238) Control (n 207) p Value In-lesion restenosis 7.5% 18.3% % 29.0% Proximal edge 0.0% 3.4% % 3.5% 0.58 In-stent 7.5% 18.3% % 26.2% Distal edge 0.0% 3.4% % 1.5% 0.66 In-stent restenosis pattern n 4 n 11 n 12 n 54 In-stent focal 0.0% 36% % 30% 0.15 In-stent diffuse 50% 46% % 61% Proliferative 0.0% 9% 1.0 8% 7% 0.19 Total occlusion 50% 9% % 2% 0.46 In-stent restenosis length (mm) Table 6 Clinical outcomes of patients with calcified and noncalcified lesions according to treatment assignment Outcome Calcified Coronary Lesions Yes No TAXUS (n 121) Control (n 126) p Value TAXUS (n 539) Control (n 524) p Value 30-d Events Stent thrombosis 0.0% 0.0% 0.4% 0.8% 0.39 TLR 0.0% 0.0% 0.0% 0.4% 0.15 Target vessel revascularization 0.0% 0.0% 0.0% 0.4% 0.15 Myocardial infarction 2.5% 1.6% % 2.5% 0.90 Death 0.0% 0.0% 0.4% 0.6% 0.63 Major adverse cardiac events 2.5% 1.6% % 2.7% yr Events Stent thrombosis 1.7% 0% % 1.0% 0.24 TLR 5.1% 11.9% % 15.7% Target vessel revascularization 7.8% 14.6% % 17.6% Myocardial infarction 4.1% 3.2% % 5.0% 0.19 Cardiac death 2.5% 0.8% % 1.4% 0.74 Major adverse cardiac events 11.8% 16.8% % 20.7% Similarly, patients with noncalcified lesions assigned to the TAXUS versus bare metal stent did not differ in their clinical or baseline angiographic characteristics (Tables 1 and 2). Procedural outcomes: Stent delivery failure occurred more commonly in calcified than in noncalcified lesions (4.0% vs 0.9%, 0.002). Stents deployed in calcified lesions also had a trend toward a higher residual diameter stenosis (5.2% 11.3% vs 3.8% 11.1%, p 0.076). Similar stent lengths and diameters were used in patients with calcified lesions assigned to the TAXUS versus bare metal stent, although the deployment pressure of the TAXUS stents was slightly lower in calcified lesions (Tables 2 and 3). The angiographic results were similar between the 2 stent groups in calcified and noncalcified lesions. Angiographic results at 9 months: Follow-up angiography was completed in 113 of 149 (76%) prespecified patients with calcified lesions and in 445 of 581 prespecified patients (77%) with noncalcified lesions. The in-stent and analysis segment angiographic measurements are listed in Table 4. Analysis segment restenosis was similar in patients with calcified and noncalcified lesions after paclitaxel-eluting stent implantation (7.5% vs 8.0% respectively, p 1.0; Table 5). In calcified lesions, the paclitaxel-eluting stent resulted in a relative reduction of in-lesion restenosis by 59% (relative risk 0.41, 95% confidence interval [CI] 0.14 to 1.22, p 0.10) compared with a relative reduction of 72% in patients with noncalcified lesions (relative risk 0.28, 95% CI 0.17 to 0.45, p ). Only a nonsignificant trend (p 0.10) was found for the interaction between the presence of calcium and treatment assignment on the occurrence of analysis segment restenosis. Of the 16 patients with restenosis after paclitaxel-eluting stent implantation (Table 5), the pattern was nonfocal (dif-

75 1246 The American Journal of Cardiology ( Figure 1. Freedom from TLR during 1-year follow-up after randomization to paclitaxel-eluting stent or bare metal control stent, stratified by presence of moderate/severe baseline lesion calcification. Table 7 Multivariate predictors of target lesion revascularization (TLR) at 1 year stratified by lesion calcium Variable Hazard Ratio (95% CI) p Value Patients with calcified lesions Randomization arm: TAXUS 0.30 ( ) Diabetes mellitus: any 5.29 ( ) Age 0.94 ( ) Number of nonstudy stents: ( ) Total stent length 1.06 ( ) Preprocedure reference vessel 0.09 ( ) diameter Preprocedure minimal luminal ( ) diameter Patients with noncalcified lesions Randomization arm: TAXUS 0.26 ( ) Total stent length 1.02 ( ) 0.03 Maximum device diameter 0.55 ( ) 0.02 CI confidence interval. fuse, proliferative, or occlusive) in all 4 calcified lesions with restenosis (100%) compared with 2 of 16 noncalcified lesions (17%) with restenosis (p 0.008). This difference was also reflected by a significantly longer length of the restenosed segment after implantation of the TAXUS stent in patients with calcified compared with noncalcified lesions ( vs mm, p 0.007). The length of the restenosed segment was shorter with TAXUS stents compared with bare metals in noncalcified lesions, but similar in length in calcified lesions (Table 5). Clinical outcomes at 30 days and 1 year: No statistically significant differences were observed in the 30-day rate of events between treatment groups in patients with and without calcified lesions (Table 6). At 1 year after TAXUS stent implantation, the TLR rates were similar in calcified and noncalcified lesions (5.1% vs 4.3%, respectively; p 0.59). Implantation of the paclitaxel-eluting stent compared with the bare metal stent reduced the rate of TLR by 56% in patients with calcified lesions (relative risk 0.44, 95% CI 0.17 to 1.16, p 0.09) and by 75% in patients with noncalcified lesions (relative risk 0.25, 95% CI 0.15 to 0.39, p ). By interaction testing, the efficacy of the paclitaxel-eluting stent in reducing the 1-year TLR rate was similar in calcified and noncalcified lesions (p 0.30). Figure 1 displays the time to TLR curves for patients with calcified versus noncalcified lesions according to treatment assignment. The relations between lesion calcification, treatment group, and target vessel revascularization were similar. The rates of death, myocardial infarction, and stent thrombosis were low and were similar between treatment groups in patients with and without calcified lesions (Table 6). By multivariate analysis, randomization to the paclitaxeleluting stent was an independent predictor of freedom from 1-year TLR in patients with calcified and noncalcified lesions, with hazard ratios of 0.30 and 0.26, respectively (Table 7). Diabetes mellitus and younger age were independent predictors of the need for 1-year TLR in patients with calcified lesions, but not in patients with noncalcified lesions. For these 2 lesion types, smaller diameter vessels (or smaller diameter device use) and longer lesions (or greater stent length) also predicted 1-year TLR. Discussion The findings of this analysis from the TAXUS-IV trial have demonstrated that safety is preserved with implantation of the paclitaxel-eluting stents in patients with and without calcified lesions. Also, the absolute angiographic restenosis rate after paclitaxel-eluting stent implantation in calcified and noncalcified lesions was similar. Among patients receiving the paclitaxel-eluting stent, the relative reduction of angiographic restenosis tended to be less pronounced in patients with calcified lesions (59%) compared with those with noncalcified lesions (72%). Among patients with restenosis in the paclitaxel-eluting stent arm, the 4 patients with calcified lesions had a diffuse or occlusive pattern of restenosis, but the small number of these observations limited the certainty of this finding. Randomization to the paclitaxel-eluting stent was a powerful independent predictor of freedom from TLR at 1 year in calcified and noncalcified lesions, with similar efficacy noted for the 2 lesions types. By protocol, patients with heavily calcified lesions were supposed to have been excluded from enrollment in TAXUS-IV and from the other randomized trials of drugeluting stents. 3 6 Nonetheless, by core laboratory analysis, a significant proportion of patients recruited to the TAXUS-IV study (19%) had moderately or severely calcified lesions. Because the safety and efficacy of drug-eluting stents are unknown in calcific stenoses, this observation offered a unique opportunity to investigate this issue. We found that compared with an equivalent design bare metal stent, the polymer-based paclitaxel-eluting TAXUS

76 Coronary Artery Disease/Calcium and Paclitaxel-Eluting Stent Outcomes 1247 stent significantly reduced late loss (the angiographic surrogate for neointimal hyperplasia) and improved the diameter stenosis at follow-up in patients with calcified and noncalcified lesions. As a result, TLR at 1 year was significantly reduced with the TAXUS stent compared with the bare metal control stent in calcified and noncalcified lesions. By multivariate analysis, implantation of the TAXUS stent was a powerful independent predictor of freedom from TLR in the 2 lesion types, with a similar relative degree of efficacy. Despite the significant reduction in late loss and the low restenosis rate in patients with calcified lesions receiving the paclitaxel-eluting stent, some possible differences in effect between calcified and noncalcified lesions bear discussion. The relative 59% reduction of angiographic restenosis in calcific lesions tended to be lower than that that seen in patients with noncalcified lesions (a 72% reduction). However, formal interaction analysis between the presence of calcium and treatment assignment on the incidence of inlesion restenosis yielded only a nonsignificant trend (p 0.10) for a difference. One potential reason the relative reduction in restenosis with the TAXUS stent tended to be less in calcified compared with noncalcified lesions is that the restenosis rate in patients randomized to bare metal stents was somewhat lower in patients with calcified lesions (18.3% vs 29.0%, p 0.13). The lower observed restenosis rate in patients with calcified lesions treated with bare metal stents is consistent with a recent intravascular ultrasound observation that neointimal proliferation is less after bare metal stent implantation in calcified compared with noncalcified lesions. 7 Another potential reason for the reduced relative efficacy of paclitaxel-eluting stents in calcified lesions is the potential for stent underexpansion, 8 but this was not observed in our study. Moreover, the absolute angiographic restenosis rate was similar with the paclitaxel-eluting stent in calcified and noncalcified lesions. It is possible that a floor for angiographic restenosis is present for many lesion types after drugeluting stent implantation that is difficult to penetrate because of edge injury and other random effects. This study had several limitations. First, this was a post hoc analysis of a patient subset that was not prespecified at the outset of the study. Second, the findings of this study should not be generalized to patients with severe calcifications because these patients were only a minority of the present study population. Third, no preintervention intravascular ultrasonography was done to confirm the location and severity of the calcifications. Nonetheless, this study is the first to highlight the performance of drug-eluting stents in this challenging patient population. 1. Stone GW, Ellis SG, Cox DA, Hermiller J, O Shaughnessy C, Mann JT, Turco M, Caputo R, Bergin P, Greenberg J, Popma JJ, Russell ME, for the TAXUS-IV Investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004;350: van der Zwet PM, Reiber JH. A new approach for the quantification of complex lesion morphology: the gradient field transform; basic principles and validation results. J Am Coll Cardiol 1994;24: Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R, for the RAVEL Study Group. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002;346: Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE, for the SIRIUS Investigators. Sirolimuseluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME, for the TAXUS II Study Group. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108: Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, Russell ME. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107: Shimada Y, Ako J, Courtney BK, Kataoka T, Sonoda S, Morino Y, Moses JW, Leon MB, Fitzgerald PJ, Yock PG, Honda Y. Influence of vessel wall calcium on neointimal growth following bare metal and sirolimus-eluting stent implantation: a 3-D intravascular ultrasound substudy of the SIRIUS trial. J Am Coll Cardiol 2004;43:45A. 8. Takebayashi H, Kobayashi Y, Mintz GS, Carlier SG, Fujii K, Yasuda T, Moussa I, Mehran R, Dangas GD, Collins MB, et al. Intravascular ultrasound assessment of lesions with target vessel failure after sirolimus-eluting stent implantation. Am J Cardiol 2005;95:

77 Neurological Complications Following Percutaneous Coronary Interventions (A Report from the New York State Angioplasty Registry) S. Chiu Wong, MD*, Robert Minutello, MD, and Mun K. Hong, MD Stroke is 1 of the most devastating complications associated with percutaneous coronary intervention. The present study used the combined 2000 to 2001 New York State Angioplasty Registry to compare the clinical characteristics and in-hospital outcomes of patients with and without stroke after percutaneous coronary intervention. Of the 76,903 patients who underwent angioplasty, 140 (0.18%) experienced stroke. Multivariate regression analysis revealed age, glycoprotein IIb/IIIa inhibitor use, acute myocardial infarction or congestive heart failure on admission, history of carotid disease, chronic renal disease, and placement of an intra-aortic balloon pump as independent predictors for stroke complicating percutaneous coronary intervention Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Since Gruentzig et al 1 introduced the concept of percutaneous coronary intervention (PCI) 2 decades ago, tremendous progress has been made in the field of interventional cardiology. With the introduction of more advanced technologies, improvement in adjunct pharmacology and maturation in operator techniques, PCI has steadily become safer, with improved periprocedure outcomes. 2 The immediate and long-term major adverse cardiac events after PCI and their associated risk factors have been meticulously analyzed and documented. Although neurologic complications are 1 of the most dreaded procedural complications associated with PCI, with an enormous impact on resource consumption and devastating consequences on a patient s prognosis and quality of life, comprehensive real world descriptions involving multicenter experiences of the incidence of, and detailed delineation of the associated clinical factors for, this debilitating complication have been scanty. The New York State Coronary Angioplasty Reporting System was initiated in It represents a collaborative effort between the New York State Department of Health and all 34 New York State hospitals with privileges to perform angioplasty. The registry provides a mechanism for uniform reporting of all angioplasty procedure results and generates a comprehensive database for evaluation of clinical outcomes and dissemination of pertinent information for physicians, hospitals, and the general public, with the ultimate goal of improving the quality of interventional cardiology services rendered statewide. After each PCI procedure, all operators in New York Department of Internal Medicine, Division of Cardiology, New York Presbyterian Hospital-Cornell Medical Center, New York, New York. Manuscript received April 13, 2005; revised manuscript received and accepted June 14, *Corresponding author: Tel: ; fax: scwong@med.cornell.edu (S.C. Wong). State are required to fill out a case report form delineating comprehensive patient demographics, preintervention clinical status, procedural findings, in-hospital complications, and patient status at discharge. Data collected at each institution are entered into a standardized database provided by the state. The quality of data submitted is ascertained through annual random chart auditing by an independent agency on the submitted clinical data in at least 1/2 of the participating institutions. The data coordinator of each hospital is interviewed, if necessary, to rectify any discrepancy and to resubmit all missing information whenever possible. From January 1, 2000 to December 31, 2001, 82,140 patients were discharged from hospitals after PCI in New York State. We compared the baseline clinical characteristics, procedural findings, and in-hospital clinical outcomes in patients with a periprocedural cerebrovascular accident with those without such a complication. To minimize preprocedural clinical events that were likely to confound subsequent adjudication of procedurally related neurologic events, 208 patients with cardiogenic shock, 4,382 patients who received thrombolytics before angioplasty, 695 patients with preprocedural hemodynamic instability, and 202 patients who underwent emergency coronary bypass surgery after PCI were excluded from the present analysis. Chronic renal insufficiency was defined as preprocedure creatinine 2.5 mg/dl or a history of renal failure requiring chronic peritoneal or hemodialysis. Congestive heart failure was defined as active heart failure within 2 weeks of the index procedure. Peripheral vascular disease was defined as a history of stroke, previous vascular surgery, angiographic or ultrasound evidence ( 50% diameter stenosis) of vascular disease within the aortoiliac, carotid, cerebrovascular, femoral, or popliteal vessels, or clinically absent pulses. A history of transient ischemic attacks or history of bruits did not qualify as evidence of peripheral vascular disease. Hemodynamic instability was defined as hypotension or a low cardiac output state requiring pharmacologic or mechanical /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

78 Coronary Artery Disease/Stroke After Percutaneous Coronary Intervention 1249 Table 1 Patient characteristics and procedural findings Variable Cerebral Vascular Event p Yes (n 146) No (n 76,936) Value Age (yrs) Women 40.7% 32.1% Diabetes mellitus 34.3% 26.7% Chronic renal insufficiency 7.1% 2.5% Peripheral vascular disease 27.1% 12.0% Hypertension 77.9% 73.0% Congestive heart failure 22.1% 5.6% Current smoker 17.9% 21.7% Previous myocardial 15.7% 7.4% infarction ( 1) Myocardial infarction 24 h 25.0% 7.6% Carotid disease 15.7% 4.1% Chronic obstructive pulmonary disease 7.9% 5.6% Left ventricular ejection 45.3% 13.0% 52.2% 11.8% fraction Cerebral vascular accident 9.3% 4.2%.009 Glycoprotein IIb/IIIa 65.7% 55.8% inhibitors Saphenous vein graft 12.9% 6.5% intervention Intra-aortic balloon pump 4.3% 0.5% Stent 87.1% 87.1% Table 2 Predictors of neurologic complications Multi-variate Regression Analysis Odds Ratio 95% Confidence Interval p Value Age (yrs) Glycoprotein IIb/IIIa inhibitors Myocardial infarction 24 h Carotid disease Chronic renal failure* Congestive heart failure on admission Intra-aortic balloon pump * Creatine 2.5 mg/dl or renal failure on dialysis. support, such as an intra-aortic balloon pump. A cerebral vascular accident was defined as transient or permanent new focal neurologic deficit after the procedure and before hospital discharge. Emergency bypass surgery was defined as bypass surgery after PCI because of ongoing chest pain, electrocardiographic changes, hypotension, or PCI complication. Continuous variables are reported as means SDs. Student s t test was used to compare the differences between the mean values. Categorical (dichotomous) variables are presented as percentages and were compared using Fisher s exact test. All probability tests are 2-tailed. p Values 0.05 were considered statistically significant. Stepwise multiple logistic regression analysis was performed to determine independent predictors for stroke after PCIs. Potential independent variables for the model included all clinical variables recorded in the database. The Hosmer-Lemeshow statistic was used to evaluate the model s calibration. Statistical Package for Social Sciences, version (SPSS, Inc., Chicago Illinois) was used for statistical data analysis. Of the 76,903 patients who met the inclusion criteria, 140 (0.18%) had experienced a cerebrovascular accident after PCI (Table 1). Patients with stroke were older, more often women, and more likely to have diabetes, chronic renal insufficiency, and peripheral vascular disease, and more likely to be in congestive heart failure. Patients with stroke also had a higher incidence of acute ( 24 hours) myocardial infarction and 1 previous myocardial infarction and a history of carotid disease and previous stroke. In addition, patients who received glycoprotein IIb/IIIa inhibitors and those who underwent saphenous vein graft intervention or intra-aortic balloon pump placement had a higher incidence of adverse neurologic complications after PCI. Multivariate logistic regression analysis revealed age, glycoprotein IIb/IIIa inhibitor use, acute ( 24 hours) myocardial infarction, history of carotid disease, chronic renal failure, congestive heart failure on admission, and placement of an intra-aortic balloon pump as independent predictors of cerebral vascular events after PCI (Table 2). Patients with neurologic complications after PCI had a markedly higher incidence of adverse in-hospital events, including a 55-fold increase in mortality compared with those without stroke (22.1% vs 0.4%, p 0.001). In addition, patients with periprocedural stroke had a significantly longer length of stay ( vs days, p 0.001). The all-encompassing nature of the New York State Angioplasty Registry database, which notes every patient who undergoes PCI in the entire state, results in a large population-based registry that is required to give a realistic and in-depth delineation of adverse neurologic events complicating real world angioplasty. Although stroke complicating coronary artery bypass surgery is well documented in published reports, 3 8 detailed reporting and analysis of the predictive factors predisposing to such an event has been limited after PCI. Cubo et al 9 noted a 0.17% incidence of stroke in 4,088 patients from 1988 to During an 18-month period, Brown and Topol 10 from the Cleveland Clinic reported a 0.3% incidence of neurologic events in 2,679 procedures. Fuchs et al 11 from the Washington Hospital Center reported a 0.38% incidence of stroke complicating PCI in 9,662 patients collected for 10 years. More recently, Dukkipati et al 12 published the largest single-center study on the subject, involving 20,679 patients from 1993 to 2002, with an event rate of 0.3%. To our knowledge, the present study constitutes the largest data set identifying the incidence and independent predictors for stroke complicating PCI. The study cohort incorporated all patients who underwent angioplasty in New York State during a 2-year period. The 0.18% incidence of

79 1250 The American Journal of Cardiology ( procedurally related stroke noted in the present analysis is lower than in other reported multicenter registries, with an incidence of 0.25% to 1.3% This difference may be attributable to the dissimilarity in patient demographics, progress made in angioplasty equipment, and maturation of operator techniques in recent years. In addition, because all periprocedural complications depended on self-initiated reporting by the operator and all clinical events were adjudicated locally at each patient catheterization laboratory, variations in the quality assurance among institutions were clearly unavoidable, and the possibility of under-reporting of complications definitely exists. Furthermore, the New York State Angioplasty Registry did not distinguish between different etiologies (hemorrhagic or embolic), anatomic locations (cerebral or vertebral-basilar distribution), timing of onset (intraprocedure or postprocedure), or severity (transient ischemic attack or cerebral vascular accident) of strokes, which might be associated with different complicating factors. Whether the size of the guiding catheter, level of anticoagulation, and the presence of atrial fibrillation were important factors contributing to periprocedural neurologic complications were not captured in the registry. Finally, the New York State Angioplasty Registry evaluated only in-hospital clinical outcomes. As a result, the long-term clinical outcomes in patients who survived the initial in-hospital neurologic insults were undefined. 1. Gruentzig AR, Senning A, Siegenthaler WE. Nonoperative dilatation of coronary-artery stenosis: percutaneous transluminal coronary angioplasty. N Engl J Med 1979;301: Williams DO, Holubkow R, Yeh W, Bourassa MG, Al-Bassam M, Block PC, Coady P, Cohen H, Cowley M, Dorros G, et al. Percutaneous coronary intervention in the current era compared with : the National Heart, Lung, and Blood Institute Registry. Circulation 2000;102: John R, Choudhri AF, Weinberg AD, Ting W, Rose EA, Smith CR, Oz MC. Multicenter review of preoperative risk factors for stroke after coronary artery bypass grafting. Ann Thorac Surg 2000;69: McKhann GM, Goldsborough MA, Borowicz LM Jr, Mellits ED, Brookmeyer R, Quaskey SA, Baumgartner WA, Cameron DE, Stuart RS, Gardner TJ. Predictors of stroke risk in coronary artery bypass patients. Ann Thorac Surg 1997;63: Roach GW, Kanchuger M, Mangano CM, Newman M, Nussmeier N, Wolman R, Aggarwal A, Marschall K, Graham SH, Ley C. Adverse cerebral outcomes after coronary bypass surgery. N Engl J Med 1996; 335: Mickleborough LL, Walkeer PM, Takagi Y, Ohashi M, Ivanov J, Tamariz M. Risk factors for stroke in patients undergoing coronary artery bypass grafting. J Thorac Cardiovasc Surg 1996;112: Bull DA, Neumayer LA, Hunter GC, Keksz J, Sethi GK, McIntyre KE, Bernhard VM. Risk factor for stroke in patients undergoing coronary artery bypass grafting. Cardiovasc Surg 1993;1: Gardner TJ, Horneffer PJ, Manolio TA, Pearson TA, Gott VL, Baumgartner WA, Borkon AM, Watkins L Jr, Reitz BA. Stroke following coronary bypass grafting: a ten-year study. Ann Thorac Surg 1985;40: Cubo E, Estefania CM, Manaco M, Monaco E, Gonzalez M, Egido JA, Gonzalez JL, Macaya C. Risk factors of stroke after percutaneous transluminal coronary angioplasty. Eur J Neurol 1998;5: Brown DL, Topol EJ. Stroke complicating percutaneous coronary revascularization. Am J Cardiol 1993;72: Fuchs S, Stabile E, Kinnaird TD, Mintz GS, Gruberg L, Canos DA, Pinnow EE, Kornowski R, Suddath WO, Satler LF, et al. Stroke complicating percutaneous coronary interventions: incidence, predictors, and prognostic implications. Circulation 2002;106: Dukkipati S, O Neill WW, Harjai KJ, Sanders WP, Deo D, Boura JA, Bartholomew BA, Yerkey MW, Sadeghi HM, Kahn JK. Characteristics of cerebrovascular accidents after percutaneous coronary interventions. J Am Coll Cardiol 2004;43: Dorros G, Cowley MJ, Simpson J, Bentivoglio LG, Block PC, Bourassa M, Detre K, Gosselin AJ, Gruntzig AR, Kelsey SF, et al. Percutaneous transluminal coronary angioplasty: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry. Circulation 1983;67: Akkerhuis KM, Deckers JW, Lincoff AM, Tcheng JE, Boersma E, Anderson K, Balog C, Califf RM, Topol EJ, Simoons ML. Risk of stroke associated with abciximab among patients undergoing percutaneous coronary intervention. JAMA 2001;286: Batchelor WB, Anstrom KJ, Muhlbaier LH, Grosswald R, Weintraub WS, O Neill WW, Peterson ED, for the National Cardiovascular Network Collaboration. Contemporary outcome trends in the elderly undergoing percutaneous coronary interventions: results in 7,472 octogenarians. J Am Coll Cardiol. 2000;36:

80 Predictors of Edge Stenosis Following Sirolimus-Eluting Stent Deployment (A Quantitative Intravascular Ultrasound Analysis from the SIRIUS Trial) Ryota Sakurai, MD a, Junya Ako, MD a, Yoshihiro Morino, MD a, Shinjo Sonoda, MD a, Hideaki Kaneda, MD a, Mitsuyasu Terashima, MD a, Ali H. M. Hassan, MD a, Martin B. Leon, MD b, Jeffrey W. Moses, MD b, Jeffrey J. Popma, MD c, Heidi N. Bonneau, RN, MS d, Paul G. Yock, MD a, Peter J. Fitzgerald, MD, PhD a, Yasuhiro Honda, MD a, *, and the SIRIUS Trial Investigators To study the interaction of the sirolimus-eluting stent and vessel margins, we analyzed the intravascular ultrasound parameters in 317 edges of 167 stents having 18 edge stenoses at 8 months of follow-up from the SIRIUS trial. Of the baseline parameters, a larger reference percentage of plaque area and a larger edge stent area/reference minimum lumen area were associated with edge stenosis in the sirolimus-eluting stent cohort compared with the incidence of edge stenosis in the bare metal stent cohort. Thus, full lesion coverage and matching the stented segment properly to the adjacent segment using intravascular ultrasound guidance may improve sirolimus-eluting stent implantation efficacy further Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Although drug-eluting stents have substantially reduced instent restenosis compared with bare metal stents, 1 4 less efficacy at reference segments is believed to be a possible limitation. Few intravascular ultrasound (IVUS) studies have examined edge stenosis after implantation of drugeluting stents. To study the interaction between the sirolimus-eluting stent (SES) and vessel margins, this study investigated possible IVUS predictors of stent edge stenosis (defined as angiographic diameter stenosis 50% within 5 mm of the vessel segment immediately proximal or distal to the stent) at follow-up after stent deployment. The present substudy data were obtained from the multicenter, randomized double blind study of the SIRolImUScoated BX velocity balloon expandable stent in the treatment of patients with de novo coronary artery lesions (SIRIUS) trial, a United States multicenter, randomized, double-blind study of the SES in de novo coronary lesions. The original study cohort, methods, and results have been previously reported. 2 The institutional review board at each investigational site approved the study, and all patients provided written informed consent. IVUS imaging was performed with a commercially available mechanical ultrasound system (Boston Scientific, Boston, Massachusetts) or a Center for Research in Cardiovascular Interventions, Stanford University Medical Center, Stanford, California; b Columbia University Medical Center, New York, New York; c Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts; and d Highlands Consulting, Incorporated, San Jose, California. Manuscript received March 17, 2005; revised manuscript received and accepted June 20, *Corresponding author: Tel: , fax: address: ivus@crci.stanford.edu (Y. Honda). dynamic aperture ultrasound system (Volcano, Rancho Cordova, California). At baseline, in each reference segment, the vessel and lumen area were measured at the site of maximum percentage of plaque area, defined as (vessel area lumen area)/vessel area 100. The minimum lumen area of each reference segment was also measured. In the stented segment, the stent area was measured at the stent edges. All measurements were done using commercially available planimetry software (TapeMeasure, Indec Systems, Mountain View, California). The IVUS parameters available and eligible for this study included 317 edges of 167 stents, with serial angiographic images available immediately after the procedure and at the 8-month follow-up examination. To assess the affect of stent overexpansion, we defined the edge stent area divided by the reference minimum lumen area as a step-up index. Continuous variables are expressed as means SDs and were compared using the Mann-Whitney U test; categorical variables are presented as numbers (percentages) and were compared using Fisher s exact test. Univariate logistic regression analysis was used to separately assess the contribution of baseline procedural, angiographic, and IVUS variables to edge stenosis. A p value 0.05 was considered significant. Six edges of six SESs and 12 edges of 12 bare metal stents had edge stenosis at the 8-month follow-up examination. In the 2 stent cohorts, no statistically significant difference was found in the baseline demographic, clinical, procedural, or angiographic characteristics between those with edge stenosis and those without. Of the baseline IVUS parameters (Table 1), in the SES cohort, the reference minimum lumen area was smaller and the reference percentage of plaque area and step-up index were larger statistically in /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

81 1252 The American Journal of Cardiology ( Table 1 Baseline intravascular ultrasound (IVUS) results Variable Edge Stenosis p Value Yes SES Reference vessel area (mm 2 ) Reference plaque area (mm 2 ) Reference minimum lumen area (mm 2 ) Edge stent area (mm 2 ) Maximum reference plaque area (%) Step-up index Edge tear or dissection 0 2 (1%) Bare metal stent Reference vessel area (mm 2 ) Reference plaque area (mm 2 ) Reference minimum lumen area (mm 2 ) Edge stent area (mm 2 ) Maximum reference plaque area (%) Step-up index Edge tear or dissection 0 7 (5%) Figure 1. Odds ratios and 95% confidence intervals for edge stenosis in the SES cohort according to baseline procedural, angiographic, and IVUS parameters derived from the univariate logistic regression analysis. MLA minimum lumen area. the edge stenosis group than in the no edge stenosis group. In contrast, no baseline IVUS parameters showed a statistically significant difference between the 2 groups in the bare metal stent cohort. No edge tear or dissection was No found in either the SES or bare metal stent edge stenosis groups. Figure 1 shows the odds ratios and 95% confidence intervals for edge stenosis in the SES cohort according to the procedural, angiographic, and IVUS parameters derived from univariate logistic regression analysis, which indicated that the reference percentage of plaque area and step-up index were univariate risk factors for edge stenosis with SESs. In the present study, IVUS measurements demonstrated a larger percentage of plaque area at the reference segment in the edge stenosis group in the SES cohort. These results indicate that inadequate lesion coverage may contribute to edge stenosis. One previous study reported the efficacy of long SES implantation for de novo coronary lesions. 5 However, several other studies showed an association between total SES length and the occurrence of intraprocedural stent thrombosis or angiographic restenosis, 6,7 although its overall superiority to bare metal stents was maintained. Therefore, full lesion coverage with SESs of proper length may be better able to achieve a reduction in edge stenosis and minimize other problems. On-line IVUS guidance may facilitate the determination of appropriate stent length, achieving the goal of covering significant pathologic features (anchoring the stent ends in relatively plaque-free vessel segments) using a single SES rather than multiple overlapped SESs. IVUS also showed a larger step-up index in the edge stenosis group in the SES cohort, providing another implication for optimal SES deployment techniques. In a previous study, residual dissection outside the stent was observed by baseline angiography or IVUS in 1/2 of the patients with SES edge stenosis. 8 Although no IVUS-detected edge dissection was found in the edge stenosis group in the present study, edge injury, such as overexpansion of the stent edge relative to the adjacent reference segment, even when not extended to edge dissection, may be the nidus for subsequent edge stenosis. However, given that incomplete SES expansion may be related to target lesion revascularization or thrombosis, 9,10 sufficient, rather not excessive, expansion of properly sized SESs may be needed to further improve the outcome of SES deployment. In the present study, the previously mentioned parameters in the bare metal stent cohort showed a similar trend as risk factors, but this tendency was not as apparent as in the SES cohort. One possible explanation for this difference may be the influence of the in-stent restenotic response on disease progression at the contiguous reference segment. Theoretically, this potential influence can be stronger in bare metal stents than in SESs because of the significantly greater in-stent vessel response after bare metal stenting. In the bare metal stent cohort of the SIRIUS trial, the length of an in-stent restenotic lesion was significantly longer, with a significantly higher ratio of a diffuse restenotic pattern, compared with that seen in the SES cohort. 2 Thus, predict-

82 Coronary Artery Disease/Edge Stenosis of Sirolimus-Eluting Stent 1253 ing edge stenosis may be more complicated after bare metal stenting, particularly using reference segment parameters alone. Several limitations existed in the present study. First, the sample size was small, especially the number of patients with edge stenosis, which precluded effective multivariate analysis to identify independent predictors. Second, those with total occlusion at follow-up were excluded due to the difficulty in differentiating between edge and in-stent problems. Finally, this was a retrospective study. Additional prospective investigations are needed with larger numbers of patients. 1. Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R. A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 2002; 346: Moses JW, Leon MB, Popma JJ, Fitzgerald PJ, Holmes DR, O Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE. Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery. N Engl J Med 2003;349: Grube E, Silber S, Hauptmann KE, Mueller R, Buellesfeld L, Gerckens U, Russell ME. TAXUS I: six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003;107: Colombo A, Drzewiecki J, Banning A, Grube E, Hauptmann K, Silber S, Dudek D, Fort S, Schiele F, Zmudka K, Guagliumi G, Russell ME. Randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for coronary artery lesions. Circulation 2003;108: Degertekin M, Arampatzis CA, Lemos PA, Saia F, Hoye A, Daemen J, Tanabe K, Lee CH, Hofma SJ, Sianos G, et al. Very long sirolimuseluting stent implantation for de novo coronary lesions. Am J Cardiol 2004;93: Chieffo A, Bonizzoni E, Orlic D, Stankovic G, Rogacka R, Airoldi F, Mikhail GW, Montorfano M, Michev I, Carlino M, Colombo A. Intraprocedural stent thrombosis during implantation of sirolimuseluting stents. Circulation 2004;109: Lemos PA, Hoye A, Goedhart D, Arampatzis CA, Saia F, van der Giessen WJ, McFadden E, Sianos G, Smits PC, Hofma SH, et al. Clinical, angiographic, and procedural predictors of angiographic restenosis after sirolimus-eluting stent implantation in complex patients: an evaluation from the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) study. Circulation 2004;109: Lemos PA, Saia F, Ligthart JM, Arampatzis CA, Sianos G, Tanabe K, Hoye A, Degertekin M, Daemen J, McFadden E, et al. Coronary restenosis after sirolimus-eluting stent implantation: morphological description and mechanistic analysis from a consecutive series of cases. Circulation 2003;108: Holmes DR Jr, Leon MB, Moses JW, Popma JJ, Cutlip D, Fitzgerald PJ, Brown C, Fischell T, Wong SC, Midei M, Snead D, Kuntz RE. Analysis of 1-year clinical outcomes in the SIRIUS trial: a randomized trial of a sirolimus-eluting stent versus a standard stent in patients at high risk for coronary restenosis. Circulation 2004;109: Regar E, Lemos PA, Saia F, Degertekin M, Tanabe K, Lee CH, Arampatzis CA, Hoye A, Sianos G, de Feyter P, et al. Incidence of thrombotic stent occlusion during the first three months after sirolimus-eluting stent implantation in 500 consecutive patients. Am J Cardiol 2004;93:

83 Relation of Early Saphenous Vein Graft Failure to Outcomes Following Coronary Artery Bypass Surgery Abdul R. Halabi, MD a, John H. Alexander, MD, MS a,, Linda K. Shaw, MSc a, Todd J. Lorenz, MD c, Lawrence Liao, MD a, David F. Kong, MD, AM a, Carmelo A. Milano, MD b, Robert A. Harrington, MD a, and Peter K. Smith, MD b Up to 20% of saphenous vein grafts (SVGs) fail within 2 years of coronary artery bypass grafting (CABG). The long-term effects of early SVG failure on major clinical events remain undefined in contemporary patient populations. We sought to examine the relation between early SVG failure and long-term outcomes after CABG. Using the Duke Cardiovascular Databank, we examined baseline clinical and angiographic characteristics and clinical outcomes among patients who underwent catheterization 1 to 18 months after their first CABG from 1986 to Patients were classified on the basis of their worst SVG stenosis as having no (<25%), noncritical (25% to 74%), critical (75% to 99%), or occlusive (100%) SVG disease. Our primary outcome measure was the composite of death, myocardial infarction, or repeat revascularization after catheterization. Of 1,243 patients included in the analysis, 27.9% had no, 11.9% had noncritical, 20.8% had critical, and 39.3% had occlusive SVG disease. At 10 years, the corresponding adjusted composite event rates were 41.2%, 56.2%, 81.2%, and 67.1%, respectively (p <0.0001). Most events occurred immediately after catheterization in patients with critical and occlusive SVG disease and were primarily repeat revascularization. On multivariate analysis, critical, nonocclusive SVG disease was the strongest predictor of the composite outcome (hazard ratio 2.36, 95% confidence interval 2.00 to 2.79, p <0.0001). In conclusion, in contemporary clinical practice, early SVG failure is associated with worse long-term outcomes after CABG Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Saphenous vein grafts (SVGs) remain the most commonly implanted surgical conduits during coronary artery bypass grafting (CABG), yet they are prone to accelerated atherosclerosis and subsequent failure. Although no standard definition of early SVG failure exists, it is generally recognized as the presence of angiographically critical or occlusive disease within 1 to 2 years after CABG. 1,2 Early SVG failure occurs in approximately 15% to 20% of grafts within 1 year after CABG, with a yearly graft attrition rate of 2% to 4%. 3 5 Affected patients often present with recurrent angina, myocardial infarction, or even sudden death. These acute events often require repeat revascularization procedures with substantial limitations and risks. 4,6 11 To understand the long-term consequences of early SVG failure better, we conducted an observational analysis investigating Divisions of a Cardiology and b Cardio-Thoracic Surgery, Duke University Medical Center and Duke Clinical Research Institute, Durham, North Carolina; and c Corgentech Incorporated, South San Francisco, California. Manuscript received February 11, 2005; revised manuscript received and accepted June 20, This study was supported by an unrestricted grant from Corgentech, Inc., South San Francisco, California, and Bristol-Myers Squibb, New York, New York. * Corresponding author: Tel: ; fax: address: john.h.alexander@duke.edu (J.H. Alexander). the association between SVG failure and clinical outcomes among patients who underwent CABG. Methods Duke Cardiovascular Databank: The methods of the Duke Cardiovascular Databank have been previously described. 12,13 In brief, all patients who have undergone cardiac catheterization, percutaneous coronary intervention, or cardiac surgery since 1969 have had their demographic, clinical, angiographic, and procedural data entered into a standard database at the time of the procedure. Co-morbid diagnoses (e.g., hypertension, dyslipidemia) were abstracted from the clinical medical record and based on standard clinical definitions. Follow-up data, including all-cause mortality, myocardial infarction, and revascularization procedures, were obtained prospectively by mailed questionnaires and telephone interviews at 6 months and 1 year and annually thereafter. A National Death Index search was conducted for nonresponders. In addition, data from clinical visits and repeat hospitalizations were obtained to ascertain the follow-up data and the occurrence of nonfatal myocardial infarctions and repeat revascularization procedures within and outside the Duke University Medical Center /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

84 Coronary Artery Disease/Early SVG Failure and Clinical Outcomes 1255 Nonfatal myocardial infarctions were defined by standard clinical, enzymatic, electrical, and angiographic criteria. Patient population: We identified all patients who underwent their first CABG, plus subsequent clinically driven cardiac catheterization performed within 1 to 18 months after surgery from January 1, 1986 to December 31, Patients were excluded if they had undergone previous valve surgery (n 4,052), had moderate or severe valvular disease (n 534), congenital heart disease (n 905), had undergone single-vessel bypass with a non SVG conduit (n 314), or had incomplete angiographic data (n 940). Patients were considered to have incomplete angiographic data when selective coronary angiography without graft angiography was performed after CABG. Patients who had undergone 1 cardiac catheterization 1 to 18 months after CABG had only the first (index) procedure included. Our final data set included 1,243 unique patients. After catheterization, clinical outcomes were assessed and included all-cause mortality, nonfatal myocardial infarction, repeat revascularization through either repeat CABG or percutaneous coronary intervention, and a composite of these 3 end points. Only clinical events occurring after the index catheterization were included in our analyses. The follow-up ascertainment rate for vital status in the present cohort was 98.9%. The institutional review board approved this research. All patients provided informed consent at cardiac catheterization in accordance with institutional guidelines. Angiographic data collection: All cardiac catheterization procedures at the Duke University Medical Center are systematically reviewed in a standardized fashion by 2 operators. Lesion characteristics are described by assessing the severity, length, type, and location within the coronary tree. Lesion severity is quantified as a percentage of the value equal to the ratio of the minimum lumen diameter over the reference vessel diameter. In an effort to minimize variability in intra- and interoperator angiographic interpretation, lesion severity was classified using the following categories: 25%, 25%, 50%, 75%, 95%, or 100%. SVGs and arterial conduits were classified according to the target artery of the distal anastomoses. Graft lesion characteristics were reported whenever a stenosis was identified. A grading scale similar to the one used for the native coronary anatomy was used to evaluate the severity of each stenosis within the affected SVG conduits. Statistical analyses: Baseline variables, collected at cardiac catheterization, are presented as percentages for discrete variables and as medians with 25th and 75th percentiles for the distribution of continuous variables. Patients were classified by their worst SVG stenosis into the following groups: no SVG disease ( 25%), noncritical SVG disease (25% or 50%), critical SVG disease (75% or 95%), and occlusive SVG disease (100%). Our primary outcome measure was the composite of death, nonfatal myocardial infarction, or revascularization after index cardiac catheterization. Secondary outcome measures included the individual primary outcomes and myocardial infarction occurring between CABG and catheterization. To minimize catheterization referral bias, only myocardial infarction events occurring after the index catheterization were included in the primary outcome measure. Cumulative event rates for each outcome as a function of time were calculated using the Kaplan-Meier method. Unadjusted 10-year event rates were examined in tabular form for each outcome. Unadjusted Kaplan-Meier plots were generated for survival and the composite end point for each of the 4 SVG disease severity groups. To describe the relation between the severity of SVG disease at index catheterization and subsequent fatal and composite outcomes, a series of multivariate Cox proportional hazards regression models was developed to adjust for differences in prognostically significant baseline clinical and angiographic characteristics. Baseline characteristics that were significant at the 0.10 level in unadjusted models and those that were believed to have clinical importance were included. The following candidate characteristics were used: gender, age, race, history of peripheral vascular disease, cerebrovascular disease, congestive heart failure, previous myocardial infarction (before CABG), myocardial infarction between CABG and index catheterization, interval between CABG and index catheterization, left ventricular ejection fraction, smoking history, hypertension, diabetes mellitus, a modified Charlson co-morbidity index, 14 dyslipidemia, a native coronary disease index incorporating the location and severity of stenosis and number of affected diseased major epicardial vessels, total number of implanted SVG conduits, number of SVG conduits with critical or occlusive disease, and patency of the in situ internal mammary artery (IMA) graft. To quantify the contribution of a patent in situ IMA graft, we included a separate indicator variable for the presence of a patent IMA graft. A history of congestive heart failure and myocardial infarction were removed from the Charlson index and examined independently because of their predictive value in patients with high-risk cardiac disease. The result of a backward elimination modeling approach was compared with the stepwise result. Whenever appropriate, we used spline functions to assess the linearity assumption for continuous variables to be studied in models of composite and patient outcomes. Variables were transformed accordingly to satisfy this assumption. Adjusted curves for survival and the composite end point were generated, and adjusted 10-year outcomes were tabulated. Left ventricular ejection fraction data were missing in 3.5% of the patients. Other variables had fewer missing data. Markov chain Monte Carlo methods of data imputation were used to estimate missing data items for the modeling efforts. All results were compared across multiple imputations and with the subset of patients with all covariates present. All statistical analyses were performed using

85 1256 The American Journal of Cardiology ( Table 1 Baseline clinical and angiographic characteristics Baseline Variable Severity of SVG Disease at Index Catheterization p Value All (n 1243) None (n 347) Noncritical (n 148) Critical (n 259) Occlusive (n 489) Age (yrs, median, IQR) 61 (53 68) 61 (52 58) 59 (53 67) 59 (53 69) 62 (54 69) Men 67.3% 70.6% 71.6% 64.9% 65.0% White 82.8% 86.7% 81.1% 79.9% 82.0% Hypertension* 69.8% 64.8% 69.6% 72.6% 71.8% Diabetes mellitus* 32.6% 30.8% 29.7% 35.1% 33.3% Dyslipidemia* 68.9% 69.5% 73.6% 66.8% 68.1% Smoking 68.5% 71.8% 66.2% 69.5% 66.5% Previous myocardial infarction 58.1% 65.7% 59.5% 49.0% 57.1% Previous percutaneous coronary intervention 24.8% 22.5% 28.4% 22.8% 26.4% Previous heart failure 30.2% 31.7% 26.0% 31.9% 29.5% Presence of third heart sound 4.8% 6.3% 2.7% 4.3% 4.7% Cerebrovascular disease 14.1% 14.4% 14.9% 14.3% 13.5% Peripheral vascular disease 18.3% 15.9% 16.2% 20.5% 19.6% Left ventricular ejection fraction (median, IQR) 54% (43 62%) 55% (43 63%) 56% (46 63%) 54% (43 64%) 53% (42 62%) No. of narrowed ( 75%) coronary arteries % 0.9% 0.0% 2.3% 1.8% % 13.0% 9.5% 13.9% 6.5% % 34.3% 30.4% 23.9% 25.8% % 51.9% 60.1% 59.8% 65.8% No. of SVG per patient (median, IQR) 3 (3 4) 3 (2 3) 3 (3 4) 3 (2 4) 3 (3 4) Presence of IMA graft 91.4% 95.4% 91.2% 88.0% 90.4% Significant ( 75%) IMA disease 12.9% 13.0% 8.8% 13.1% 13.9% Interval from CABG to index catheterization (d, median, IQR) 204 ( ) 227 ( ) 203 ( ) 164 (98 299) 214 ( ) * Co-morbidity diagnoses based on standard clinical definitions. IQR interquartile range. Statistical Analysis Systems software (SAS Institute, Cary, North Carolina). Results Baseline clinical characteristics: The median time from CABG to index catheterization was 204 days (interquartile range 111 to 354). The median follow-up after catheterization was 6.7 years (interquartile range 3.0 to 11.5) for the overall population and 7.6 years (interquartile range 3.1 to 12.4) for patients who survived through the follow-up period. The baseline clinical and angiographic characteristics of the 1,243 patients are listed overall and classified by SVG disease severity at index catheterization in Table 1. Most were men (67.3%) and white (82.8%). The median age was 61 years (interquartile range 53 to 68). Approximately 1/3 of all patients had diabetes mellitus, and 2/3 had systemic hypertension. The left ventricular ejection fraction was comparable between study groups (median 54%). Baseline angiographic characteristics: Of the 1,243 patients included in the study, 27.9% had no SVG disease, 11.9% had noncritical SVG disease, 20.8% had critical SVG disease, and 39.3% had occlusive SVG disease at index catheterization. Underlying native 3-vessel coronary artery disease was present in 60% of the overall study population. Patients with occlusive SVG disease had the highest prevalence of 3-vessel disease at the index catheterization (p 0.001). The median number of SVG conduits was 3.0. Of all study patients, 91.4% had IMA grafts, and 12.9% had significant IMA disease at the index catheterization. With the exception of 3-vessel disease, no significant baseline angiographic differences were found among the 4 study groups. Clinical outcomes: A total of 161 myocardial infarctions occurred between CABG and index catheterization. The myocardial infarction rate between CABG and catheterization was highest in patients with occlusive SVG disease (19.0%), followed by patients with critical (10.8%), noncritical (8.8%), and no (7.8%) SVG disease. After catheterization, 465 patients died, 170 had a nonfatal myocardial infarction, and 646 required repeat revascularization during the follow-up period (1986 to 2004). The rate of percutaneous and surgical revascularization procedures among those requiring repeat revascularization was 84.7% and 15.3%, respectively. Unadjusted cumulative event rates are listed in Table 2. No difference was found in either unadjusted or adjusted mortality among the 4 groups (Figure 1). Myocardial infarction was more common within 5 years among patients with critical and occlusive SVG disease. However, with longer follow-up, myocardial infarction became most frequent among patients with noncritical SVG disease. The

86 Coronary Artery Disease/Early SVG Failure and Clinical Outcomes 1257 Table 2 Unadjusted events rates according to severity of saphenous vein graft (SVG) disease at index catheterization Outcome Variable Years After Index Cardiac Catheterization Death None 3.8% 10.3% 15.8% 22.9% 35.6% Noncritical 4.1% 9.6% 17.0% 22.8% 37.3% Critical 1.9% 7.5% 17.0% 28.9% 42.2% Occlusive 5.4% 12.7% 20.0% 29.5% 42.7% Myocardial infarction None 2.6% 4.6% 6.7% 9.9% 13.5% Noncritical 2.9% 4.6% 7.7% 14.9% 32.8% Critical 3.1% 6.6% 8.3% 9.5% 10.9% Occlusive 3.4% 7.4% 9.9% 13.9% 23.1% Repeat revascularization None 19.1% 21.3% 24.9% 31.6% 35.6% Noncritical 23.4% 26.1% 33.0% 44.6% 48.1% Critical 73.4% 73.8% 75.7% 77.2% 81.1% Occlusive 42.0% 45.4% 48.7% 52.8% 60.5% Composite outcome* None 20.6% 23.7% 28.4% 35.0% 40.8% Noncritical 24.8% 28.3% 35.2% 48.0% 57.0% Critical 73.4% 73.8% 75.7% 77.7% 81.6% Occlusive 42.8% 46.9% 52.0% 57.3% 67.4% * Composite outcome included death, nonfatal myocardial infarction, or repeat revascularization. Figure 2. Adjusted Kaplan-Meier MACE-free survival. MACE major adverse coronary events. with occlusive (67.1%), noncritical (56.2%), and no (41.2%) SVG disease (p ). Predictors of mortality and clinical outcomes: Multivariate predictors of mortality and the composite clinical outcome are listed in Table 3. Significant predictors of mortality included the Charlson co-morbidity index, reduced left ventricular ejection fraction, older age, presence of carotid bruits, congestive heart failure class, and hypertension. Significant predictors of the composite clinical outcome were the presence of critical, nonocclusive SVG disease, number of SVG conduits with critical or occlusive disease, absence of a third heart sound, absence of myocardial infarction, and increased left ventricular ejection fraction. Critical, nonocclusive SVG disease was the strongest independent predictor of the composite clinical outcome (hazard ratio 2.36, 95% confidence interval 2.00 to 2.79, p ). The reference population was the patient group without SVG disease at the index catheterization. Discussion Figure 1. Adjusted Kaplan-Meier survival. rate of repeat revascularization was highest among patients with critical SVG disease, followed by patients with occlusive, noncritical, and no SVG disease. The primary composite of death, myocardial infarction, and revascularization occurred more frequently in patients with critical or occlusive SVG disease than in those with no or noncritical SVG disease (p ; Table 2). Patients with critical SVG disease had the highest event rate, primarily driven by a very high rate of early revascularization. After adjustment (Figure 2), patients with critical SVG disease continued to have the highest 10-year event rate (81.2%), followed by those In this contemporary population, early SVG disease was associated with an increased risk of long-term adverse clinical outcomes. Among patients who underwent cardiac catheterization 1 to 18 months after CABG, the composite of death, myocardial infarction, and repeat revascularization was significantly more likely among patients with critical or occlusive SVG disease than in those with noncritical or no SVG disease at catheterization. The number of grafts with critical or occlusive disease and the presence of a graft with critical but nonocclusive disease were independent predictors of a worse outcome. These adverse outcomes were primarily driven by a high rate of repeat revascularization immediately after catheterization. The rate of repeat revascularization was highest among patients with critical, nonocclusive SVG disease,

87 1258 The American Journal of Cardiology ( Table 3 Multivariable predictors of clinical events Outcome Variable Composite Clinical Outcome* Mortality Chi-square HR (95% CI) p Value Chi-square HR (95% CI) p Value Critical SVG disease ( ) No. of SVGs with critical or occlusive disease ( ) S3 heart sound ( ) Previous myocardial infarction ( ) Ejection fraction (per 5%) ( ) ( ) Charlson co-morbidity index ( ) Age (per 10 yrs) ( ) Carotid bruits ( ) Congestive heart failure class ( ) Hypertension ( ) * Composite outcome included death, nonfatal myocardial infarction, or repeat revascularization. Reference population for each resulting HR was patient group without SVG disease at index catheterization. Statistically nonsignificant associations with mortality. Statistically nonsignificant associations with composite clinical outcome. CI confidence interval; HR hazard ratio. followed by patients with occlusive, noncritical, and no SVG disease. The presence of critical angiographic SVG disease at catheterization leads to an increased rate of revascularization. We did not, however, observe a difference in mortality among the SVG disease groups. Repeat revascularization or other disease-modifying interventions preferentially applied to patients with more significant disease may have lessened the differences in mortality and/or nonfatal myocardial infarction. Alternatively, the relatively small sample size may have prevented us from detecting small potential differences in mortality. Our results concur with those of previous studies linking significant SVG disease with adverse clinical outcomes. 4,15,16 In a comprehensive effort to examine this issue, Fitzgibbon and colleagues 4 evaluated a large singlecenter cohort of patients investigated during a 25-year span that included 5,065 grafts implanted in 1,388 patients. Their study showed a relation between graft occlusion occurring 1 year after CABG and subsequent reoperation and mortality. Our study, from a contemporary clinical population, found a similar relation between early SVG failure and adverse outcomes. Our study also included patients with critical but nonocclusive SVG disease, thus establishing a substantial relation between less-than-occlusive significant SVG disease and clinically important outcomes. Our study was limited by the selected population included in the Duke Cardiovascular Databank, the inclusion of patients who survived to undergo subsequent cardiac catheterization, and because the baseline clinical and angiographic characteristics and outcomes were assessed from catheterization rather than CABG. Finally, we did not evaluate the influence of other arterial conduits. 17,18 In contemporary clinical practice, early SVG failure is associated with worse long-term outcomes primarily because of a high rate of repeat revascularization among those with critical, nonocclusive SVG disease. These results underscore the substantial morbidity associated with early SVG failure and the importance of developing strategies to improve the durability of CABG. Acknowledgment: We acknowledge the invaluable contributions of Judy Stafford, MS (catheterization and surgical data management) and Charles B. McCants, MS (patient follow-up) from the Duke Cardiovascular Databank Group. 1. Motwani JG, Topol EJ. Aortocoronary saphenous vein graft disease: pathogenesis, predisposition, and prevention. Circulation 1998;97: Canos DA, Mintz GS, Berzingi CO, Apple S, Kotani J, Pichard AD, Satler LF, Suddath WO, Waksman R, Lindsay J Jr, Weissman NJ. Clinical, angiographic, and intravascular ultrasound characteristics of early saphenous vein graft failure. J Am Coll Cardiol 2004;44: Campeau L, Enjalbert M, Lesperance J, Bourassa MG, Kwiterovich P Jr, Wacholder S, Sniderman A. The relation of risk factors to the development of atherosclerosis in saphenous-vein bypass grafts and the progression of disease in the native circulation: a study 10 years after aortocoronary bypass surgery. N Engl J Med 1984;311: Fitzgibbon GM, Kafka HP, Leach AJ, Keon WJ, Hooper GD, Burton JR. Coronary bypass graft fate and patient outcome: angiographic follow-up of 5,065 grafts related to survival and reoperation in 1,388 patients during 25 years. J Am Coll Cardiol 1996;28: Goldman S, Zadina K, Moritz T, Ovitt T, Sethi G, Copeland JG, Thottapurathu L, Krasnicka B, Ellis N, Anderson RJ, Henderson W, for the VA Cooperative Study Group #207/297/364. Long-term patency of saphenous vein and left internal mammary artery grafts after coronary artery bypass surgery: results from a Department of Veterans Affairs Cooperative Study. J Am Coll Cardiol 2004;44: Cameron A, Kemp HG Jr, Green GE. Reoperation for coronary artery disease: 10 years of clinical follow-up. Circulation 1988;78:I158 I Loop FD, Lytle BW, Cosgrove DM, Woods EL, Stewart RW, Golding LA, Goormastic M, Taylor PC. Reoperation for coronary atherosclerosis: changing practice in 2,509 consecutive patients. Ann Surg 1990; 212: Lefkovits J, Holmes DR, Califf RM, Safian RD, Pieper K, Keeler G, Topol EJ, for the CAVEAT-II Investigators. Predictors and sequelae of

88 Coronary Artery Disease/Early SVG Failure and Clinical Outcomes 1259 distal embolization during saphenous vein graft intervention from the CAVEAT-II trial. Circulation 1995;92: Reeves F, Bonan R, Cote G, Crepeau J, deguise P, Gosselin G, Campeau L, Lesperance J. Long-term angiographic follow-up after angioplasty of venous coronary bypass grafts. Am Heart J 1991; 122: Savage MP, Douglas JS Jr, Fischman DL, Pepine CJ, King SB III, Werner JA, Bailey SR, Overlie PA, Fenton SH, Brinker JA, Leon MB, Goldberg S, for the Saphenous Vein De Novo Trial Investigators. Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. N Engl J Med 1997;337: Le May MR, Labinaz M, Marquis JF, Laramee LA, O Brien ER, Williams WL, Jelley JL, Woodend K, Higginson LA. Predictors of long-term outcome after stent implantation in a saphenous vein graft. Am J Cardiol 1999;83: Eisenstein EL, Shaw LK, Anstrom KJ, Nelson CL, Hakim Z, Hasselblad V, Mark DB. Assessing the clinical and economic burden of coronary artery disease: Med Care 2001;39: Califf RM, Harrell FE Jr, Lee KL, Rankin JS, Hlatky MA, Mark DB, Jones RH, Muhlbaier LH, Oldham HN Jr, Pryor DB. The evolution of medical and surgical therapy for coronary artery disease: a 15-year perspective. JAMA 1989;261: Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chron Dis 1987;40: Weintraub WS, Jones EL, Craver JM, Guyton RA. Frequency of repeat coronary bypass or coronary angioplasty after coronary artery bypass surgery using saphenous venous grafts. Am J Cardiol 1994;73: Weintraub WS, Jones EL, Morris DC, King SB III, Guyton RA, Craver JM. Outcome of reoperative coronary bypass surgery versus coronary angioplasty after previous bypass surgery. Circulation 1997; 95: Desai ND, Cohen EA, Naylor CD, Fremes SE, for the Radial Artery Patency Study Investigators. A randomized comparison of radialartery and saphenous-vein coronary bypass grafts. N Engl J Med 2004;351: Cameron J, Trivedi S, Stafford G, Bett JH. Five-year angiographic patency of radial artery bypass grafts. Circulation 2004;110(suppl II): II23 II26.

89 Therapeutic Lifestyle Changes and Drug Treatment for High Blood Cholesterol in China and Application of the Adult Treatment Panel III Guidelines Paul Muntner, PhD a,b,, Dongfeng Gu, MD c, Robert F. Reynolds, ScD d, Xigui Wu, MD c, Jichun Chen, MD c, Paul K. Whelton, MD a,b, and Jiang He, MD, PhD a,b The prevalence of elevated blood cholesterol in China has increased during the past several decades. We estimated the percentage of the Chinese population for whom therapeutic lifestyle changes and drug therapy to lower blood cholesterol should be considered by applying the United States National Cholesterol Education Panel s Adult Treatment Panel III guidelines to a nationally representative sample of the Chinese population from the International Collaborative Study of Cardiovascular Disease in Asia. Serum samples were collected for 14,919 Chinese adults, 35 to 74 years old, in 2000 and 2001, after an overnight fast of >8 hours and their low-density lipoprotein (LDL) cholesterol level was calculated using the Freidewald equation. Using the Adult Treatment Panel III guidelines, 85.9 million Chinese adults (18.2%) should initiate therapeutic lifestyle changes to lower their LDL cholesterol and 35.0 million (7.4%) should be considered for lifestyle changes and lipid-lowering drug therapy. Of those for whom drug therapy should be considered, 4.7 million (13.4%) reported having been told they had high cholesterol by a healthcare provider and 1.6 million (33.7% of those aware of their high cholesterol) were receiving lipidlowering medication leaving 33.4 million Chinese adults with untreated elevated LDL cholesterol (95.5% of those with elevated LDL cholesterol). A 10% populationwide reduction in LDL cholesterol would reduce the number of Chinese adults who should be considered for drug therapy by 45% to 19.3 million (4.1% of adults). In conclusion, most adults in China with an elevated LDL cholesterol remain untreated Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) The United States National Cholesterol Education Program s (NCEP) Adult Treatment Panel III (ATP-III), in tandem with an update including implications from recent clinical trials, has provided recommendations for the use of cholesterol-lowering drug therapy. 1,2 Although national guidelines for the treatment of high cholesterol for Chinese adults have not been established, in 1997, the Chinese Journal of Cardiology published an editorial report recommending low-density lipoprotein (LDL) cholesterol cutpoints at which lifestyle modification and drug therapy should be initiated. 3 The present study sought to estimate the number and percentage of Chinese adults for whom therapeutic lifestyle changes and lipid-lowering drug therapy might be appropriate using the most current NCEP a Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana; b Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana; c Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medial College, Beijing, China; and d Global Epidemiology, Pfizer Incorporated, New York, New York. Manuscript received April 4, 2005; revised manuscript received and accepted June 22, * Corresponding author: Tel: ; fax: address: pmuntner@tulane.edu (P. Muntner). ATP-III guidelines for the primary analyses and the Chinese Journal of Cardiology editorial board guidelines for secondary analyses. Additionally, among those for whom therapeutic lifestyle change and lipid-lowering drug therapy would be recommended, we calculated the percentage who were aware of their diagnosis of high cholesterol and the percentage who had engaged in lipid-lowering therapy. Methods Study population: The International Collaborative Study of Cardiovascular Disease in ASIA (InterASIA) was a cross-sectional study of cardiovascular disease risk factors in nationally representative samples of the general population aged 35 to 74 years in China and Thailand. It was conducted in 2000 and 2001 and has been previously described in detail. 4 In China, a total of 19,012 subjects from 20 primary sampling units (street districts in urban districts or townships in rural districts) were randomly selected and invited to participate in the survey. Of this group, 15,259 adults who were aged 35 to 74 years at the time of the survey agreed to participate in the interview, examination, and blood specimen collection procedure. We excluded 43 participants with missing high-density lipoprotein (HDL) /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

90 Preventive Cardiology/Cholesterol Treatment in China 1261 cholesterol and/or total cholesterol values and 285 participants with a triglyceride level 400 mg/dl, resulting in a final sample of 14,919 participants for the present analysis. Data collection: During the clinic visits, trained research staff administered a standardized questionnaire. Of relevance to the present analysis, participants were asked, Have you ever been told by a doctor or other health professional that your blood cholesterol level was high? Those who answered in the affirmative were considered to be aware of having a high cholesterol concentration. Participants who said yes to the questions During the past 2 weeks, did you take prescribed medicines for your high blood cholesterol? or During the past 2 weeks, have you been controlling your weight or losing weight (or exercising or eating fewer high fat or high cholesterol foods)? were considered to be taking pharmacologic drug therapy and/or following lifestyle therapeutic changes, respectively, to lower their blood cholesterol. Overnight fasting blood samples were drawn by venipuncture to measure serum total cholesterol, HDL cholesterol, and triglyceride levels. 5 Total cholesterol, HDL cholesterol, and serum triglycerides were analyzed enzymatically on a Hitachi 7060 Clinical Analyzer (Hitachi High-Technologies Corporation, Tokyo, Japan) using commercial reagents. LDL cholesterol was calculated using the Friedewald equation (LDL cholesterol total cholesterol HDL cholesterol triglycerides/5). 6 Major coronary heart disease risk factors: The ATP- III guidelines have defined major coronary heart disease (CHD) risk factors to be cigarette smoking, hypertension, HDL cholesterol 40 mg/dl, family history of premature CHD, and older age ( 45 years for men and 55 years for women). In contrast, a HDL cholesterol 60 mg/dl is considered to be a protective CHD risk factor. In this study, blood pressure was measured 3 times using a standardized protocol adapted from procedures recommended by the American Heart Association. 7 Participants were then classified as having hypertension if, on the basis of all available blood pressure measurements, they had systolic blood pressure 140 mm Hg and/or diastolic blood pressure 90 mm Hg, and/or they reported that they were currently taking antihypertensive medication. Participants who reported having smoked 100 cigarettes during their lifetime were classified as current smokers if they answered affirmatively to the question Do you smoke cigarettes now? The NCEP ATP-III guidelines have defined a family history of premature CHD as CHD in a first-degree male relative at 55 years of age or in a first-degree female relative at 65 years of age. However, a family history of CHD from the InterA- SIA study was limited to a history of myocardial infarction at 50 years among first-degree relatives, so this criterion was used to identify a family history of premature CHD. The number of major CHD risk factors present was determined by summing the number of risk factors and subtracting 1 for those who had a high HDL cholesterol level ( 60 mg/dl). CHD and CHD risk equivalents: The presence of CHD was assessed as a self-reported history of a heart attack. CHD risk equivalents were defined (assessed) as a history of stroke (self-report), diabetes mellitus (self-reported history of diabetes mellitus with concurrent medication use and/or a fasting plasma glucose of 126 mg/dl), angina (Rose questionnaire), or 20% risk of CHD within the next 10 years. Although the ATP-III guidelines have recommended using the Framingham risk equation to estimate a patient s 10-year CHD risk, this formula has been reported to overestimate the 10-year CHD risk in the Chinese population. Therefore, we used the calibrated 10-year CHD risk equation developed by Liu et al, in the Chinese Multi-Provincial Cohort Study. 8,9 ATP-III risk categories: The ATP-III guidelines classify patients into 1 of 3 mutually exclusive risk categories. The lowest risk category includes those without CHD or CHD risk equivalents and with 0 or 1 major CHD risk factor. The intermediate risk category includes those without CHD or its risk equivalents but with 2 CHD risk factors. The high-risk category includes those with CHD or a CHD risk equivalent. The institutional review board at the Tulane University Health Sciences Center and relevant ethics committees and other regulatory bodies in China approved the study. All participants provided written informed consent before data collection. During the study, participants with untreated conditions identified during the examination were referred to their usual primary healthcare provider. Statistical analysis: The prevalence of ATP-III defined CHD or CHD risk equivalents and major CHD risk factors was determined separately for men and women. The distribution of the population into the NCEP ATP-III defined risk categories was determined by age group (35 to 44, 45 to 54, 55 to 64, and 65 to 74 years), gender, and geographic location of residence (north, south, urban, and rural China). Differences across groups were assessed using the Wald chi-square test. The percentage of the population that was a candidate for therapeutic lifestyle changes and for whom drug therapy should be considered to lower their LDL cholesterol was also calculated, as was the percentage of participants who were aware of their diagnosis of high cholesterol and were candidates for therapeutic lifestyle changes and/or for treatment with lipid-lowering drug therapy. The percentages who adopted therapeutic lifestyle changes and were taking cholesterol-lowering medications among those who were aware of their diagnosis of having high blood cholesterol and among all those for whom therapeutic lifestyle changes and consideration of drug therapy were recommended according to the NCEP ATP-III guidelines were calculated. The total number of Chinese adults for whom therapeu-

91 1262 The American Journal of Cardiology ( Table 1 Prevalence of coronary heart disease (CHD) or risk equivalents and CHD risk factors in Chinese men and women, aged 35 to 74 years Variable Men Women CHD or risk equivalents Any 9.7% (0.4) 12.2% (0.5) Myocardial infarction/stroke 2.2% (0.2) 1.6% (0.2) Diabetes mellitus 4.8% (0.3) 5.5% (0.3) Angina pectoris 2.8% (0.2) 4.9% (0.3) 10-yr risk of CHD 20% 0.1% (NA) 0.1% (0.1) CHD risk factors* 2 Risk factors 47.6% (0.8) 15.7% (0.6) Cigarette smoking 60.2% (0.8) 6.9% (0.4) Hypertension 28.2% (0.7) 25.6% (0.7) Age 45 yrs in men 61.4% (0.8) 31.0% (0.7) Age 55 yrs in women Family history of CHD 1.6% (0.2) 1.5% (0.2) HDL 40 mg/dl 21.3% (0.6) 15.4% (0.5) HDL 60 mg/dl 23.1% (0.7) 25.9% (0.7) Data are presented as percentages (SEs). * Among participants without coronary heart disease or risk equivalents. NA not applicable (sample size too small [n 20] to permit reliable estimate). Table 2 Prevalence of Adult Treatment Panel III (ATP III) risk categories in adult Chinese population Variable CHD or Risk Equivalents* ATP III Risk Category 2 Risk Factors 0 1 Risk Factor Total 10.9% (0.3) 28.7% (0.5) 60.3% (0.5) Age group (yrs) % (0.4) 11.2% (0.5) 82.2% (0.6) % (0.6) 34.0% (1.0) 54.9% (1.0) % (0.8) 44.3% (1.2) 40.3% (1.2) % (1.2) 47.5% (1.6) 35.4% (1.6) Men 9.7% (0.4) 43.0% (0.8) 47.4% (0.8) Women 12.2% (0.5) 13.8% (0.5) 74.0% (0.7) North 16.0% (0.6) 32.2% (0.8) 51.9% (0.8) South 7.3% (0.4) 26.2% (0.7) 66.5% (0.7) Urban 15.2% (0.5) 29.1% (0.6) 55.7% (0.7) Rural 9.8% (0.4) 28.7% (0.6) 61.5% (0.6) Data are presented as percentages (SEs). * Included diabetes mellitus, angina, and presence of multiple risk factors such that 10-yr risk of CHD calculated by Framingham risk equation is 20%. Included cigarette smoking, hypertension, older age, family history of CHD, and low HDL cholesterol; high HDL cholesterol is protective CHD risk factor and offsets presence of 1 CHD risk factor. Without CHD or risk equivalents. p comparing age groups, men and women, north and south, and urban and rural residence. tic lifestyle changes and drug therapy was recommended according to the NCEP ATP-III guidelines was estimated overall and stratified by gender, area of residence (north, south, urban, and rural), and ATP-III risk category. Additionally, because therapeutic lifestyle changes have the potential to lower LDL cholesterol, we calculated the number and percentage of adults in China for whom drug therapy should be considered according to the NCEP ATP-III guidelines even if their LDL cholesterol were to decrease by 10%. Finally, the percentage and number of adults in China for whom therapeutic lifestyle changes and drug therapy should be considered was calculated using cutpoints determined from a 1997 report published in the Chinese Journal of Cardiology. 3 For this analysis, subjects were considered candidates for therapeutic lifestyle changes and drug therapy if their LDL cholesterol was 100 and 120 mg/dl, respectively, in the presence of CHD or CHD risk equivalents, or was 120 and 140 mg/dl, respectively, in the absence of CHD or CHD risk equivalents but in the presence of 2 CHD risk factors, or was 140 and 160 mg/dl, respectively, in the absence of CHD or CHD risk equivalents in the presence of only 0 to 1 CHD risk factor. All calculations were weighted to the 2000 civilian noninstitutionalized adult population of China using census data. Sampling weights were adjusted on the basis of the proportion of participants without a LDL cholesterol measurement in each age and gender stratum. Using this approach, sampling weights were corrected for differences in missing data across age gender strata, but it was assumed that data within each stratum were missing at random. The survey commands in STATA software (College Station, Texas) were applied to account for the complex sampling design of InterASIA and obtain variance estimates. 10 Results The prevalence of CHD or CHD risk equivalents and 2 CHD risk factors are listed for men and women in Table 1. The most common CHD risk equivalent for men and women was diabetes mellitus. The most common CHD risk factors among men were cigarette smoking and age 45 years. Hypertension and age 55 years were the most common CHD risk factors among women. Table 2 lists the distribution of the InterASIA population into the ATP-III defined CHD risk categories. The presence of CHD or CHD risk equivalents was progressively more common at older age, among women, and in residents of northern and urban areas of China. The presence of 2 CHD risk factors in participants without CHD or CHD risk equivalents was also more common at an older age and in northern China. A higher percentage of men than women had 2 CHD risk factors. The prevalence of 2 CHD risk factors was similar among residents living in urban and rural areas of China. The percentage of the population without a CHD or CHD risk equivalent and with only 0 to 1 CHD risk factor was lower at an older age, among men, and in north and urban areas of China. The percentage of adults in China with a LDL cholesterol level that warranted therapeutic lifestyle changes and drug therapy as defined by the NCEP ATP-III guidelines is listed in Table 3. A low percentage of those in whom

92 Preventive Cardiology/Cholesterol Treatment in China 1263 Table 3 Percentage of Chinese adults in whom therapeutic lifestyle changes and consideration of drug therapy were indicated, were aware of their diagnosis of high blood cholesterol, and were currently undertaking therapeutic lifestyle changes and drug therapy to lower cholesterol Variable Therapeutic Lifestyle Change Consideration of Drug Therapy Recommended Aware* Treated Treated* Recommended Aware* Treated Treated* Total 18.2% (0.4) 10.7% (0.8) 62.0% (3.7) 6.7% (0.6) 7.4% (0.3) 13.4% (1.3) 33.7% (5.4) 4.5% (0.9) Age group (yrs) % (0.5) 5.6% (1.1) 75.5% (6.4) 4.4% (1.1) 3.0% (0.3) 5.4% (1.7) NA NA % (0.8) 11.2% (1.5) 57.6% (7.0) 6.4% (1.2) 6.8% (5.1) 12.8% (2.6) 49.6% (10.9) 6.4% (2.2) % (1.0) 14.2% (1.5) 66.5% (5.3) 9.6% (1.3) 11.8% (0.8) 19.5% (2.7) 22.2% (6.1) 4.3% (1.3) % (1.5) 10.3% (1.8) 53.4% (9.2) 5.5% (1.1) 15.9% (1.2) 12.1% (2.5) 41.6% (11.9) 5.0% (2.2) Men 18.8% (0.6) 10.6% (1.0) 68.3% (4.7) 7.3% (0.9) 6.7% (0.4) 14.4% (2.1) 30.2% (7.6) 4.3% (1.3) Women 17.5% (0.6) 10.7% (1.1) 55.0% (5.6) 6.0% (0.8) 8.2% (0.4) 12.5% (1.7) 37.1% (7.6) 4.6% (1.3) North 26.0% (0.7) 14.5% (1.2) 66.6% (4.4) 9.7% (1.0) 11.3% (0.5) 17.2% (1.9) 35.5% (6.4) 6.1% (1.4) South 12.5% (0.5) 4.8% (0.5) 41.0% (5.4) 2.1% (0.4) 4.6% (0.3) 6.6% (0.9) 25.2% (5.8) 1.7% (0.5) Urban 25.8% (0.6) 15.4% (0.9) 55.3% (3.1) 8.7% (0.7) 11.3% (0.4) 18.8% (1.5) 20.8% (3.5) 3.9% (0.7) Rural 16.2% (0.5) 8.8% (1.0) 66.8% (6.0) 5.9% (0.8) 6.4% (0.3) 11.0% (1.8) 43.5% (8.7%) 4.8% (1.3) Data are presented as percentages (SEs). * Among all patients recommended therapeutic lifestyle changes or consideration of drug therapy. Based on NCEP ATP-III guidelines. Of those aware of their diagnosis of high blood cholesterol. p ; p 0.01; p 0.05, comparing rates across age group (trend), men and women, north and south, and urban and rural residence. NA not applicable (sample size too small [n 20] to permit reliable estimate). Figure 1. Number of Chinese adults who were candidates for therapeutic lifestyle changes or consideration of drug therapy using current LDL cholesterol levels and after 10% reduction in LDL cholesterol. lifestyle changes and drug therapy would be recommended reported being aware of their diagnosis of high blood cholesterol. However, most patients aware of their diagnosis of high LDL cholesterol had initiated therapeutic lifestyle changes, with drug therapy used by approximately 1/3 of patients aware of their diagnosis of high LDL cholesterol. Overall, 10% of Chinese adults for whom therapeutic lifestyle changes and drug therapy to lower LDL cholesterol was indicated were receiving such treatment. The recommendation for therapeutic lifestyle changes and for consideration of drug therapy and the awareness of these recommendations were more common at an older age and in northern and urban areas of China (Table 3). The percentage of men and women for whom therapeutic lifestyle changes was recommended and the rates of awareness were similar for men and women. In contrast, consideration of drug therapy was recommended for a higher percentage of women than men. The adoption of therapeutic lifestyle changes was more common among residents of northern China than their counterparts living in the south. Among all those with elevated LDL cholesterol, the adoption of therapeutic lifestyle changes was more common in urban than in rural areas of China. However, among participants aware of their diagnosis of elevated LDL cholesterol, a higher percentage of rural, than urban, residents were taking drug therapy to lower their blood cholesterol. Finally, drug therapy was more common among northern, than among southern, residents with elevated LDL cholesterol. Overall, 85.9 million Chinese adults had a LDL cholesterol level at which the NCEP ATP-III guidelines recommend therapeutic lifestyle changes (Figure 1). Additionally, 35.0 million Chinese adults had an elevated LDL cholesterol level to the extent that the NCEP ATP-III guidelines recommend consideration of lipid-lowering drug therapy. Most patients for whom drug therapy was indicated had CHD or a CHD risk equivalent. A 10% population-wide reduction in LDL cholesterol would reduce the need for drug therapy by 45% to 19.3 million Chinese residents. Figure 2 presents the number of Chinese adults with an elevated LDL cholesterol who were candidates for therapeutic lifestyle changes and consideration of drug therapy according to NCEP ATP-III recommendations by age group, gender, geographic location, and urban or rural residence. The number of Chinese adults who were candidates for therapeutic lifestyle changes was highest in the 45- to

93 1264 The American Journal of Cardiology ( 54-year age group, and the number for whom drug therapy to lower their LDL cholesterol was indicated was highest in the 55- to 64-year age group. More men than women were candidates for therapeutic lifestyle changes, and consideration of drug therapy was indicated more often for women than for men. A greater number of northern, compared with southern, and rural, compared with urban, residents, respectively, were candidates for therapeutic lifestyle changes and consideration of drug therapy to lower their LDL cholesterol. Using the cutpoints from the 1997 Chinese National Cholesterol Treatment Guidelines, therapeutic lifestyle changes were indicated for million Chinese adults (26.3%) and drug therapy to lower LDL cholesterol was indicated for 63.2 million adults (13.4%). Using these cutpoints, therapeutic lifestyle changes to lower LDL cholesterol were indicated for 34.6 million Chinese adults (67.0%) with CHD or a CHD risk equivalent and 49.5 million (36.4%) and 40.3 million (14.1%) Chinese adults without CHD or a CHD risk equivalent but with 2and0to1CHD risk factors, respectively. The corresponding numbers of Chinese adults who should be considered for drug therapy was 22.6 (43.8%), 24.4 (18.0%), and 16.2 million (5.7%), respectively. Discussion Figure 2. Number of male and female, northern and southern, and urban and rural dwelling Chinese adults who were candidates for therapeutic lifestyle changes and for whom drug therapy should be considered. Table 4 Number (in millions) and percentage of adults, 35 to 74 years old, in United States and China for whom therapeutic lifestyle changes or drug therapy to lower low density lipoprotein (LDL) cholesterol is indicated using National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III) guidelines Variable Therapeutic Lifestyle Changes United States China Consideration of Drug Therapy United States China n % n % n % n % Total % % % % Age group (yrs) % % % % % % % % % % % % % % % % Men % % % % Women % % % % The results of the present study suggest a substantial need for therapeutic lifestyle changes and/or consideration of drug therapy to lower LDL cholesterol levels in the Chinese general population. A high proportion of Chinese adults have a LDL cholesterol level higher than the cutpoints recommended for treatment in the NCEP ATP-III guidelines. Specifically, the results of our study suggest that 85.9 million Chinese adults should undertake therapeutic lifestyle changes and 35.0 million should be considered for drug therapy to lower their LDL cholesterol. However, only a very small proportion of those eligible had undertaken these risk reduction maneuvers. To provide a context for the present results, we compared the findings to corresponding results for the United States obtained from the Third National Health and Nutrition Examination Survey (NHANES III). Overall, a lower percentage of Chinese adults aged 35 to 74 years have elevated LDL cholesterol. Therapeutic lifestyle changes and consideration of drug therapy to lower LDL cholesterol are indicated for 39.1% and 20.1%, respectively, of adults in the United States and 18.2% and 7.4%, respectively, of Chinese adults (Table 4). In contrast, the absolute number of adults for whom therapeutic lifestyle changes and drug therapy to lower their LDL cholesterol is warranted is substantially higher in China than in the United States. Overall, therapeutic lifestyle changes aimed at lowering LDL cholesterol are recommended for 85.9 million Chinese adults 35 to 74 years of age compared with 40.5 million adults in the United States. Furthermore, according to the NCEP guidelines, drug therapy should be considered to lower LDL cholesterol levels in almost twice as many adults in China compared with the United States (35.0 vs 20.8 million, respectively).

94 Preventive Cardiology/Cholesterol Treatment in China 1265 Among the Chinese population with elevated LDL cholesterol, the proportion of subjects aware of this diagnosis and currently receiving treatment for their elevated LDL cholesterol was extremely low (6.7%). A major barrier to awareness of high LDL cholesterol is the low frequency of measuring serum cholesterol in China. According to unpublished data from InterASIA, only 9.6% of the population reported ever having had a blood cholesterol measurement before the survey. The high prevalence of hypercholesterolemia and low awareness of this diagnosis highlights the need for routine blood cholesterol measurements for adults in China. Studies have noted that CHD is the leading cause of mortality worldwide. In 1990, CHD accounted for 6.3 million deaths. 11,12 Additionally, cardiovascular disorders were found to be the leading cause of death in all world regions except India and Sub-Saharan Africa, where it was among the 3 leading causes of death. A recent analysis found that interventions to lower cholesterol concentration, including mass media health and patient-level education and treatment for high cholesterol, are very cost effective strategies. 13 For example, projected costs were as low as $32 per year for disability-adjusted life year saved in economically developing regions that included China. 13 The NCEP ATP-III guidelines provide treatment recommendations based on patients LDL cholesterol levels in conjunction with their absolute CHD risk. However, these guidelines are based on treatment trials and cohort studies from Western populations. A recent study from the Chinese Multi-Provincial Cohort Study indicated a much lower CHD incidence rate in China compared with the population in Framingham, Massachusetts. 8,9 In the present analysis of a representative sample of Chinese adults, 1% of the population had a 10-year CHD risk 20% after calibrating the Framingham risk equation. 8,9 In contrast, using the Framingham risk equation without calibration, 9.7% of men and 1% for women had a 10-year CHD risk 20% (data not shown). Given the differential in 10-year predicted CHD risk among men, it is necessary to understand the magnitude of CHD risk reduction achievable and the associated cost effectiveness of applying the NCEP ATP-III drug treatment guidelines to the Chinese population. Randomized controlled trials have demonstrated the benefit of statin therapy in lowering LDL cholesterol among Chinese adults. A report from China has recommended the use of cutpoints lower than those recommended in the NCEP ATP-III guidelines to initiate treatment. The lower cutpoints result in 63.2 million adults who should be considered for pharmacologic lipid-lowering therapy. Randomized controlled trials and prospective cohort studies should be conducted in the Chinese population to determine who would benefit most from pharmacologic cholesterol-lowering treatment. 1. NCEP Expert Panel. Executive Summary of the Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285: Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation 2004;110: Qi F, Zhonglin W, Tianhai N, Geng S, Zaijia C, Zongliang L, Chuanxiong L, Beifan Z, Junren Z, Yongkang Z, et al. Suggestions of prevention and treatment of dyslipidemia. Chin J of Cardiol 1997;255: He J, Neal B, Gu D, Suriyawongpaisal P, Xin X, Reynolds R, Mac- Mahon S, Whelton PK. International collaborative study of cardiovascular disease in Asia: design, rationale, and preliminary results. Ethn Dis 2004;14: Allain CC, Poon LS, Chan CS, Richmond W, Fu PC. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20: Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1972;18: Perloff D, Grim CE, Flack JM, Frohlich ED, Hill M, McDonald M, Morgenstern BZ. Human blood pressure determination by sphygmomanometry. Circulation 1993;88: Wilson PW, D Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97: Liu J, Hong Y, D Agostino RB Sr, Wu Z, Wang W, Sun J, Wilson PW, Kannel WB, Zhao D. Predictive value for the Chinese population of the Framingham CHD risk assessment tool compared with the Chinese Multi-Provincial Cohort Study. JAMA 2004;291: StataCorp. STATA statistical software, release 6.0. College Station, TX: STATA Corporation, Lopez AD. Assessing the burden of mortality from cardiovascular diseases. World Health Stat Q 1993;46: Murray CJL, Lopez AD. The Global Burden of Disease: A Comprehensive Assessment of Mortality and Disability from Diseases, Injuries, and Risk Factors in 1990 and Projected to Boston: Harvard School of Public Health, 1996: Ezzati M, Hoorn SV, Rodgers A, Lopez AD, Mathers CD, Murray CJ. Estimates of global and regional potential health gains from reducing multiple major risk factors. Lancet 2003;362:

95 Gemfibrozil Reduces Small Low-Density Lipoprotein More in Normolipemic Subjects Classified as Low-Density Lipoprotein Pattern B Compared With Pattern A H. Robert Superko, MD a,b, *, Kaspar K. Berneis, MD c, Paul T. Williams, PhD d, Manfredi Rizzo, MD d,e, and Peter D. Wood, PhD, DSc f We tested the hypothesis that gemfibrozil has a differential effect on low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclass distributions and postprandial lipemia that is different in subjects classified as having LDL subclass pattern A or LDL pattern B who do not have a classic lipid disorder. Forty-three normolipemic subjects were randomized to gemfibrozil (1,200 mg/day) or placebo for 12 weeks. Lipids and lipoproteins were determined by enzymatic methods. The mass concentrations of lipoproteins in plasma were determined by analytic ultracentrifugation and included the S f intervals: 20 to 400 (very LDL), 12 to 20 (intermediatedensity lipoprotein), 0 to 12 (LDL), and HDL 2 mass (F to 9.0) and HDL 3 mass (F to 3.5). Postprandial measurements of triglycerides and lipoprotein(a) were taken after the patients consumed a 500 kcal/m 2 test meal. Treatment with gemfibrozil, compared with placebo, significantly reduced fasting plasma triglycerides (difference from placebo SE; mg/dl, p 0.02), total cholesterol ( mg/dl, p 0.04), apolipoprotein B ( mg/dl, p 0.006), very LDL mass of S f 20 to 400 ( mg/dl, p 0.02), S f 20 to 60 ( mg/dl, p 0.05), S f 60 to 100 ( mg/dl, p 0.05), and increased peak S F ( Svedberg, p 0.08). Gemfibrozil reduced the postprandial triglyceride level significantly at 3 (p 0.04) and 4 (p 0.05) hours after the test meal. A significantly different subclass response to gemfibrozil was observed in those with LDL pattern A versus B. Those with LDL pattern B had a significantly greater reduction in the small LDL mass S f 0to7(p 0.04), specifically regions S f 0to3 (p 0.009) and S f 3to5(p 0.009). In conclusion, normolipemic subjects with either predominantly dense or buoyant LDL respond differently to gemfibrozil as determined by the changes in LDL subclass distribution. Thus, treatment with gemfibrozil may have additional antiatherogenic effects in those with LDL pattern B by decreasing small dense LDL that is not apparent in those with pattern A Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Although subjects classified as having low-density lipoprotein (LDL) subclass pattern A and B have been shown to respond differently to diet and nicotinic acid therapy, 1,2 a differential lipoprotein subclass response to fibrate in normolipemic patients has not been reported. Specifically, we hypothesized that those with LDL pattern B would Methods Subjects and trial design: In a double-blind, randomized, placebo-controlled trial design, 43 normolipemic suba Fuqua Heart Center/Piedmont Hospital, Atlanta, Georgia; b Cholesterol, Genetics, and Heart Disease Institute, Portola Valley, California; c University Hospital Bruderholz, Bruderholz, Switzerland; d Lawrence Orlando Berkeley National Laboratory, University of California, Berkeley, California; e Department of Clinical Medicine and Emerging Diseases, University of Palermo, Palermo, Italy; and f Stanford University School of Medicine, Palo Alto, California. Manuscript received January 31, 2005; revised manuscript received and accepted June 24, This study was supported by Parke Davis Pharmaceuticals, Warner- Lambert Co., Morris Plains, New Jersey. * Corresponding author: Tel: ; fax: address: robert.superko@piedmont.org (H.R. Superko). exhibit significantly greater reductions in fasting plasma concentrations of small, dense LDL and intermediate-density lipoprotein, postprandial lipemia, and a significantly greater increase in high-density lipoprotein (HDL) 2 concentrations compared with identically treated subjects with LDL pattern A. We therefore tested, in a randomized, controlled clinical trial, whether subjects with normolipemic LDL patterns A or B responded differently to gemfibrozil treatment. After a meal, a significant change can occur in postprandial lipemia that may affect coronary artery disease risk. 3 Therefore, we also examined whether the postprandial lipemia response to gemfibrozil treatment was related to the LDL subclass pattern /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

96 Preventive Cardiology/Gemfibrozil Effect on LDL Subclasses 1267 jects (38 men and 5 women; aged 21 to 65 years) were randomized to gemfibrozil (1,200 mg/day) or placebo for 12 weeks after a 6-week American Heart Association phase I diet wash-out period. Subjects were excluded if they had a medical condition or used medications that could influence plasma lipoproteins. Subjects were required to have total cholesterol values of 250 mg/dl and fasting triglyceride values of 300 mg/dl. All participants completed 4-day diet records at baseline and at the end of treatment. These were analyzed for total calories; percentage of calories from fat, carbohydrate, protein, and alcohol; cholesterol content; polyunsaturated/saturated fat ratio; and micronutrients. The body mass index (BMI) was calculated as kilograms of weight divided by height in meters squared. The institutional human use committee approved the study, and all subjects signed an approved informed consent form. A modified definition of the metabolic syndrome was used to explore the potential difference in patients with the metabolic syndrome. 4 Because uncontrolled hypertension and medications that affect plasma lipoproteins were exclusion criteria, hypertension was not present in this population. For the purposes of analysis, the metabolic syndrome was defined as fasting triglycerides of 150 mg/dl and a BMI 25 kg/m 2. Baseline fasting blood samples for lipid and lipoprotein analysis were obtained from the patients after a 12- to 16-hour fast, avoidance of vigorous physical activity, and before the initiation of any therapy. Venous blood samples were drawn with the subject in a sitting position. Postprandial measurements of triglycerides and lipoprotein(a) (Lp(a)) were made after the patients consumed a 500 kcal/m 2 test meal of cream, sugar, and milk that contained 45% of its calories from fat. The test meal was consumed after the fasting blood draw. Additional blood samples were taken at 3, 4, 5, and 8 hours after the test meal while the subjects remained in the clinic area and consumed nothing except water. Laboratory methods: Plasma was prepared from the blood samples within 30 minutes and the blood and plasma samples were kept at 4 C. Plasma lipid and lipoprotein cholesterol concentrations were determined using the methods of the Lipid Research Clinics. 5 Triglycerides, total cholesterol, and lipoprotein cholesterol values were measured by enzymatic procedures (Abbott ABA 200 instrument, Abbott Park, Illinois). HDL cholesterol was determined by the dextran sulfate-magnesium precipitation procedure. 6 LDL cholesterol was calculated from the following equation: LDL cholesterol total cholesterol [HDL cholesterol (triglycerides/5)]. During the study, the laboratory remained standardized for lipid measurements through the Centers for Disease Control National Heart, Lung, and Blood Institute Lipoprotein Standardization Program. 7 The concentrations of lipoproteins in plasma (as total mass) were determined at the Donner Laboratory, University of California at Berkeley, using computer analysis of the results of analytic ultracentrifugation. 8 This technique generates a Schlieren curve, which describes the distribution of lipoproteins according to their high-density flotation (F) and low- to very-low-density flotation (S f ) rates. The intervals include the total lipoprotein mass concentrations of the following S f intervals: 20 to 400 (very-low-density lipoprotein [VLDL]), 12 to 20 (intermediate-density lipoprotein), and 0 to 12 (LDL). The HDL 2 mass and HDL 3 mass were determined as the sum of the flotation intervals F to 9.0 and F to 3.5, respectively. Classification of LDL pattern A versus B was based on whether the LDL peak (S F ) was 5.2 (pattern A) or 5.2 (pattern B). 9 Apolipoprotein A-I and B assays were performed by a competitive enzyme-linked immunoassay procedure using well-characterized and specific monoclonal antibodies. 10,11 Lp(a) concentrations were measured with an enzyme-linked immunosorbent assay kit (Macra Lp(a) Terumo Diagnostics Division, Tokyo, Japan). Internal quality assurance for apolipoproteins was monitored at 2 levels for each analyte on an on-going basis using specifically prepared frozen pools. Throughout the period in which all apolipoprotein measurements were performed, the laboratory participated in the Centers for Disease Control International Union of Immunology Societies apolipoprotein standardization program. 12 Apolipoprotein E isoforms were determined by isoelectric focusing of VLDL apolipoproteins and phenotypes designated according to recommended nomenclature. 13 Statistical analysis: Mean differences between placebo and gemfibrozil were compared using an unpaired t test. Two-way analysis of variance was used to test whether treatment differences in the lipoprotein change between baseline and follow-up were affected by the LDL pattern at baseline. Correction for the change in BMI was performed using analysis of covariance. Results Baseline values: No significant differences were found between the treatment arms for baseline BMI, lipids, apolipoproteins, Lp(a), VLDL mass distribution, intermediatedensity lipoprotein mass distribution, LDL mass distribution, HDL mass distribution, postprandial triglycerides, or Lp(a) (Table 1). The distribution of the apolipoprotein E isoform was not different between groups. Of the patients in the gemfibrozil and placebo groups, 15 and 17 had apolipoprotein E 3/3, 4 and 4 had apolipoprotein E 4/3 or 4/4, and 2 and 1 had apolipoprotein E 2/3, respectively. The treatment arms also did not differ in their nutrient intake at baseline, including dietary cholesterol, total calories, percentage of calories from saturated, unsaturated, and monounsaturated fats, and percentage of calories from carbohydrates and alcohol (analyses not shown). As expected, subjects with pattern B had significantly higher mean triglycerides, VLDL (S F 20 to 400), intermediate-density lipoprotein (S F 12 to 20), and apolipoprotein B and significantly lower HDL cholesterol, HDL 2 mass, HDL 3 mass, and apolipoprotein A-I concen-

97 1268 The American Journal of Cardiology ( Table 1 Baseline lipid, lipoprotein subclasses, and apolipoproteins in the placebo and gemfibrozil groups Variable Gemfibrozil Placebo p Value BMI (kg/m 2 ) Triglycerides (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Apolipoprotein A I (mg/dl) Apolipoprotein B (mg/dl) Lp(a) (mg/dl) LDL mass (mg/dl) S f S f S f S f S f IDL mass S f (mg/dl) VLDL mass (mg/dl) S f S f S f S f LDL peak flotation rate (S f ) HDL mass (mg/dl) F F Postprandial triglycerides (mg/dl) Average h h h h Postprandial Lp(a) (mg/dl) 4 h h Data are presented as means SDs. IDL intermediate-density lipoprotein. trations compared with those with pattern A (Table 2). Patients with pattern B had denser LDL, as reflected by a significantly higher mass for the patient flotation intervals between S f 0 to 5 and significantly lower mass concentrations for patient flotation intervals within S f 7 to 12. They also had higher postprandial triglycerides (p ) than those with pattern A. Fasting and postprandial Lp(a) did not differ by LDL pattern. In the patient group with metabolic syndrome (n 12), 81.8% had LDL pattern B compared with 35.5% in the group without metabolic syndrome (n 31, chi-square p 0.008). At baseline, the metabolic syndrome group had significantly higher fasting triglycerides (p ), apolipoprotein B (p 0.004), dense LDL S f 3to5(p 0.03), VLDL S f 20 to 60 (p 0.003), S f 60 to 100 (p ), and S f 100 to 400 (p ) and significantly lower HDL cholesterol (p 0.02), peak S f (p 0.007), and buoyant LDL S f 7to12(p 0.02). Treatment response: Unexpectedly, a significantly greater reduction occurred in BMI in the gemfibrozil than in the Table 2 Differences between low-density lipoprotein (LDL) patterns A and B at baseline Variable Pattern A (n 22) Pattern B (n 21) P Value BMI (kg/m 2 ) Triglycerides (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Apolipoprotein A I (mg/dl) Apolipoprotein B (mg/dl) Lp(a) (mg/dl) LDL mass (mg/dl) S f S f S f S f S f IDL mass S f 2 20 (mg/dl) VLDL mass (mg/dl) S f S f S f S f LDL peak flotation rate (S f ) HDL mass (mg/dl) F F Postprandial triglycerides (mg/dl) Average h h h h Postprandial Lp(a) (mg/dl) 4 h h Data are presented as means SDs. Abbreviation as in Table 1. placebo group ( kg/m 2,p 0.001). When adjusted for changes in BMI (Table 3), gemfibrozil-treated subjects had significantly greater (mean SE) reductions in plasma concentrations of triglycerides ( mg/ dl), total cholesterol ( mg/dl), apolipoprotein B ( mg/dl), VLDL mass of S f 20 to 400 ( mg/dl), S f 20 to 60 ( mg/dl), and S f 60 to 100 ( mg/dl), and borderline significantly greater increases in peak S F ( Svedberg, p 0.08). In addition, adjustment for BMI also increased the significance of the marginal treatment effects to p 0.05 for LDL mass of S f 5to7( mg/dl) and apolipoprotein A-I ( mg/dl). Gemfibrozil had no significant effect on fasting and postprandial Lp(a). Treatment response by LDL patterns A and B: Table 3 also lists the changes in the gemfibrozil and placebo groups separated by LDL patterns A and B. Analysis for an interaction between phenotype and treatment group re-

98 Preventive Cardiology/Gemfibrozil Effect on LDL Subclasses 1269 Table 3 Effects of gemfibrozil treatment on plasma lipids, lipoprotein subclasses, and apolipoproteins Variable LDL Pattern A LDL Pattern B Significance* Gemfibrozil Placebo Gemfibrozil Placebo Treatment Interaction Triglycerides (mg/dl) Total cholesterol (mg/dl) LDL cholesterol (mg/dl) HDL cholesterol (mg/dl) Apo A I (mg/dl) Apo B (mg/dl) Lp(a) (mg/dl) LDL peak flotation rate (S f ) LDL mass (mg/dl) S f S f S f S f S f IDL mass S f mg/dl VLDL mass (mg/dl) S f S f S f S f HDL 2 mass F mg/dl HDL 3 mass F mg/dl Postprandial triglycerides (mg/dl) Average h h h h Postprandial Lp(a) (mg/dl) 4h h Data are presented as means SEs. * Treatment significance is the difference between combined (pattern A and B) gemfibrozil group compared with placebo (drug effect) adjusted for change in BMI; interaction is interaction between phenotype and treatment group. Abbreviation as in Table 1. vealed a significantly different response to gemfibrozil in those with LDL pattern A versus pattern B. Total small, dense LDL mass S f 0 to 7 and, in particular, the dense regions S f 0to3andS f 3 to 5 were reduced significantly more in those with LDL pattern B compared with those with pattern A. A borderline significant difference was observed for VLDL mass S f 100 to 400 (p 0.07) and HDL 2 mass F to 9.0 (p 0.07). Figure 1 shows that compared with those with pattern A at baseline, gemfibrozil in those with pattern B produced significantly greater decreases in small LDL mass concentrations of S f 0 to 7 (pattern B vs A difference SE vs mg/dl) and, more specifically, LDL of S f 0to3( vs mg/dl) and S f 3to5( vs mg/dl). Treatment response by metabolic syndrome classification: In the gemfibrozil treatment group, no significant difference was found between those classified with or without the metabolic syndrome for changes in BMI and all lipoprotein measurements, with the exception of significantly greater LDL cholesterol (p 0.04) and HDL 2 (F3.5 to 9.0, p 0.08) increases in patients with the metabolic syndrome. Postprandial triglyceride response: Thirty-seven subjects (19 placebo and 18 gemfibrozil) provided postprandial lipoprotein measurements at baseline and the end of treatment. Figure 2 shows the significant differences in fasting and postprandial triglycerides in those with LDL pattern A versus pattern B at baseline. Gemfibrozil had a greater effect on average triglyceride reduction compared with placebo (Table 3). When adjusted for changes in BMI, the reduction in postprandial triglycerides by gemfibrozil was significant for triglycerides at 3 and 4 hours and marginally significant when averaged over the 4 time points. Lp(a) values did not change significantly in the postprandial period. Those with LDL pattern B, compared with pattern A, had significantly greater postprandial triglyceride reduction at 3 and 8 hours. Averaged over the 8-hour postprandial period, those with LDL pattern B had significantly greater triglyceride reduction.

99 1270 The American Journal of Cardiology ( Figure 1. Net effect of 12 weeks of gemfibrozil treatment on LDL mass concentrations by LDL flotation interval in those with LDL patterns A or B. Plotted values are mean differences between gemfibrozil and placebo, and bars represent SE. Figure 2. Baseline difference in postprandial triglyceride (TG) values in those with LDL subclass patterns A or B. Discussion Fibrate therapy has been shown to improve the lipoprotein profile in patients with combined hyperlipidemia and type 2 diabetes mellitus with mixed hyperlipoproteinemia by reducing levels of triglyceride-rich lipoproteins and small dense LDLs and increasing HDL. 14,15 Consistent with other reports, 16,17 we have shown that 1,200 mg/day of gemfibrozil reduced fasting triglycerides by 40% (p 0.02), LDL cholesterol by 5% (p NS), and increased HDL cholesterol by 6% (p NS). At the end of treatment, BMI had decreased significantly more in the gemfibrozil group than in the placebo group. However, after statistical adjustment for the change in BMI, the differences in triglycerides, total cholesterol, small LDL and apolipoprotein B remained significantly different between the gemfibrozil and placebo groups. The greatest percentage of reduction in lipoproteins was in the very largest VLDL particles (S f 100 to 400, 73% reduction) and intermediate-size VLDL particles (S f 60 to 100, 58% reduction). The percentage of reduction in smaller VLDL particles (S f 20 to 60, 16% reduction) was only 1/2 the magnitude (29% reduction) as the reduction in larger VLDL particles. This suggests a preferential reduction of the largest VLDL particles. This may account for the smaller triglyceride reduction in normolipidemic subjects who have less VLDL between S f 60 to 400 than do dyslipidemic subjects. The atherogenic lipoprotein profile is characterized by elevated triglycerides, VLDL, intermediate-density lipoprotein, low HDL, insulin resistance, and an abundance of small, dense LDL particles, termed pattern B. 18 Our primary hypothesis was to test whether the response was significantly different from gemfibrozil treatment in patients without classic hyperlipidemia who were classified as having either LDL pattern B or A with regard to improvements in lipoprotein subclasses and fasting and postprandial lipoprotein concentrations. Our analyses indicated that gemfibrozil produced significantly greater reductions in small LDL in those subjects who were initially classified as having LDL pattern B compared with those with pattern A. The results were unlikely to be a result of regression to the mean because the differential response was revealed in a controlled study (i.e., regression to the mean would affect the gemfibrozil and placebo conditions equally). The plasma concentrations of baseline LDL S f 0to3andS f 3to5and the LDL peak flotation rate were similar in the gemfibrozil and placebo groups. No significant treatment by LDL pattern interaction was found for baseline S f 0to3andS f 3to 5. The decrease in small dense LDL in those with pattern B was confirmed by gradient gel electrophoresis (data not shown). These observations all argue against the differential response being a result of regression to the mean. The lipoprotein subclass distribution characteristics of LDL patterns B and A in this normolipemic sample exhibited the same characteristic lipoprotein subclass profile as has been reported for hyperlipidemic populations. At baseline, fasting apolipoprotein B and fasting and postprandial triglycerides were significantly higher in subjects with LDL pattern B versus A and HDL cholesterol and apolipoprotein A to I were lower in subjects with pattern B versus A. No differences were found in total cholesterol, LDL cholesterol, or Lp(a) by LDL pattern. The LDL and HDL subclass distributions revealed a predominance of dense LDL, greater intermediate-density lipoprotein (S F 12 to 20), greater postprandial lipemia, and less HDL 2 (F to

100 Preventive Cardiology/Gemfibrozil Effect on LDL Subclasses ) in those with pattern B compared with those with pattern A. The metabolic syndrome, like the LDL pattern B, is associated with elevated triglycerides and VLDL. 4,19 This study revealed that the atherogenic lipoprotein profile, characterized by an abundance of VLDL, small LDL, and reduced HDL 2, exists in 36% of patients without the metabolic syndrome. In this study, the lipoprotein subclass distribution changes induced by gemfibrozil were not significantly different in patients with or without the metabolic syndrome. The postprandial triglyceride response revealed a significant reduction in the average postprandial triglycerides of 30% in response to gemfibrozil compared with placebo. This reduction was significant at 3 and 4 hours after the test meal. Those with LDL pattern B exhibited significantly greater postprandial triglyceride reduction in response to gemfibrozil compared with those with LDL pattern A. No effect was found of the fat load on Lp(a) and no effect of gemfibrozil on Lp(a). Conflicting studies have reported that Lp(a) may, or may not, increase after a meal Our study results extend this observation to healthy patients with LDL pattern B or A. The clinical significance of this investigation is linked to the importance of lipoprotein subclass distribution and postprandial lipemia to clinical events and arteriographic outcomes. The plasma lipoprotein profile accompanying a predominance of small dense LDL particles is associated with approximately a 3-fold increased risk of coronary artery disease. This has been demonstrated in case-control studies of myocardial infarction and angiographically documented coronary disease In several of these studies, the disease risk associated with small dense LDL was no longer significant after adjusting for covariates, including triglycerides or other risk factors. However, statistical analysis of these trials has indicated that the LDL peak particle diameter is a coronary artery disease risk factor independent of traditional lipid risk factors. 27 Also, a 13-year follow-up study of the Quebec Cardiovascular Study has reported a strong and independent association between small LDL levels and coronary artery disease risk in men. 28 The presence of an abundance of dense, small LDL particles identifies a high-risk group (LDL pattern B) that may benefit from a differential response to treatment with regard to LDL and HDL subclass distribution, as we have demonstrated for the first time in this investigation in a normolipidemic population. The Helsinki investigation hinted at such a possibility when they reported a 34% reduction in clinical events in all men treated with gemfibrozil, but in men with a baseline triglycerides 204 mg/dl and a LDL cholesterol/hdl cholesterol ratio 5, a 71% reduction in clinical events was reported. 29 The elevated triglycerides and high total cholesterol/hdl cholesterol ratio in this Helsinki subgroup suggest the effect would be enriched in those with LDL pattern B. Our investigation suggests that part of this enhanced benefit attributed to gemfibrozil in this Helsinki subset may have been due to the greater effect of gemfibrozil on small, dense LDL in those with pattern B compared with those with pattern A. Investigations using arteriographic change as an outcome variable have reported that arteriographic progression in the control group is significantly greater in patients with a predominance of small, dense LDL and that arteriographic benefit is concentrated in patients with a predominance of small, dense LDL who receive treatment that tends to lower small dense LDL Gemfibrozil improves the abnormal lipoprotein subclass distribution in normolipidemic patients with a predominance of dense, small LDL (LDL pattern B). The differential effect of gemfibrozil on lipoprotein subclasses in those with pattern B may help explain the greater reduction in clinical end points reported in subsets of patients in clinical trials with triglyceride and HDL cholesterol parameters likely to reflect a predominance of subjects with the LDL subclass pattern B trait. 1. Dreon DM, Fernstrom H, Miller B, Krauss RM. Low density lipoprotein subclass patterns and lipoprotein response to a reduced-fat diet in men. 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The Center for Disease Control-National Heart, Lung and Blood Institute Lipid Standardization Program: an approach to accurate and precise lipid measurements. Clin Lab Med 1989;9: Lindgren FT, LCJ, Hatach FT. The isolation and quantitative analysis of serum lipoproteins. In: Nelson GJ, ed. Blood Lipids and Lipoproteins: Quantitation, Composition and Metabolism. New York: Wiley- Interscience, 1972: Miller BD, Alderman EL, Haskell WL, Fair JM, Krauss RM. Predominance of dense low-density lipoprotein particles predicts angiographic benefit of therapy in the Stanford Coronary Risk Intervention Project. Circulation 1996;94: Hogle DM, Smith RS, Curtiss LK. Quantitation of plasma apolipoprotein A-I using two monoclonal antibodies in an enzyme-linked immunosorbent assay. J Lipid Res 1988;29: Young SG, Smith RS, Hogle DM, Curtiss LK, Witztum JL. Two new monoclonal antibody-based enzyme-linked assays of apolipoprotein B. Clin Chem 1986;32: Cooper GR, Smith SJ, Wiebe DA, Kuchmak M, Hannon WH. 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101 1272 The American Journal of Cardiology ( 14. Guerin ME, Bruckert PJ, Dolphin G, Turpin MJ, Chapman MJ. Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol 1996;16: Frost RJ, Otto C, Geiss HC, Schwandt P, Parhofer KG. Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia. Am J Cardiol 2001;87: Robins SJ, Collins D, Wittes JT, Papademetriou V, Deedwania PC, Schaefer EJ, McNamara JR, Kashyap ML, Hershman JM, Wexler LF, Rubins HB. Relation of gemfibrozil treatment and lipid levels with major coronary events: VA-HIT a randomized controlled trial. JAMA 2001;285: Gotto AM Jr, Breen WJ, Corder CN, Dunn JK, Goldberg A, Knopp RH, Schrott H, Sprecher D, for the Lopid SR Work Group I. Oncedaily, extended-release gemfibrozil in patients with dyslipidemia. Am J Cardiol 1993;71: Superko HR, Chronos NA. Hypercholesterolemia and dyslipidemia. issues for clinicians. Curr Treatment Options CV Med 2004;5: Isomaa B, Henricsson M, Almgren P, Tuomi T, Taskinen MR, Groop L. The metabolic syndrome influences the risk of chronic complications in patients with type II diabetes. Diabetologia 2001;44: Pfaffinger D, Schuelke J, Kim C, Fless GM, Scanu AM. Relationship between Apo[a] isoforms and Lp[a] density in subjects with different Apo[a] phenotype: a study before and after a fatty meal. J Lipid Res 1991;32: Cohn JS, Lam CW, Sullivan DR, Hensley WJ. Plasma lipoprotein distribution of apolipoprotein(a) in the fed and fasted states. Atherosclerosis 1991;90: Hoppichler F, Kraft HG, Sandholzer C, Lechleitner M, Patsch JR, Utermann G. Lipoprotein(a) is increased in triglyceride-rich lipoproteins in men with coronary heart disease, but does not change acutely following oral fat ingestion. Atherosclerosis 1996;122: Miller BD, Alderman EL, Haskell WL, Fair JM, Krauss RM. Predominance of dense low-density lipoprotein particles predicts angiographic benefit or therapy in the Stanford Coronary Risk Intervention Project. Circulation 1996;94: Stampfer MJ, Krauss RM, Blanche PJ, Holl LG, Sacks FM, Hennekens CH. A prospective study of triglyceride level, low density lipoprotein particle diameter, and risk of myocardial infarction JAMA 1996; 276: Gardner CD, Fortmann SP, Krauss RM. Association of small lowdensity lipoprotein particles with the incidence of coronary artery disease in men and women. JAMA 1996;276: Lamarche B, Tchernof A, Moorjani S, Cantin B, Dagenais GR, Lupien PJ, Despres JP. Small, dense low-density lipoprotein particles as a predictor of the risk of ischemic heart disease in men: prospective results from the Quebec cardiovascular study. Circulation 1997;95: Austin MA. Triglyceride, small, dense low-density lipoprotein, and the atherogenic lipoprotein phenotype. Curr Atheroscler Rep 2000;2: St. Pierre AC, Cantin B, Dagenais GR, Mauriege P, Bernard PM, Despres JP, Lamarche B. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men. Arterioscler Thromb Vasc Biol 2005;25: Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Manttari M, Heinonen OP, Frick MH. Joint effects of serum triglyceride and LDL cholesterol and HDL cholesterol concentrations on coronary heart disease risk in the Helsinki Heart Study: implications for treatment. Circulation 1992;85: Krauss RM. Relationship of intermediate and low-density lipoprotein subspecies to risk of coronary artery disease. Am Heart J 1987;113(2 Pt 2): Watts GF, Mandalia S, Brunt JN, Slavin BM, Coltart DJ, Lewis B. Independent associations between plasma lipoprotein subfraction levels and the course of coronary artery disease in the St. Thomas Atherosclerosis Regression Study (STARS). Metabolism 1993;42: Haskell WL, Alderman EL, Fair JM, Superko HR, Maron DJ, Champagne MA, Mackey SF, Williams PT, Krauss RM, Farquhar JW. Beneficial angiographic and clinical response to multifactor modification in the Stanford Coronary Risk Intervention Project (SCRIP). Circulation 1994;89: Zambon A, Hokanson JE, Brown BG, Brunzell JD. Evidence for a new pathophysiological mechanism for coronary artery disease regression: hepatic lipase-mediated changes in LDL density. Circulation 1999;99: Williams PT, Superko HR, Haskell WL, Alderman EA, Blanche PJ, Holl LG, Krauss RM. Smallest LDL particles are most strongly related to coronary disease progression in men. Arterioscler Thromb Vasc Biol 2003;23:

102 Relation of Plasma Glucose and Endothelial Function in a Population-Based Multiethnic Sample of Subjects Without Diabetes Mellitus Carlos J. Rodriguez, MD, MPH a,d, *, Yumiko Miyake, MD a, Cairistine Grahame-Clarke, MD a, Marco R. Di Tullio, MD a, Robert R. Sciacca, EngScD a, Bernadette Boden-Albala, DrPH b,e, Ralph L. Sacco, MD, MS b,c, and Shunichi Homma, MD a To determine whether endothelial dysfunction precedes the clinical diagnosis of diabetes mellitus, we investigated the relation of endothelial flow-mediated dilation (FMD) with fasting plasma glucose among a multiethnic population-based cohort of 579 nondiabetic subjects without previous myocardial infarction or stroke enrolled in the Northern Manhattan Study (age 66 9 years; 41% men, 16% white, 15% black, and 68% Hispanic). Impaired fasting glucose or prediabetic status, defined as a fasting glucose level of 100 to 125 mg/dl, was present in 95 subjects (16%). Endothelial function was determined using FMD during reactive hyperemia. Multiple linear regression analyses were used to assess the relation between plasma glucose and endothelial function after adjustment for potential confounders. FMD was significantly lower ( % vs %, p 0.003) in those with impaired fasting glucose than in subjects with normal fasting glucose. Prediabetic status was significantly associated with impaired FMD (odds ratio 1.9, 95% confidence interval 1.1 to 3.1, p 0.02). After adjustment for age, gender, body mass index, and hypertensive status, a higher fasting glucose was significantly associated with a lower FMD ( , p 0.04) in a continuous linear relation. Thus, for each 10-mg/dl increase in plasma glucose, a 0.24% decrease occurred in FMD. Impaired FMD was present among prediabetics. An elevated fasting plasma glucose level is associated with impaired endothelial function among nondiabetics. These results further support the role of hyperglycemia in the pathogenesis of vascular dysfunction at different stages of diabetes development and the role of impaired fasting glucose as a risk factor for macrovascular disease Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) It is well known that endothelial dysfunction precedes the onset of overt cardiovascular disease. 1 Because the hyperglycemic diagnosis of impaired fasting glucose (IFG) precedes the onset of frank diabetes, nitric oxide synthesis could also be impaired in the prediabetic state. Thus, we investigated whether hyperglycemia influences endothelial function among nondiabetic subjects. The Northern Manhattan Study (NOMAS) was designed as a prospective cohort study of stroke risk factors among a tri-ethnic (white, black, and Hispanic) urban population. The methods of subject recruitment and enrollment in the NOMAS have been described in previous publications. 2,3 In Departments of a Medicine and b Neurology and c Sergievsky Center, Columbia University College of Physicians and Surgeons; and d Department of Epidemiology and e Department of Sociomedical Science, Columbia University Mailman School of Public Health, New York, New York. Manuscript received February 11, 2005; revised manuscript received and accepted June 20, This project was supported in part by Grant R0I NS from the National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. * Corresponding author: Tel: ; fax: address: cjr10@columbia.edu (C.J. Rodriguez). brief, random digit dialing of approximately 25,000 households was performed by Audits and Surveys (Langhorne, Pennsylvania). Community participants were enrolled in the NOMAS if they had never been diagnosed with stroke, were 40 years old, and had resided in Northern Manhattan for 3 months in a household with a telephone. The institutional review board at Columbia University Medical Center approved the study. Trained research assistants collected information about risk factors through standardized interviews, and the study physicians performed physical and neurologic examinations. Standard techniques were used to measure blood pressure, height, weight, fasting lipid panels, and fasting glucose, as described in previous publications. 2,3 Hypertension was defined as a systolic blood pressure of 140 mm Hg or a diastolic blood pressure of 90 mm Hg or the patient s self-report of a history of hypertension or antihypertensive use. Diabetes mellitus was indicated by a fasting plasma glucose (FPG) value 126 mg/dl, the subject s selfreport of such a history, or insulin or oral hypoglycemic medication use. The most recent American Diabetes Association criteria for the diagnosis of IFG or prediabetes included the new cut-off points of FPG 100 and 126 mg/dl. 4 Arterial endothelial function was noninvasively assessed as /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

103 1274 The American Journal of Cardiology ( the brachial artery response to flow-mediated dilation (FMD) during reactive hyperemia using high-resolution B-mode ultrasonography. 5 Subjects were evaluated in a quiet, temperature-controlled room. Electrocardiographic leads were connected, and the signal was displayed on a monitor. The brachial artery was longitudinally imaged 6 cm above the antecubital fossa using a 15-MHz linear array probe (Hewlett- Packard Sonos 5500, Hewlett-Packard, Andover, Massachusetts). Magnified images were gated to the R wave of the electrocardiographic QRS complex, and the flow velocities at the mid-artery were estimated using pulsed Doppler. Forearm ischemia was induced by interrupting the arterial blood supply with a cuff inflated to suprasystolic pressures (approximately 250 mm Hg) for 3 minutes. Reactive hyperemia was induced by the quick release of the cuff while images of the brachial artery were recorded on S-VHS tapes for 30 seconds before and 90 seconds after cuff deflation. Immediately after the cuff release, arterial flow velocity was measured for 10 seconds to confirm induction of increased flow velocity. An automatic cuff inflator/deflator and a blood pressure monitor (Hokanson E20 rapid cuff inflator, Bellvue, Washington; AG101 inflator air source, and Critikon Dinamap vital sign monitor, Critikon, Tampa, Florida) were used to minimize the variability in the procedure associated with cuff inflation/deflation. All studies were analyzed offline by a reader blinded to the subjects clinical status. End-diastolic frames were digitized at baseline and 60 seconds after cuff deflation by a digital frame grabber. The arterial diameter was then measured using a digital caliper at a comparable site at baseline and after cuff release (model LG3, Scion, Frederich, Maryland). Five points along the brachial artery anterior wall (media adventitia interface) and posterior wall were manually chosen by the reader. Three consecutive cardiac cycles were analyzed for the baseline and hyperemia studies of each subject and the measurements averaged. FMD was determined as the maximal percentage of change of the post-occlusion arterial diameter relative to the mean baseline measurement. The percentage of change in the vessel diameter after reactive hyperemia was calculated according to the following algorithm: [(brachial artery diameter at hyperemia brachial artery diameter at baseline)/brachial artery diameter at baseline] 100. Intra- and interobserver variabilities in endothelial reactivity measurements are 1.3% and 2.7%, respectively (n 15). For subjects with IFG and a normal fasting glucose, means were calculated for continuous variables and proportions for categorical variables. Univariate comparisons were performed using t tests for continuous data and the chisquare test for categorical data. Simple and multiple linear regression analyses were then used to analyze the association between blood glucose and endothelial reactivity before and after adjusting for potential confounding demographic and medical variables, including age, gender, body mass index, hypertensive status, current cigarette smoking, and total cholesterol, high-density cholesterol, triglyceride, and low-density lipoprotein levels. Analysis of variance was Table 1 Cohort demographics Fasting Glucose Normal (n 484) Impaired (n 95) p Value Age (yrs) Women/men 58%/42% 62%/38% 0.57 Body mass index (kg/m 2 ) Hypertension 61% 71% 0.08 Cigarette smoking 15% 17% 0.79 Total cholesterol (mg/dl) Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Triglycerides (mg/dl) Fasting plasma glucose (mg/dl) Baseline arterial diameter (mm) Table 2 Regression coefficients of univariate linear regression analysis between vascular function and clinical variables Variable Estimate SE p Value Age (yrs) Gender* Body mass index Cigarette smoking Hypertension Total cholesterol (mg/dl) Low-density lipoprotein (mg/dl) High-density lipoprotein (mg/dl) Triglycerides (mg/dl) * Men were the reference group. Nonsmokers were the reference group. Nonhypertensives were the reference group. performed to investigate the effect of differing glucose values on FMD within the IFG and normal groups. FMD below the upper tertile ( 7.5%) was associated with a higher risk of myocardial infarction, stroke, and vascular death in our cohort. 6 Thus, abnormal or impaired FMD was defined as 7.5% for categorical analysis. Statistical significance was determined at the 0.05 level using 2-sided tests. Statistical analyses were conducted using Statistical Analysis Systems, version 8.2, computer software (SAS Institute, Cary, North Carolina). Endothelial function measurements were obtained in 909 subjects, 64 of whom were excluded from the analysis because of a previous myocardial infarction. Of the remaining 846, 187 were diabetic and 80 were not fasting at the glucose blood draw, leaving 579 nondiabetic subjects whose fasting blood glucose was available for analysis. The mean age of the total cohort was 66 9 years; 59% were women, and 68% were Hispanic, 15% black, and 16% white. Most had hypertension (62%), and the mean body mass index was kg/m 2. Table 1 lists the patient characteristics and laboratory results by glucose category. Total cholesterol and triglyceride levels were significantly higher among subjects with IFG. Age, gender, body mass

104 Preventive Cardiology/Endothelial Function and Glucose in Nondiabetics 1275 Table 3 Predictors of endothelial dysfunction multiple linear regression analysis* Variable Estimate SE p Value Age (yrs) Gender Body mass index Hypertension Glucose (mg/dl) Figure 1. Relation of plasma glucose to endothelial reactivity. * Variables used for the multivariate model included age, gender, and all significant (p 0.05) univariate predictors; when low-density lipoprotein, high-density lipoprotein, and triglycerides (log transformed) were included in model, effect of glucose failed to reach significance (p 0.068). Men were the reference group. Nonhypertensives were the reference group. Figure 2. Odds ratios for abnormal flow-mediated brachial artery dilation by fasting glucose level. A fasting glucose category of 90 mg/dl was the referent. CI confidence interval. index, hypertensive status, current cigarette smoking, baseline brachial artery diameter, low-density lipoprotein level, and high-density cholesterol level were not significantly different, irrespective of glucose category. Table 2 lists the associations of FMD with the other variables tested by univariate linear regression analysis. Age, body mass index, and hypertensive status correlated significantly with FMD. Fasting glucose showed a modest, yet statistically significant, continuous linear inverse association with FMD (Figure 1). For example, for every 25 mg/dl increase in fasting glucose (approximately 2 SDs), a 0.8% decrease occurred in FMD. Figure 2 shows an evident trend in risk of impaired FMD by fasting glucose level. To assess the independent association of fasting blood glucose or hyperglycemia with FMD, multivariate linear regression analysis was used. Multivariate analysis controlling for all the univariate predictors of FMD (age, body mass index, and hypertensive status) revealed that higher fasting blood glucose independently predicted decreased FMD ( 0.024, p 0.042; Table 3). To analyze the effect of glucose category on the percentage of change in brachial artery diameter in response to reactive hyperemia, we compared the mean FMD by glucose category. Figure 3. Endothelial reactivity according to FPG category. Comparison of FMD levels among different FPG categories ( 90, 90 to 99, 100 to 109, and 110 to 125 mg/dl), with significant (p 0.05) differences between 110 to 125 and 90 and 90 to 99 mg/dl. The mean FMD was significantly higher (6.1% 3.7%) in the 478 subjects with normal fasting glucose levels than in the 95 prediabetic subjects (4.9% 3.8%, p 0.003) with IFG. Thus, prediabetic status was associated with a 25% decrease in endothelial function compared with subjects with a normal fasting glucose. Prediabetic status also significantly increased the risk of having abnormal FMD (odds ratio 1.9, 95% confidence interval 1.1 to 3.1, p 0.02). These associations remained significant on multivariate analysis, including age, gender, hypertensive status, total cholesterol level, low-density lipoprotein level, high-density cholesterol level, triglyceride level, and body mass index (p 0.01 and p 0.04, respectively). Within the glucose range of 110 to 125 mg/dl, FMD was significantly reduced compared with a glucose level of 90 or 90 to 99 mg/dl (p 0.05; Figure 3). FMD within the glucose range of 100 to 109 mg/dl was not significantly reduced. The results of this study demonstrate that in a multiethnic nondiabetic population free of overt cardiovascular disease, FPG has an inverse, linear, and independent correlation with

105 1276 The American Journal of Cardiology ( endothelial function as measured by FMD. Thus, elevated FPG confers risk on a continuous scale. In particular, prediabetics as defined by the new American Diabetes Association criteria had significantly worse endothelial function than those with normal FPG levels. Previous studies of small, selected populations have also suggested that patients with abnormal, although nondiabetic, glucose homeostasis have worsened endothelial function. 7 9 Our study, however, is the largest to measure FMD systematically and correlate it with fasting glucose levels in a multiethnic, population-based cohort of nondiabetic subjects, and the first to do this using the new American Diabetes Association criteria for IFG. It is becoming clear that diabetes mellitus is just the tip of the iceberg, with prediabetic patients sharing an increased risk of cardiovascular disease. 10 In 1 study, prediabetic status was a powerful predictor of outcome, with 7-year survival rates similar to that of patients with overt diabetes. 11 We found that endothelial dysfunction exists among prediabetics. Prediabetic and diabetic subjects alike have subclinical atherosclerotic disease likely related to prolonged and repeated exposure of the vessel wall to hyperglycemia, which may be present for many years, thus contributing to the risk of subsequent macrovascular complications. 12,13 Recently, the American Diabetes Association changed its criteria for defining IFG, lowering the fasting glucose cutoff from 110 to 100 mg/dl. 4 By doing so, the number of prediabetic patients in the United States has substantially increased. Using the National Health and Nutrition Examination Survey data set (total population of 182 million) to evaluate the affect, 14 IFG prevalence has increased from 6.7% to 24.1% (an increase equivalent to 30 million patients). Endothelial dysfunction has been shown to be predictive of cardiovascular events. 15,16 Our findings further emphasize that prediabetic patients should be focused on and targeted for lifestyle interventions (e.g., diet and exercise) to control glycemia and possibly normalize endothelial function and stop progression to frank diabetes and cardiovascular disease. A recent study demonstrated that among overweight nondiabetic subjects, the decrease in plasma glucose concentration induced by weight loss was associated with an improvement in endothelial function. 17 Another study showed that using thiazolidinediones in prediabetic subjects decreased levels of asymmetric dimethylarginine, an nitric oxide synthase inhibitor, improving endothelial function. 18 Thus, pharmacologic intervention among prediabetics may also be of benefit. Furthermore, monitoring endothelial function may have clinical use to guide risk reduction therapy in these patients. Enhanced endothelial function (by sequential testing of FMD) in response to an intervention has identified a group of patients who have an improved cardiovascular prognosis. 19 This needs to be studied further among prediabetics. Given that our study was cross-sectional, the chronologic sequence of events could not be assessed. However, it is unlikely that the outcome (FMD) caused the predictor (hyperglycemia). Although it is possible that another process causes FMD and hyperglycemia separately, we attempted to adjust for potential confounders in our multivariate model. Neither a history of ever smoking nor current smoking was related to FMD in our cohort. Biochemical measurements to determine tobacco use may have been useful, given a possible bias or inaccuracy in smoking status determined by subject recall. Another limitation of our study was that serum measurements of C-reactive protein, insulin levels, and oxidative stress (e.g., thiobarbituric acid-reactive substances) were not obtained. Although the role of plasma glucose in endothelial dysfunction may be direct, glucose may also be a marker for these other concomitant abnormalities. In this large, multiethnic population-based cohort, hyperglycemia was independently associated with endothelial dysfunction among nondiabetics with IFG. Prediabetic subjects had significantly worse endothelial function than subjects with normal fasting glucose levels. This further supports the role of hyperglycemia in the pathogenesis of vascular dysfunction at different stages of the development of diabetes, suggesting that exposure of the endothelium to hyperglycemia plays an important role in the development of atherosclerosis even among prediabetics. 1. Widlansky ME, Gokce N, Keaney JF Jr, Vita JA. The clinical implications of endothelial dysfunction. J Am Coll Cardiol 2003;42: Sacco RL, Gan R, Boden-Albala B, Lin IF, Kargman DE, Hauser WA, Shea S, Paik MC. Leisure-time physical activity and ischemic stroke risk: the Northern Manhattan Stroke Study. Stroke 1998;29: Rodriguez CJ, Sacco RL, Sciacca RR, Boden-Albala B, Homma S, Di Tullio MR. Physical activity attenuates the effect of increased left ventricular mass on the risk of ischemic stroke: the Northern Manhattan Stroke Study. J Am Coll Cardiol 2002;39: Genuth S, Alberti KG, Bennett P, Buse J, Defronzo R, Kahn R, Kitzmiller J, Knowler WC, Lebovitz H, Lernmark A, et al. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2003;26: Corretti MC, Anderson TJ, Benjamin EJ, Celermajer D, Charbonneau F, Creager MA, Deanfield J, Drexler H, Gerhard-Herman M, Herrington D, et al. Guidelines for the ultrasound assessment of endothelial-dependent flow-mediated vasodilation of the brachial artery: a report of the International Brachial Artery Reactivity Task Force. JAm Coll Cardiol 2002;39: Grahame-Clarke C, Rodriguez CJ, Sacco RL, Sciacca RR, Boden- Albala B, DiTullio MR, Homma S. Endothelial dysfunction predicts cardiovascular events in a multi-ethnic population (Northern Manhattan Study) (abstr). J Am Coll Cardiol 2004;42(suppl):475A. 7. Quinones MJ, Hernandez-Pampaloni M, Schelbert H, Bulnes-Enriquez I, Jimenez X, Hernandez G, De La Rosa R, Chon Y, Yang H, Nicholas SB, et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Intern Med 2004;140: Thomas GN, Chook P, Qiao M, Huang XS, Leong HC, Celermajer DS, Woo KS. Deleterious impact of high normal glucose levels and other metabolic syndrome components on arterial endothelial function and intima-media thickness in apparently healthy Chinese subjects: the CATHAY study. Arterioscler Thromb Vasc Biol 2004;24: Vehkavaara S, Seppala-Lindroos A, Westerbacka J, Groop PH, Yki- Jarvinen H. In vivo endothelial dysfunction characterizes patients with impaired fasting glucose. Diabetes Care 1999;22:

106 Preventive Cardiology/Endothelial Function and Glucose in Nondiabetics Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care 2002;25: Gerstein HC, Pais P, Pogue J, Yusuf S. Relationship of glucose and insulin levels to the risk of myocardial infarction: a case-control study. J Am Coll Cardiol 1999;33: Hsueh WA, Quinones MJ. Role of endothelial dysfunction in insulin resistance. Am J Cardiol 2003;92:10J 17J. 13. Hunt KJ, Williams K, Rivera D, O Leary DH, Haffner SM, Stern MP, Gonzalez Villalpando C. Elevated carotid artery intima-media thickness levels in individuals who subsequently develop type 2 diabetes. Arterioscler Thromb Vasc Biol 2003;23: Davidson MB, Landsman PB, Alexander CM. Lowering the criterion for impaired fasting glucose will not provide clinical benefit. Diabetes Care 2003;26: Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G. Prognostic significance of endothelial dysfunction in hypertensive patients. Circulation 2001;104: Quyyumi AA. Prognostic value of endothelial function. Am J Cardiol 2003;91(suppl):19H 24H. 17. Raitakari M, Ilvonen T, Ahotupa M, Lehtimaki T, Harmoinen A, Suominen P, Elo J, Hartiala J, Raitakari OT. Weight reduction with very-low-caloric diet and endothelial function in overweight adults: role of plasma glucose. Arterioscler Thromb Vasc Biol 2004;24: Nash DT. Insulin resistance, ADMA levels, and cardiovascular disease. JAMA 2002;287: Modena MG, Bonetti L, Coppi F, Bursi F, Rossi R. Prognostic role of reversible endothelial dysfunction in hypertensive postmenopausal women. J Am Coll Cardiol 2002;40:

107 Experience With Statin Use in Patients With Chronic Hepatitis C Infection Kimberly Gibson, PharmD a, and Joseph P. Rindone, PharmD b, * We reviewed the liver enzymes of patients with chronic hepatitis C infection currently taking statin drugs. We found no significant elevation of liver enzymes during statin treatment of the 17 patients reviewed Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) The prevalence of hepatitis C virus (HCV) infection has been estimated to be 1.8% of the general population, meaning that millions of individuals in the United States are affected. 1 It is inevitable that many of these patients will have concomitant hypercholesterolemia that may require the use of lipid-lowering drugs, in particular, statins. To our knowledge, no data have shown whether statin drugs are deleterious in patients with HCV infection, especially concerning liver function. We, therefore, undertook a review of patients with HCV infection at our facility who were taking statins to assess whether statin use was associated with a significant elevation of liver enzymes. We also examined patients with HCV infection who were not taking statins to ascertain whether these drugs had been previously discontinued because of hepatic side effects. All patients with the diagnosis of chronic HCV infection without hepatic coma (International Classification of Diseases-9 [ICD-9]code ) and those who were hepatitis C antibody-positive (ICD-9 code ) were reviewed. Those patients taking a statin drug were included for detailed analysis. The medical records of these patients were reviewed for the type of statin used, the latest dose, baseline (when available) aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, maximum AST and ALT levels, most recent AST and ALT levels, and duration of statin use (up to the time of the last liver profile). The upper limit of normal for AST and ALT is 47 and 72 IU/L, respectively, in our laboratory. In addition, quantitative HCV ribonucleic acid, as measured by polymerase chain reaction, was collected when HCV was diagnosed. Patients who underwent a course of antiviral therapy were noted. The medical records of patients not taking a statin were also reviewed for possible documentation of previous statin intolerance due to hepatic side effects. A total of 219 patients with a diagnosis of HCV were identified. Of the 219 patients, 17 were identified as using statin (Table 1). All were men, with a mean age of 58 9 years. All statin users were taking simvastatin, with the mean dose (latest) of mg/day. Nine patients had been taking lovastatin initially before changing to simvaa Flagstaff Medical Center, Flagstaff, Arizona; and b Northern Arizona Veterans Affairs Health Care System, Prescott, Arizona. Manuscript received March 4, 2005; revised manuscript received and accepted June 20, * Corresponding author: Tel: ; fax: address: Joseph.Rindone@med.va.gov (J. Rindone). Table 1 Demographics and liver studies Age (yrs) Simvastatin Dose (mg) HCV Quantitative (IU/ml) Baseline ALT/AST (IU/L) Maximum ALT/AST (IU/L) Most Recent ALT/AST (IU/L) Duration of Statin Use (mo) 51 5 None 33/34 59/52 59/ ,160,000 65/43 42/ None 25/17 16/ ,000 87/61 65/47 45/ ,000, /60 111/ None 39/29 28/ None 30/27 34/26 26/ ,800,000 54/43 42/34 42/ ,620 44/45 44/ None 31/28 28/29 21/ None 37/27 32/ ,500 28/32 24/31 24/ None 32/32 39/29 25/ None 96/55 58/ ,230,000 51/36 86/59 74/ None 92/56 92/ None 44/31 39/ /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

108 Preventive Cardiology/Statins and Hepatitis C Infection 1279 statin. Of the 17 patients, 2 had received interferon and ribavirin; 1 while on simvastatin and 1 before simvastatin was initially prescribed. Baseline liver enzymes were available for 8 patients. Five patients had 1 liver enzyme elevation while on a statin. The greater increase was 1.5 times the upper limit of normal. Of the 219 patients with a diagnosis of HCV infection, 202 were not taking statins at the time of this review. No documentation of previous statin use resulting in discontinuation owing to hepatic side effects was found for these patients. Our experience with statin use at this facility showed that statins are not associated with significant liver enzyme elevations in patients with HCV infection. The largest liver enzyme level was 1.5 times the upper limit of normal, well below the ceiling of 3 times the upper limit of normal set by an American Heart Association consensus statement governing statin use. 2 Additional study in this area would be desirable to corroborate our findings, especially of patients who may have biochemical evidence of more severe infection. 1. VA treatment guidelines: patients with chronic hepatitis C. Fed Pract 2003;20(suppl 5): Pasternak RC, Smith SC, Bairey-Merz CN, Grundy SM, Cleeman JI, Lenfant C. ACC/AHA/NHLBI clinical advisory on the use and safety of statins. Circulation 2002;106:

109 Relation of the Prothrombotic State to Increasing Age (from the Framingham Offspring Study) Geoffrey H. Tofler, MD a, *, Joseph Massaro, PhD b, Daniel Levy, MD c, Murray Mittleman, MD d, Patrice Sutherland, BSc c, Izabela Lipinska, PhD b, James E. Muller, MD e, and Ralph B. D Agostino, PhD f A greater life expectancy has led to an increasing proportion of elderly patients. Increasing age is an important risk factor for cardiovascular disease, but the mechanism of risk is not well understood. Because thrombosis plays a key role in plaque development and the onset of acute coronary syndromes, the age-related increase in cardiovascular risk may be a result of a prothrombotic imbalance. The study aim was to examine the relation between age and thrombotic potential in the Framingham Offspring Cohort. Hemostatic factors previously associated with cardiovascular risk were measured in 3,230 patients (55% women) without evidence of cardiovascular disease who were participating in cycle 5 of the Framingham Offspring Study. The subjects were divided by age into decades. Advancing age was associated with a significant increase in fibrinogen and von Willebrand factor levels and measures of impaired fibrinolytic potential (plasminogen activator inhibitor and tissue plasminogen activator antigens). For men, the mean fibrinogen levels were 21% higher in those >70 years versus those aged <40 years (326 vs 268 mg/dl, p <0.001 for linear trend). The mean fibrinogen levels were 15% higher in older than in younger women (330 vs 286 mg/dl, p <0.001). The significant relations persisted after multivariate adjustment. In conclusion, advancing age is associated with elevated levels of hemostatic factors indicative of a prothrombotic state. Because these factors are also associated with endothelial dysfunction, these findings are consistent with an injurious effect of age on the endothelium. Measures to reduce thrombotic potential may be of particular value in the elderly, because they counter the prothrombotic state that develops with aging Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) The increase in life expectancy has led to an increasing proportion of elderly patients in the population. Advancing age is an important risk factor for cardiovascular disease (CVD) among men and women. 1 Although age is not modifiable, an improved understanding of the mechanism by which age is associated with increased risk may lead to further preventive measures. Given the importance of thrombosis in the causation of acute coronary syndromes and plaque development, 2,3 the increase in cardiovascular risk with age may be due in part to a prothrombotic imbalance. Although such a link between advancing age and prothrombotic changes has been described a Royal North Shore Hospital, Sydney, Australia; b Boston University School of Public Health, Boston, Massachusetts; c National Heart, Lung, and Blood Institute s Framingham Heart Study, Framingham, Massachusetts; d Beth Israel Deaconess Medical Center; e Massachusetts General Hospital; and f Boston University School of Mathematics and Statistics, Boston, Massachusetts. Manuscript received March 11, 2005; revised manuscript received and accepted June 14, This study was supported by a Grant-in-Aid ( ) from the American Heart Association ( ), Dallas, Texas; and the National Institutes of Health, Bethesda, Maryland (RO1-HL-48157); and National Heart, Lung, and Blood Institute Contract HC-38038, Bethesda, Maryland. * Corresponding author: Tel: ; fax address: gtofler@nsccahs.health.nsw.gov.au (G.H. Tofler). in previous reports, 1,4 the Framingham Heart Study provided the opportunity to examine this relation separately in men and women. The extensive risk factor information available from the Framingham Offspring Cohort Study subjects permitted adjustment for potential confounders. We measured levels of fibrinogen, factor VII, von Willebrand factor, plasma viscosity, plasminogen activator inhibitor (PAI-1) antigen, and tissue plasminogen activator (t-pa) antigen and report their associations with advancing age. Methods Study population: The study subjects were members of the Framingham Offspring Study, a long-term, prospective evaluation of risk factors for CVD. For this cross-sectional analysis, we collected data from consecutive subjects examined from 1991 to 1995 during the fifth Offspring Study examination cycle. The average age of the subjects was 54 years (range 26 to 82). We excluded subjects with clinical or objective evidence of CVD. Patients who reported smoking 1 cigarette/day during the year before the index examination were classified as current smokers. Body mass index was computed by dividing the weight in kilograms by the height in meters squared. Diabetes mellitus was considered present if the fasting blood glucose /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

110 Preventive Cardiology/Age and the Prothrombotic State 1281 Table 1 Clinical characteristics stratified by age men Variable 40 (n 98) (n 394) (n 504) (n 371) 70 (n 93) p Value* Age (yrs) 35.7 (0.3) 45.4 (0.1) 54.3 (0.1) 63.9 (0.2) 72.3 (0.3) Body mass index (kg/m 2 ) 27.2 (0.5) 28.0 (0.2) 28.6 (0.2) 28.1 (0.2) 27.5 (0.4) 0.62 Smoker 27.6% 25.1% 19.2% 14.3% 7.5% Diabetes mellitus 1.0% 3.0% 7.1% 11.5% 13.9% Total cholesterol (mg/dl) 187 (3) 201 (2) 202 (2) 204 (2) 200 (4) HDL cholesterol (mg/dl) 45.8 (1.3) 43.0 (0.5) 43.2 (0.5) 43.3 (0.6) 43.6 (1.4) 0.50 Glucose level (mg/dl) 96.0 (2.6) 98.5 (1.1) (1.3) (2.0) (4.0) Triglyceride level (mg/dl) 124 (9) 159 (6) 165 (6) 163 (5) 158 (11) 0.08 Alcohol (oz/wks) 3.0 (0.3) 3.7 (0.2) 3.9 (0.2) 3.6 (0.2) 3.4 (0.5) 0.69 Systolic blood pressure (mm Hg) 118 (1.3) 123 (0.7) 128 (0.7) 136 (1.0) 138 (1.8) Diastolic blood pressure (mm Hg) 74 (0.9) 78 (0.5) 79 (0.4) 76 (0.5) 72 (1.1) 0.04 Hypertension 11.2% 21.8% 34.2% 53.8% 54.8% Data are presented as means (SEMs) for continuous variables. * Assessed linear trend. HDL high-density lipoprotein. Table 2 Clinical characteristics stratified by age women Variable 40 (n 102) (n 507) (n 587) (n 457) 70 (n 117) p Value* Age (yrs) 36.0 (0.3) 45.1 (0.1) 54.0 (0.1) 63.9 (0.1) 72.5 (0.2) Body mass index (kg/m 2 ) 25.5 (0.5) 25.9 (0.2) 26.9 (0.2) 27.2 (0.2) 27.9 (0.2) Smoker 27.5% 24.1% 18.4% 15.4% 10.3% Diabetes mellitus 0.9% 1.7% 4.2% 6.7% 8.5% Total cholesterol (mg/dl) 187 (3) 201 (2) 202 (2) 204 (2) 200 (3) HDL cholesterol (mg/dl) 54.7 (1.4) 56.4 (0.6) 56.5 (0.6) 56.2 (0.8) 55.5 (1.4) 0.96 Glucose level (mg/dl) 88 (0.8) 93 (0.9) 97 (1.1) 102 (1.4) 102 (2.0) Triglyceride level (mg/dl) 88 (4) 113 (4) 139 (3) 157 (5) 155 (8) Alcohol (oz/wks) 1.2 (0.1) 1.8 (0.1) 1.7 (0.1) 1.7 (0.1) 1.6 (0.2) 0.93 Systolic blood pressure (mm Hg) 107 (1.2) 115 (0.7) 124 (0.7) 131 (0.9) 141 (1.8) Diastolic blood pressure (mm Hg) 67 (0.8) 72 (0.4) 74 (0.4) 73 (0.4) 71 (1.0) 0.04 Hypertension 4.9% 14.0% 27.3% 46.2% 63.2% Hormonal replacement therapy 6.9% 13.0% 32.7% 19.9% 10.2% Data are presented as means (SEMs) for continuous variables. * Assessed linear trend. HDL high-density lipoprotein. level was 140 mg/dl or if insulin or oral hypoglycemic agents were used. Hypertension was defined as systolic arterial pressure 140 mm Hg or diastolic arterial pressure 90 mm Hg or the use of antihypertensive medication. Alcohol consumption was assessed as the reported number of ounces per day of beer (12 oz. per glass), wine (4 oz. per glass), and spirits (1 oz. per glass). Women using hormonal replacement therapy in the year before the examination were classified as hormonal replacement therapy users. Subjects with established coronary disease or stroke were excluded from the analysis. A total of 3,230 subjects (1,460 men and 1,770 women) met the entry criteria and were divided by decade of age for the present analysis. Blood sampling and hemostatic analyses: Blood samples were collected from an antecubital vein between 8 and 9 A.M., after an overnight fast. The blood sample was anticoagulated with 3.8% sodium citrate (9:1 vol/vol) and kept on crushed ice until centrifugation. Plasma was separated by centrifugation at 2,500g for 30 minutes at 4 C. Plasma aliquots were quickly frozen and stored at 70 C for subsequent analysis. PAI-1 antigen levels were determined with a commercially available enzyme-linked immunosorbent assay (ELISA) according to the description of Declerck et al 5 (TintElize PAI-1, Biopool AB, Umea, Sweden). Fibrinogen levels were determined according to the method of Clauss. 6 t-pa antigen levels were measured using an ELISA (TintElize t-pa, Biopool AB), according to the procedure described by Ranby et al. 7 Factor VII antigen levels were measured with an ELISA using a commercially available kit (Diagnostica Stago, Parsippany, New Jersey). von Willebrand factor antigen levels were measured with an ELISA, as previously described. 8 The intraassay coefficient of variation was 2.6% for fibrinogen, 3.0% for factor VII, 5.5% for t-pa antigen, 8.8% for von Willebrand factor, and 9.6% for PAI-1 antigen. Statistical analysis: We used analysis of covariance to investigate the relation between age and hemostatic risk factors. Subjects were divided by age decade. A series of models were fit with each of the hemostatic risk factors as the depen-

111 1282 The American Journal of Cardiology ( Table 3 Hemostatic risk factors stratified by age men Variable 40 (n 98) (n 394) (n 504) (n 371) 70 (n 93) p Value* Unadjusted Adjusted Fibrinogen (mg/dl) 268 (4) 284 (3) 300 (2) 324 (3) 326 (6) PAI-1 antigen (ng/ml) 19.4 (1.9) 25.0 (0.9) 25.0 (0.7) 24.9 (0.8) 24.6 (2.8) t-pa antigen (ng/ml) 7.95 (0.58) 9.20 (0.22) 9.94 (0.16) (0.37) (0.48) von Willebrand factor (%) 101 (4) 118 (2) 127 (2) 139 (2) 152 (5) Plasma viscosity (cps) 1.23 (0.01) 1.23 (0.01) 1.24 (0.01) 1.25 (0.01) 1.25 (0.01) Factor VII antigen (%) 94.3 (1.3) 97.7 (0.7) 98.3 (0.7) 97.2 (0.8) 98.6 (1.7) Data are presented as means (SEMs). Analysis for PAI-1 and t-pa antigen performed using logarithmic transformation. * Assessed linear trend across age in decades. Adjusted for smoking, diabetes mellitus, body mass index, high-density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, hypertension, and alcohol use. Table 4 Hemostatic risk factors stratified by age women Variable 40 (n 102) (n 507) (n 587) (n 457) 70 (n 117) p Value* Unadjusted Adjusted Fibrinogen (mg/dl) 286 (5) 297 (3) 308 (2) 325 (3) 330 (5) PAI-1 antigen (ng/ml) 13.9 (1.1) 18.0 (0.6) 21.1 (0.7) 23.9 (0.9) 22.9 (1.3) t-pa antigen (ng/ml) 5.75 (0.29) 7.09 (0.16) 8.21 (0.16) 9.88 (0.22) (0.33) von Willebrand factor (%) 116 (4) 116 (2) 124 (2) 138 (2) 144 (4) Plasma viscosity (cps) 1.22 (0.01) 1.24 (0.01) 1.25 (0.01) 1.26 (0.01) 1.25 (0.01) Factor VII antigen (%) 94.6 (1.3) 98.8 (0.6) (0.7) (0.80) (1.5) Data are presented as means (SEMs). Analysis for PAI-1 and t-pa antigen performed using logarithmic transformation. * Assessed linear trend across age in decades. Adjusted for smoking, diabetes mellitus, body mass index, high-density lipoprotein cholesterol, total cholesterol, triglycerides, systolic blood pressure, diastolic blood pressure, hypertension, alcohol use, and hormonal replacement therapy. dent variable. The mean values and SEM are presented for each of the hemostatic risk factors. Logarithmic transformation of the PAI-1 antigen, t-pa antigen, and triglyceride levels was performed to attain a normal distribution. Baseline clinical characteristics across age decades were compared using simple linear regression and simple logistic regression analyses for continuous and discrete variables, respectively. Unadjusted p values are given, as are p values adjusted for body mass index, diabetes mellitus, smoking, alcohol intake, total cholesterol level, high-density lipoprotein cholesterol level, triglyceride level, systolic and diastolic blood pressure, and hypertension and, for women, hormonal replacement therapy. Values for 2-tailed p 0.05 were considered statistically significant. Results Clinical characteristics: Among men and women, significant increases occurred in glucose and total cholesterol levels and the incidence of diabetes mellitus with age (Tables 1 and 2). In addition, among women, an increase occurred in body mass index and triglyceride level with age. Smoking decreased as age increased for men and women. Also, systolic blood pressure and the prevalence of hypertension increased with age for men and women. Diastolic blood pressure for men and women and hormonal replacement therapy for women increased with age from 40 years to 50 to 59 years, but then decreased with additional aging. Age and hemostatic risk factors: On unadjusted analysis, highly significant increases were found in fibrinogen, factor VII, von Willebrand factor, PAI-1 antigen, t-pa antigen, and plasma viscosity with age (Tables 3 and 4). With the exception of factor VII and plasma viscosity, these relations persisted after adjustment for body mass index, cigarette smoking, diabetes mellitus, total cholesterol, high-density lipoprotein cholesterol level, triglyceride level, systolic blood pressure, diastolic blood pressure, hypertension, and alcohol use and, for women, hormonal replacement therapy. Discussion This analysis from the Framingham Offspring Study provides evidence that increasing age is associated with a prothrombotic state among men and women, unadjusted and adjusted for potential confounders. This status, which was indicated by increased levels of fibrinogen, von Willebrand factor, PAI-1 antigen, and t-pa antigen, may provide an explanation for the marked increase in CVD that occurs with age. 1

112 Preventive Cardiology/Age and the Prothrombotic State 1283 Accumulating evidence has suggested the importance of hemostatic cardiovascular risk factors. First, acute coronary syndromes have been shown to be primarily due to partial or complete thrombotic vessel occlusion at the site of a ruptured atherosclerotic plaque. 2,3 Second, several hemostatic factors have been identified that are associated with increased cardiovascular risk. 5,9 12 For example, fibrinogen is as powerful a risk factor for cardiovascular events as are other traditional risk factors, such as cholesterol. 13 Furthermore, traditional risk factors such as smoking and hyperlipidemia have been associated with elevated hemostatic factors and may act in part by these factors. In addition, studies demonstrating a preventive effect for aspirin and coumadin are consistent with the importance of the thrombotic state. 14 Our findings are consistent with those from the European Concerted Action on Thrombosis and Disabilities Angina Pectoris Study, in which age was associated with higher levels of fibrinogen, von Willebrand factor antigen, and t-pa antigen. 15,16 Aillaud and colleagues 17 found that an elderly group (mean age 80 years) had higher levels of fibrinogen and von Willebrand factor, PAI-1, and t-pa antigen and a higher erythrocyte sedimentation rate and shorter activated partial thromboplastin time than a younger group (mean age 22 years). Factor VII has also been reported to increase with age, 18,19 as has prothrombin fragment 1.2 and fibrinopeptide A, reflecting in vivo thrombin generation. 20 Because many hemostatic factors are also markers of endothelial dysfunction and vascular inflammation, the prothrombotic factors we measured may be a mechanism by which a low-grade inflammatory state associated with age leads to CVD. Wei et al 21 demonstrated increasing plasma interleukin-6 with age. Daynes and colleagues 22 proposed that endogenous production of interleukin-6 becomes less precisely regulated with aging and thus results in inflammation. However, no consistent relation between age and high-sensitivity C-reactive protein has been demonstrated Potential risks need to be considered for each patient; however, antithrombotic measures may be of particular benefit in the elderly because they counter the prothrombotic state that develops with aging. 1. Tracy RP, Bovill EG. Thrombosis and cardiovascular risk in the elderly. Arch Pathol Lab Med 1992;116: DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303: Davies MJ, Thomas A. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N Engl J Med 1984;310: Ernst E, Resch KL. Fibrinogen as a cardiovascular risk factor: a meta-analysis and review of the literature. Ann Intern Med 1993;118: Declerck PJ, Alessi MC, Verstreken M, Kruithof EKO, Juhan-Vague I, Collen D. Measurement of plasminogen activator inhibitor I in biologic fluids with a murine monoclonal antibody-based enzymelinked immunosorbent assay. Blood 1988;71: Clauss A. Gerinnungsphysiologishe schnellmethode zur bestimmung des fibrinogens. Acta Hematol 1957;17: Ranby M, Bergsdorf N, Nilsson T, Mellbring G, Winblad B, Bucht A. Age dependence of tissue plasminogen activator concentrations in plasma, as studied by an improved enzyme-linked immunosorbent assay. Clin Chem 1986;32: Penny WF, Weinstein M, Salzman EW, Ware JA. Correlation of circulating von Willebrand factor levels with cardiovascular hemodynamics. Circulation 1991;83: Ridker PM, Vaughan DE, Stampfer MJ, Manson JE, Hennekens CH. Endogenous tissue-type plasminogen activator and risk of myocardial infarction. Lancet 1993;341: Jansson JH, Nilsson TK, Johnson O. von Willebrand factor in plasma: a novel risk factor for recurrent myocardial infarction and death. Br Heart J 1991;66: Juhan-Vague I, Pyke SDM, Alessi MC, Jesperson J, Haverkate F, Thompson SG, on behalf of the ECAT Study Group. Fibrinolytic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. Circulation 1996;94: Conlan MG, Folsom AR, Finch A, Davis CE, Sorlie P, Marcucci G, Wu KK, for the Atherosclerosis Risk in Communities (ARIC) Study. Associations of factor VIII and von Willebrand factor with age, race, sex and risk factors for atherosclerosis. Thromb Hemost 1993;70: Meade TW, Mellows S, Brozovic M, Miller GJ, Chakrabarti RR, North WR, Haines AP, Stirling Y, Imeson JD, Thompson SG. Haemostatic function and ischaemic heart disease: principal results of the Northwick Park Heart Study. Lancet 1986;2: Hennekens CH, Buring JE, Sandercock P. Aspirin and other antiplatelet agents in the secondary and primary prevention of cardiovascular disease. Circulation 1989;80: Thompson SG, Kienast J, Pyke SDM, Haverkate F, van de Loo JCW, for the ECAT Angina Pectoris Study. Hemostatic factors and the risk of myocardial infarction or sudden death in patients with angina pectoris. N Engl J Med 1995;332: Haverkate F, Thompson SG, Duckert F. Hemostasis factors in angina pectoris: relation to gender, age and acute-phase reaction. Thromb Hemost 1995;73: Aillaud MF, Pignol F, Alessi MC, Harle JR, Escande M, Mongin M, Juan-Vague I. Increase in plasma concentration of plasminogen activator inhibitor, fibrinogen, von Willebrand factor, factor VIII:C and in erythrocyte sedimentation rate with age. Thromb Haemost 1986;55: Balleisen L, Baily J, Epping PH, Schulte H, van de Loo J. Epidemiologic study on factor VII, factor VIII and fibrinogen in an industrial population: baseline data on the relation to age, gender, body-weight, smoking, alcohol, pill-using and menopause. Thromb Hemostas 1985; 54: Scarabin PY, Van Dreden P, Bonithon-Kop C, Orssaud G, Bara L, Conard J, Samama M. Age-related changes in factor VII activation in healthy women. Clin Sci 1988;75: Cushman M, Psaty BM, Macy E, Bovill EG, Cornell ES, Kuller LH, Tracy RP. Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. Arterio Thromb Vasc Biol 1996;16: Wei J, Xu H, Davies JL, Hemmings GP. Increase of plasma IL-6 concentration with age in healthy subjects. Life Sci 1992;51: Daynes RA, Araneo BA, Ershler WB, Maloney C, Li G, Ryu S. Altered regulation of IL-6 production with normal aging. J Immunol 1993;150: Ford ES, Giles WH, Myers GL, Mannino DM. Population distribution of high-sensitivity C-reactive protein among US men: findings from National Health and Nutrition Examination Survey Clin Chem 2003;49: Rifai N, Ridker PM. Population distributions of C-reactive protein in apparently healthy men and women in the United States: implication for clinical interpretation. Clin Chem 2003;49: Wener MH, Daum PR, McQuillan GM. The influence of age, sex and race on the upper reference limit of serum C-reactive protein concentration. J Rheumatol 2000;27:

113 Relation of Coronary Atherosclerosis Determined by Electron Beam Computed Tomography and Plasma Levels of N-terminal Pro-Brain Natriuretic Peptide in a Multiethnic Population-Based Sample (The Dallas Heart Study) Shuaib M. Abdullah, MD a, Amit Khera, MD, MSc a, Sandeep R. Das, MD, MPH a, Harold G. Stanek, MS a, Russell M. Canham, MD a, Anne K. Chung, BS a, David A. Morrow, MD, MPH b, Mark H. Drazner, MD, MSc a, Darren K. McGuire, MD, MHSc a, and James A. de Lemos, MD a, * Elevated plasma levels of B-type natriuretic peptide (BNP) and N-terminal pro-bnp (NT pro-bnp) are seen in the setting of cardiac ischemia and are associated with adverse outcomes in patients with coronary artery disease. The mechanisms leading to natriuretic peptide elevation in patients with coronary artery disease, including the contribution of coronary atherosclerosis itself, have not been fully elucidated. Measurement of NT pro-bnp, electron beam computed tomography, and cardiac magnetic resonance imaging were performed in 2,445 subjects from the Dallas Heart Study who were free of heart failure and renal insufficiency. Electron beam computed tomography determined coronary artery calcium scores were categorized as none (<10), mild (>10 to <100), moderate (>100 to <400), and severe (>400). NT pro- BNP levels increased significantly across increasing coronary artery calcium score categories (p < for trend). In multivariate models adjusted for age, gender, race, body mass index, hypertension, history of myocardial infarction, angina, angiotensin-converting enzyme inhibitor use, -blocker use, left ventricular (LV) ejection fraction, and LV mass, higher coronary artery calcium scores remained independently associated with higher log NT pro-bnp levels (p 0.03). This association persisted in similar models excluding patients with low LV ejection fractions, LV hypertrophy, angina pectoris, and a history of myocardial infarction. In conclusion, these findings support the hypothesis that coronary atherosclerosis may directly influence the activation of the cardiac neurohormonal system Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Although elevated levels of B-type natriuretic peptide (BNP) and the N-terminal portion of its pro-hormone (NT pro-bnp) are associated with poor cardiovascular prognosis in patients presenting with acute coronary syndromes and stable coronary artery disease, 1 5 the pathophysiologic mechanisms leading to increased synthesis and secretion of BNP and NT pro-bnp in patients with coronary artery disease have not been fully elucidated. The primary stimulus for natriuretic peptide release is believed to be cardiomyocyte stretch. 6 In patients with coronary artery disease, myocardial ischemia may cause transient left ventricular (LV) systolic and diastolic dysfunction and, consequently, increase LV wall stress, leading indirectly to elevated plasma BNP and NT pro-bnp levels. However, several recent studies have suggested that cardiac ischemia may directly influence natriuretic peptide release, independent of changes in LV function. 7,8 In addition, evidence has shown that BNP may be synthesized within the coronary arteries and that its expression may correlate with the degree of atherosclerosis. 9 Recently, studies performed in patients with acute coronary syndromes and stable coronary artery disease have suggested an association between the extent of atherosclerosis and plasma natriuretic peptide levels, but these studies did not evaluate patients with subclinical atherosclerosis and did not fully account for the effects of LV structural and functional abnormalities In a large and well-phenotyped population-based study, we evaluated the association between coronary atherosclerosis, as measured by electron beam computed tomography (EBCT), and cira Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center, Dallas, Texas; and b Brigham and Women s Hospital, Boston, Massachusetts. Manuscript received April 15, 2005; revised manuscript received and accepted June 20, This study was supported by the Donald W. Reynolds Foundation, Dallas, Texas, and Roche Diagnostics, Indianapolis, Indiana, and partially supported by USPHS GCRC grant M01-RR00633 from the National Institutes of Health/NCRR-CR, Bethesda, Maryland. Dr. de Lemos was supported by grants and received consulting fees from Roche Diagnostics, Indianapolis, Indiana. * Corresponding author: Tel: ; fax: address: James.delemos@utsouthwestern.edu (J.A. de Lemos) /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

114 Preventive Cardiology/Coronary Atherosclerosis and NT Pro-BNP 1285 culating levels of NT pro-bnp, after accounting for potential influences of LV structural or functional abnormalities. Methods Study population: The Dallas Heart Study is a population-based, multiethnic, probability sample of subjects in Dallas County. Details of the study design and the characteristics of the enrolled cohort have been previously described. 13 All participants provided informed consent to participate in the study, and the Institutional Review Board of the University of Texas Southwestern Medical Center approved the study protocol. The study involved 3 separate visits, with the first consisting of field interviews and blood pressure, heart rate, and weight measurements in 6,101 subjects aged 18 to 65 years. At the second visit, fasting blood and urine samples were collected in 3,398 of the subjects aged 30 to 65 years from visit 1. In visit 3, cardiac magnetic resonance imaging and EBCT were performed on 2,971 visit 2 subjects aged 30 to 65 years. Of the subjects completing visit 3, those with serum creatinine 2 mg/dl or missing serum creatinine value (n 14), or with selfreported heart failure (n 109) were excluded from all analyses. In addition, those with unavailable EBCT scans (n 181), cardiac magnetic resonance imaging scans (n 206), or plasma NT pro-bnp levels (n 16) were excluded, to yield a final sample of 2,445 subjects for the multivariate analysis. Variable definition: The definitions of the variables have been previously described. 14 The average of 5 sequential blood pressure readings at visit 3 was taken, and hypertension was defined as average systolic blood pressure 140 mm Hg, diastolic blood pressure 90 mm Hg, or the use of antihypertensive medication. Diabetes was defined as a fasting glucose level 126 mg/dl, nonfasting glucose level 200 mg/dl, or the previous diagnosis of diabetes mellitus coupled with the use of any glucose-lowering medication. Hypercholesterolemia was defined as calculated low-density lipoprotein cholesterol 160 mg/dl on a fasting sample, direct low-density lipoprotein cholesterol 160 mg/dl on a nonfasting sample, total cholesterol 240 mg/dl, or the use of statin medication. A history of congestive heart failure or myocardial infarction was determined by patient self-report. Angina pectoris was defined as self-reported chest pain with exertion plus fulfillment of 1 additional criteria from the Rose Angina Questionnaire 15 : location, effect of pain on level of exertion, improvement of pain with rest, or duration of pain. NT pro-bnp assay: Blood was collected during visit 2 in tubes containing ethylenediaminetetraacetic acid and was maintained at 4 C for 4 hours before being processed. Samples were centrifuged at 1,430g for 15 minutes, and the plasma was removed and stored in 100- l aliquots at 80 C. Assays for NT pro-bnp were performed by study personnel blinded to the clinical information using the Elecsys NT pro-bnp assay (Roche Diagnostics, Indianapolis, Indiana). The lower detection limit of the assay is 5 pg/ml, and all values 5 pg/ml (n 330) were designated as 2.5 pg/ml for statistical analysis. The sensitivity analysis, substituting values of 1.5 and 3.5 pg/ml for values 5 pg/ml, revealed similar results. Cardiac imaging: EBCT scans were performed using an Imatron C-150XP EBCT scanner (Imatron Inc., San Bruno, California), using a previously described protocol. 16 Coronary artery calcium (CAC) scores were expressed in Agatston units, 17 and the mean of 2 consecutive scans was used as the final EBCT score, unless only 1 scan was obtained. A score 10 was selected as a data-derived threshold to define the presence of calcium to maximize the signal-to-noise ratio and reproducibility. 16 CAC scores were classified using a previously described classification scheme 18 : no calcium (CAC score 0 to 10), mild ( 10 to 100), moderate ( 100 to 400), and severe ( 400). Cardiac magnetic resonance imaging was performed using a Phillips Medical Systems 1.5 Tesla Intera magnet (Philips Medical Systems, Cleveland, Ohio). Contours were generated for end-diastolic and end-systolic phases and data on LV end-diastolic volume, LV end-systolic volume, and LV ejection fraction were calculated from short-axis sequences. Depressed LV ejection fraction was defined as 55%. 19 Gender-specific LV hypertrophy was defined as 89 g/m 2 in women and 112 g/m 2 in men, which were the LV mass/body surface area ratios of 2 SDs in an ultrahealthy subpopulation of the Dallas Heart Study cohort (n 380). Statistical analysis: Statistical analyses were performed using Statistical Analysis Systems, version 9.1 (SAS Institute, Cary, North Carolina), statistical software package. Univariate analysis was performed using the Wilcoxon rank sum test to identify clinical variables associated with plasma NT pro-bnp levels. The comparison of NT pro-bnp levels across CAC scores was performed using the linear trend across ordered variables. Multivariate linear regression models were used to determine the independent association of CAC categories with NT pro-bnp. NT pro-bnp was log transformed for these analyses because of its skewed distribution. In these models, CAC was evaluated as a continuous variable (log [CAC 1]) and as a categorical variable using the ordinal CAC categories previously described. 18 In all analyses, 2-sided p values 0.05 were considered significant. Results Subjects with older age, female gender, non-black race, lower body mass index, history of hypertension, myocardial infarction, or angina, use of angiotensin-converting enzyme inhibitors or blockers, reduced LV ejection fraction, and LV hypertrophy had significantly higher plasma levels of

115 1286 The American Journal of Cardiology ( Table 1 Variables associated with NT pro-bnp levels* Variable n Median NT pro-bnp level (pg/ml) IQR p Value Age (yrs) Gender Women Men Race Non-black Black Body mass index (kg/m 2 ) Smoker 0.8 No Yes Hypertension No Yes Diabetes mellitus 0.7 No Yes Hypercholesterolemia 0.6 No Yes Angiotensin-converting enzyme inhibitor use No Yes Blocker use No Yes Previous myocardial infarction No Yes Angina pectoris 0.03 No Yes Ejection fraction % % Left ventricular hypertrophy No Yes * Those with congestive heart failure and serum creatinine 2 mg/dl excluded. Cutoff at median levels for body mass index and age. Defined as average of 5 systolic blood pressure measurements 140 mm Hg or diastolic blood pressure measurements 90 mm Hg or use of antihypertensive medications at visit 3. Defined as fasting glucose 126 mg/dl, nonfasting glucose of 200 mg/dl, or previous diagnosis coupled with the use of hypoglycemic medication. Defined as fasting calculated LDL 160 mg/dl, nonfasting direct LDL 160 mg/dl, total cholesterol 240 mg/dl, or use of statin medication. IQR interquartile range; LDL low-density lipoprotein. Figure 1. Log NT pro-bnp values across CAC score categories. Those with congestive heart failure or creatinine 2 mg/dl were excluded. Median values, line within the box; 25th and 75th percentiles, lower and upper box margins, respectively; 5th and 95th percentiles lower and upper ends of whiskers, respectively. Number of subjects in each CAC score category listed at bottom of the figure. p for trend. NT pro-bnp than subjects not meeting these criteria (Table 1). In contrast, no association was observed between diabetes mellitus, tobacco use, and hypercholesterolemia and plasma NT pro-bnp levels. Association between CAC scores and NT pro-bnp levels: NT pro-bnp levels increased significantly across CAC categories (p trend ; Figure 1). After adjustment for age, gender, race, body mass index, hypertension, history of myocardial infarction, symptoms of angina, angiotensin-converting enzyme inhibitor and -blocker use, LV ejection fraction, and LV mass, a significant association remained between CAC score and log (NT pro-bnp) (Table 2). Using CAC as a continuous variable (log [CAC 1]), rather than as ordered categories, did not alter these results (p 0.03). In these 2 models, stable angina pectoris and a history of myocardial infarction remained significantly associated with plasma NT pro-bnp levels. When the multivariate analyses were repeated after excluding subjects with a history of myocardial infarction (n 29), stable angina (n 134), LV hypertrophy (n 236), or LV ejection fraction 55% (n 38), a significant association remained between CAC category and NT pro- BNP plasma levels (Table 2). This association also remained significant when CAC categories were replaced with log (CAC 1) (p 0.02). Discussion In a large and carefully phenotyped population-based cohort, we have demonstrated for the first time an independent association between the burden of coronary atherosclerosis, as measured by EBCT, and circulating levels of NT pro- BNP. This association persisted after adjusting for LV struc-

116 Preventive Cardiology/Coronary Atherosclerosis and NT Pro-BNP 1287 Table 2 Multivariate regression models for log NT pro-bnp Variable Model 1* Model 2 Parameter Estimate p Value Parameter Estimate p Value Age (yrs) Men Black race Body mass index (kg/m 2 ) Hypertension Angiotensin-converting enzyme inhibitor blocker Healed myocardial infarct NA NA Stable angina pectoris NA NA LV ejection fraction NA NA LV mass CAC * Those with congestive heart failure and serum creatinine 2 mg/dl excluded. Those with congestive heart failure, serum creatinine 2 mg/dl, stable angina, history of myocardial infarction, low ejection fraction, and left ventricular hypertrophy excluded. NA not applicable. tural and functional parameters, a history of myocardial infarction, and symptoms of angina pectoris, suggesting that atherosclerosis itself may stimulate natriuretic peptide synthesis and release. In addition, we have confirmed the previously demonstrated associations of stable angina pectoris and a history of myocardial infarction with natriuretic peptide levels. 11,20,21 These findings support an increasing body of evidence suggesting that factors other than cardiomyocyte stretch may be involved in activation of the cardiac neurohormonal system in patients with coronary artery disease. The findings from several experimental models support the hypothesis that cardiac ischemia per se may lead to synthesis and release of natriuretic peptides. After coronary artery ligation in the rat, BNP is released from stored pools as early as 2 and 5 minutes after ligation, a period during which no change in cardiac filling pressures is detectable. 22 Likewise, in ex vivo preparations of whole rat hearts and isolated atrial or ventricular myocytes perfused with hypoxic buffer, BNP synthesis and release is augmented Transient increases in plasma BNP levels have been detected in patients undergoing percutaneous transluminal angiography, even in the absence of changes in hemodynamic parameters, but no significant difference was seen in patients undergoing diagnostic coronary angiography. 7 In patients with stable angina pectoris, but without heart failure or significant LV dysfunction, BNP messenger RNA expression from tissue samples obtained at coronary artery bypass graft surgery was higher in areas with stress-inducible ischemia than in areas without ischemia. 26 Finally, euvolemic patients with unrepaired cyanotic congenital heart disease were shown to have higher NT pro-bnp plasma levels than those with noncyanotic heart disease and those with structurally normal hearts. 25 Several previous studies have shown an association between the angiographic severity of coronary atherosclerosis and plasma natriuretic peptide levels in patients with symptomatic stable angina 8 and those with non ST-elevation acute coronary syndromes. 27 In addition, among a subset of patients with non ST-elevation acute coronary syndromes who underwent coronary angiography in the TACTICS- Thrombolysis In Myocardial Infarction 18 study, higher BNP levels were associated with more severe and more proximal coronary atherosclerosis and with slower flow in the culprit artery. 10 Because these studies evaluated only patients with symptomatic coronary artery disease, they could not delineate the role of atherosclerosis versus the role of ischemia in stimulating natriuretic peptide synthesis and release. Our study extends these findings by demonstrating an association between atherosclerosis and natriuretic peptide levels in a low-risk population-based cohort without symptomatic heart failure or ischemia. One possible explanation for our findings is that patients with obstructive coronary atherosclerosis may experience asymptomatic ischemia, leading to activation of the cardiac neurohormonal system. However, the association between atherosclerotic burden and NT pro-bnp persisted after excluding subjects with angina pectoris or previous myocardial infarction and extended to those with modest coronary calcium levels (CAC score 100 to 400), who are unlikely to have significant asymptomatic ischemia. 28 A second and more intriguing possibility is that the coronary atherosclerosis itself may be a source of natriuretic peptides. Casco et al 9 have recently demonstrated the presence of BNP within intimal and adventitial smooth muscle cells of coronary arteries with advanced atherosclerosis that were harvested from patients undergoing cardiac transplantation. Moreover, BNP messenger RNA expression was increased in vessels more advanced pathologically compared with vessels with less advanced atherosclerosis. Future studies are needed to elucidate the mechanisms of natriuretic peptide release in patients with atherosclerosis and to determine whether this is a direct effect or an indirect effect that is mediated by other neurohormones, such as endothelin I and angiotensin II. 6,29 The direct clinical implications of our findings are limited, because the contribution of CAC scores to NT pro- BNP variability was modest. Multiple factors likely contributed to the modest elevation in plasma NT pro-bnp levels seen in patients with coronary artery disease, including concomitant LV systolic or diastolic dysfunction, direct and indirect effects of myocardial ischemia, and atherosclerosis itself. However, the present findings do suggest plausible mechanisms that may explain previous observations showing an association between natriuretic peptide levels and

117 1288 The American Journal of Cardiology ( outcomes in patients with coronary artery disease and may have implications for therapy in the future. Better characterization of the pathophysiologic mechanisms stimulating the synthesis and release of natriuretic peptides may help to identify treatment options for high-risk patients with evidence of neurohormonal activation. For example, the recent Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial failed to show a benefit of angiotensin-converting enzyme inhibitors in patients with stable coronary artery disease and preserved LV ejection fraction, 30 suggesting that not all patients with coronary artery disease may derive a benefit from a standard form of treatment. Elevated plasma levels of BNP or NT pro-bnp may identify a subset of patients with coronary artery disease who benefit from angiotensin-converting enzyme inhibitors in the absence of LV dysfunction. This study had several limitations. 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119 Effect of Rosuvastatin on C-Reactive Protein and Renal Function in Patients With Chronic Kidney Disease Anil Verma, MD a, Karthik M. Ranganna, MD a, Rani S. Reddy, MD a, Mandeep Verma, MBBS a, and Neil F. Gordon, MD, PhD b, * The purpose of this 20-week, open-label, randomized clinical trial was to evaluate the effect of rosuvastatin on fasting serum lipids and lipoproteins, high-sensitivity C-reactive protein (hs-crp), and the glomerular filtration rate (GFR) in 91 patients with chronic kidney disease. Patients were randomized to rosuvastatin 10 mg/day (n 48) or to no lipid-lowering treatment (n 43) for 20 weeks. In contrast to patients not receiving rosuvastatin, patients receiving rosuvastatin tended to derive more favorable improvements from baseline values in low-density lipoprotein cholesterol ( 43%, p <0.001, vs 7%, p NS; p <0.001 for change with rosuvastatin treatment vs change with no antilipemic treatment), hs-crp ( 47%, p <0.001, vs 7%, p NS; p <0.001 for change with rosuvastatin treatment vs change with no antilipemic treatment), and GFR (11%, p <0.05, vs 4%, p NS; p NS for change with rosuvastatin treatment vs change with no antilipemic treatment) Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Recent studies suggest that statins may retard the progression of chronic kidney disease. 1,2 Although dyslipidemia is a risk factor for the progression of renal insufficiency, 3,4 it has been postulated that the benefits of statins on renal function may be modulated by mechanisms other than lipid reduction (i.e., pleiotropic effects) and that not all statins are necessarily beneficial. 5,6 The aim of this 20-week, openlabel, randomized clinical trial was to evaluate the effect of rosuvastatin on fasting serum lipids and lipoproteins and the glomerular filtration rate (GFR) in 91 patients with chronic kidney disease. Because statins are hypothesized to exert their renoprotective effect in part through anti-inflammatory activity, 1,2 we also studied the effect of rosuvastatin on high-sensitivity C-reactive protein (hs-crp) in this patient population. a Candler Internal Medicine, Metter, Georgia; and b Center for Heart Disease Prevention, St. Joseph s/candler Health System, Savannah, Georgia. Manuscript received February 23, 2005; revised manuscript received and accepted June 22, * Corresponding author: Tel: ; fax: address: ngordon@interventusa.com (N.F. Gordon). Study participants included 91 adult male (n 32) and female (n 59) volunteers who met the following criteria: age 18 years; diagnosed chronic kidney disease, as defined by GFR 60 ml/min/1.73 m 2 body surface area 7 ;no clinical evidence of acute renal failure; not undergoing hemodialysis; not recently hospitalized for any reason; no known recent acute illness or infection; not currently taking antilipemic medications; no history of statin therapy discontinuation because of adverse events; no known contraindications to statin therapy; fasting low-density lipoprotein cholesterol 100 mg/dl, high-density lipoprotein cholesterol 40 mg/dl, and/or triglycerides 150 mg/dl; and ability to attend the study clinic once every 4 weeks for 20 weeks. This was a prospective, open-label, randomized clinical trial. On completion of baseline testing, patients were randomized to receive either rosuvastatin 10 mg once daily or no antilipemic drug therapy for 20 weeks. Clinic visits were scheduled every 4 weeks. All laboratory tests were performed at baseline and again after 20 weeks using identical procedures. Laboratory tests included the measurement of fasting serum lipids and lipoproteins (with the calculation of low-density lipoprotein cholesterol using Friedewald s equation), hs-crp, creatinine, alanine aminotransferase, aspartate aminotransferase, and creatine kinase. Alanine aminotransferase, aspartate aminotransferase, and creatine kinase were also measured on 1 additional occasion during the study. GFR was calculated using the abbreviated Modification of Diet in Renal Disease formula 8 as follows: GFR 186 (serum creatinine in mg/dl) (age in years) (0.742 if female) (1.210 if black). Although blood pressure and hemoglobin A1c were not prespecified study outcome variables, seated blood pressure and hemoglobin A1c (in patients with diabetes mellitus) were measured at baseline, and blood pressure measurements were repeated at clinic visits as part of the patients regular medical care. For categorical variables, the statistical significance of differences among patients assigned to the 2 groups was evaluated at baseline using chi-square tests. For continuous variables, the statistical significance of baseline differences among patients assigned to the 2 groups was evaluated using unpaired Student s t tests (parametric parameters) and Mann-Whitney tests (nonparametric parameters). The statistical significance of within-group changes from baseline was analyzed using paired Student s t tests (parametric /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

120 Preventive Cardiology/Rosuvastatin and Renal Function 1291 Table 1 Baseline demographic and clinical characteristics Characteristic Rosuvastatin Treatment (n 48) No Antilipemic Treatment (n 43) Age (yrs) Men 19 (40%) 13 (30%) Women 29 (60%) 30 (70%) African-American 15 (31%) 15 (35%) Caucasian 33 (69%) 28 (65%) Diabetes mellitus 22 (46%) 20 (47%) Hemoglobin A1c (%) Hypertension 41 (85%) 42 (98%) Cigarette smoker 9 (19%) 8 (19%) Values are expressed as mean SD. Hemoglobin A1c was measured only in patients with diabetes mellitus. There were no statistically significant baseline differences between the 2 groups of patients. parameters) and Wilcoxon s matched-pairs signed-rank tests (nonparametric parameters). Statistical differences between the 2 groups were evaluated on the change from baseline using unpaired Student s t tests (parametric parameters) and Mann-Whitney tests (nonparametric parameters). Tests were 2 sided, and statistical significance was established at the 0.05 confidence level. Values are expressed as mean SD, with the exception of hs-crp, which is presented as median and interquartile range. Of the 91 patients entered into this study, 48 were randomized to rosuvastatin treatment, and 43 were randomized to no antilipemic treatment. Baseline demographic and clinical variables are listed in Table 1 for the 2 groups of study participants. Randomization did not result in statistically significant differences between patients assigned to the 2 groups. Of the 48 patients randomized to rosuvastatin treatment, 3 patients withdrew because of myalgia that was not associated with elevated serum creatine kinase levels, and 1 patient died from sepsis. Of the 43 patients randomized to no antilipemic treatment, 3 patients were lost to follow-up and 1 patient died from pneumonia. No patients in either group experienced elevations in serum alanine aminotransferase or aspartate aminotransferase to 3 times the upper limit of normal or elevation in serum creatine kinase to 10 times the upper limit of normal during the study. Changes in the main outcome measures after 20 weeks of rosuvastatin treatment or no antilipemic treatment are listed in Table 2. Although rosuvastatin treatment reduced lowdensity lipoprotein cholesterol by 43% (p 0.001), lowdensity lipoprotein cholesterol did not change significantly with no antilipemic treatment (p for the change from baseline with rosuvastatin treatment vs the change from baseline with no antilipemic treatment). Similarly, although rosuvastatin reduced the median hs-crp by 47% (p 0.001), the median hs-crp did not change significantly with no antilipemic treatment (p for the change from baseline with rosuvastatin treatment vs the change from baseline with no antilipemic treatment). As can be seen in Table 2, GFR increased significantly (11%, p 0.05) with 20 weeks of rosuvastatin treatment. In contrast, GFR did not change significantly (4% increase, p NS) with no antilipemic treatment (p NS for the change from baseline with rosuvastatin treatment vs the change from baseline with no antilipemic treatment). Although blood pressure was not a prespecified study outcome variable, analysis of values recorded at the baseline (rosuvastatin treatment: /74 8 mm Hg; no antilipemic treatment: /76 10 mm Hg) and 20-week (rosuvastatin treatment: /71 9mmHg; no antilipemic treatment: /74 12 mm Hg) clinic visits did not reveal statistically significant differences between patients assigned to the 2 groups. A previous meta-analysis of 13 prospective controlled trials demonstrated a modest but favorable effect of lipid-lowering drugs on GFR in patients with renal disease. 9 Similarly, a recent retrospective pooled analysis of data obtained from a diverse group of 10,000 patients who received rosuvastatin in its recommended dose range (5 to 40 mg/day) for up to 3.8 years documented increases in GFR early and later in the course of rosuvastatin therapy. 10 Moreover, in the latter study, the beneficial effect of rosuvastatin 10 mg/day (i.e., the dose most commonly used for the treatment of hyperlipidemia) on GFR appeared to be similar, irrespective of baseline renal function. 10 Our study is the first prospective randomized clinical trial, to our knowledge, to evaluate the effect of rosuvastatin on GFR in patients with chronic kidney disease. Our finding of a statistically significant improvement from baseline values in GFR with rosuvastatin treatment is consistent with the observations from the metaanalysis and retrospective analysis and is supportive of a potential renoprotective effect of rosuvastatin in patients with chronic kidney disease. The underlying mechanism by which rosuvastatin and other statins may improve GFR in patients with chronic kidney disease has yet to be fully elucidated. 1,2,5,6,9,10 A variety of factors may contribute to the progression of renal impairment in patients with chronic kidney disease, including hyperlipidemia. As anticipated, rosuvastatin induced a substantial reduction in low-density lipoprotein cholesterol in our study. Other postulated benefits of statins for patients with chronic kidney disease include favorable effects on renal hemodynamics, endothelial function, monocyte recruitment, mesangial cell proliferation, mesangial matrix accumulation, immunomodulation, and inflammation. 5 In view of the emerging evidence that chronic renal insufficiency may be associated with chronic inflammation, a hypothesis that has attracted considerable recent attention is that the renoprotection afforded by statin therapy may be mediated by the attenuation of the inflammatory response to renal parenchymal injury. Although this hypothesis cannot be directly addressed by the present study, our data clearly show that rosuvastatin treatment is accompanied by a sub-

121 1292 The American Journal of Cardiology ( Table 2 Changes in clinical outcome measures Outcome Measure Rosuvastatin Treatment (n 44) No Antilipemic Treatment (n 39) p Value* Baseline Follow-Up Change Baseline Follow-Up Change Total cholesterol (mg/dl) ( 30%) (2%) LDL cholesterol (mg/dl) ( 43%) (7%) HDL cholesterol (mg/dl) ( 2%) (6%) 0.05 Triglycerides (mg/dl) ( 20%) ( 6%) NS hs-crp (mg/dl) Median ( 47%) (7%) IQ range Creatinine (mg/dl) ( 3%) ( 1%) NS GFR (ml/min/1.73 m 2 ) (11%) (4%) NS With the exception of hs-crp, values are expressed as mean SD. * p value for change from baseline with rosuvastatin treatment versus no antilipemic treatment. Within-group changes from baseline were statistically significant where indicated ( p 0.001; p 0.01; p 0.05). HDL high-density lipoprotein; IQ interquartile; LDL low-density lipoprotein. stantial reduction in the inflammatory biomarker hs-crp in patients with chronic kidney disease. In addition to renoprotection, a rosuvastatin-mediated reduction in inflammation could also be expected to confer a reduced risk for cardiovascular events independent of rosuvastatin s lowdensity lipoprotein cholesterol lowering effect. 14,15 The major strengths of our study include the prospective, randomized design and inclusion of a relatively large proportion of women, African-Americans, and patients with diabetes mellitus and hypertension. There are also several potential limitations to the present study. These potential limitations include that the study was not double blind or placebo controlled, the use of a single dose of rosuvastatin (which precludes the extrapolation of our findings to larger or smaller doses), the relatively short duration of the intervention, our failure to measure changes in potential confounding variables (such as glycemic control in patients with diabetes mellitus), the estimation of GFR, and that the observed improvement from baseline values in GFR with rosuvastatin treatment did not differ to a statistically significant degree from the change from baseline values in GFR with no antilipemic treatment. Although further research is warranted, the results of this prospective randomized clinical trial clearly show that rosuvastatin 10 mg/day therapy has favorable anti-inflammatory effects in patients with chronic kidney disease and are supportive of potential accompanying renoprotective benefits. 1. Afzali B, Haydar AA, Vinen K, Goldsmith DJA. Beneficial effects of statins on the kidney: the evidence moves from mouse to man. Nephrol Dial Transplant 2004;19: Afzali B, Haydar AA, Vinen K, Goldsmith DJA. From Finland to Fatland: beneficial effects of statins for patients with chronic kidney disease. J Am Soc Nephrol 2004;15: Schaeffner ES, Kurth T, Curhan GC, Glynn RJ, Rexrode KM, Baigent C, Buring JE, Gaziano JM. Cholesterol and the risk of renal dysfunction in apparently healthy men. J Am Soc Nephrol 2003;14: Appel GB, Radhakrishnan J, Avram MM, DeFronzo RA, Escobar- Jimenez F, Campos MM, Burgess E, Hille DA, Dickson TZ, Shahinfar S, et al, for the RENAAL Study Investigators. Analysis of metabolic parameters as predictors of risk in the RENAAL study. Diabet Care 2003;26: Tonelli M, Moye L, Sacks FM, Cole T, Curhan GC, for the Cholesterol and Recurrent Events (CARE) Trial Investigators. Effect of pravastatin on loss of renal function in people with moderate chronic renal insufficiency and cardiovascular disease. J Am Soc Nephrol 2003;14: Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, Elisaf M. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study. J Clin Pathol 2004;57: National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(suppl):S1 S Levey AS, Greene T, Kusek J, Beck GJ, Group MS. A simplified equation to predict glomerular filtration rate from serum creatinine. J Am Soc Nephrol 2000;11:A Fried LF, Orchard TJ, Kasiske BL, for the Lipids and Renal Disease Progression Meta-Analysis Study Group. Effect of lipid reduction on the progression of renal disease: a meta-analysis. Kidney Int 2001;59: Vidt DG, Cressman MD, Harris S, Pears JS, Hutchinson HG. Rosuvastatin-induced arrest in progression of renal disease. Cardiology 2004;102: Garg AX, Blake PG, Clark WF, Clase CM, Haynes RB, Moist LM. Association between renal insufficiency and malnutrition in older adults: results from the NHANES III. Kidney Int 2001;60: Kaysen GA. The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol 2001;12: Shlipak MG, Fried LF, Crump C, Bleyer AJ, Manolio TA, Tracy RP, Furberg CD, Psaty BM. Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. Circulation 2003;107: Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, Pfeffer MA, Braunwald E, for the Pravastatin or Atorvastatin Evaluation and Infection Therapy Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Investigators. C-reactive protein levels and outcomes after statin therapy. N Engl J Med 2005;352: Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, Orazem J, Magorien RD, O Shaughnessy CO, Ganz P, for the Reversal of Atherosclerosis With Aggressive Lipid Lowering (REVERSAL) Investigators. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med 2005;352:29 38.

122 Prognostic Significance of Nonsustained Ventricular Tachycardia During Dobutamine Stress Echocardiography David E. Cox, MD, Laurance D. Farmer, MD, John R. Hoyle, MD, and Gretchen L. Wells, MD, PhD* Nonsustained ventricular tachycardia (NSVT) is a well-recognized side effect during dobutamine stress echocardiography (DSE). This study sought to evaluate the prognostic implications of NSVT during DSE on 1,266 consecutive dobutamine stress echocardiograms performed over 1 year. NSVT, defined as >3 consecutive ventricular premature beats, occurred in 65 of 1,266 patients (5.1%). There was no absolute increased risk in all-cause mortality between the NSVT and no NSVT groups (22% vs 17%, p 0.15) during the 3-year follow-up. Survival curves generated by the Kaplan-Meier method also demonstrated no increased risk in mortality between the NSVT and no NSVT groups (p 0.43). When only studies with negative results for inducible ischemia were taken into account, survival curves showed no significant difference in all-cause mortality (p 0.26). Studies with negative results for inducible ischemia were also stratified according to the ejection fraction (EF). Patients without inducible ischemia and mildly reduced to normal EFs (>0.45) did not have significant differences in survival between the NSVT and no NSVT groups over the 3-year follow-up (p 0.86). However, patients without inducible ischemia and moderately reduced EFs (0.35 to 0.45) who had NSVT during DSE had significantly reduced survival over the follow-up (p 0.01) Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Dobutamine stress echocardiography (DSE) has established efficacy in the diagnosis of coronary artery disease and the evaluation of myocardial viability. Noncardiac side effects such as headache, dizziness, nausea, and anxiety are not uncommon, but are usually well-tolerated. 1 The most common cardiovascular side effects are hypotension, angina, and supraventricular or ventricular arrhythmias. Ventricular arrhythmias have been reported in approximately 2% to 6% of patients in various studies, most commonly nonsustained ventricular tachycardia (NSVT). 1 5 The prognostic significance of NSVT during DSE has been a point of conjecture in terms of whether significant ventricular ectopy is an independent predictor of increased risk for further adverse cardiovascular events or cardiac death. 5 8 We have retrospectively reviewed our DSE database to examine the effects of NSVT on all-cause mortality. Data regarding dobutamine stress echocardiograms are maintained on 2 electronic databases at our institution. Our echocardiographic reporting system is a locally developed searchable database containing reports from 1991 onward, as well as stress echocardiographic variables, such as baseline and stress wall motion score indexes (based on a 16-segment Wake Forest University Baptist Medical Center, Winston-Salem, North Carolina. Manuscript received April 1, 2005; revised manuscript received and accepted June 24, * Corresponding author: Tel: ; fax: address: gwells@wfubmc.edu (G.L. Wells). scale), baseline ejection fractions (EFs), left ventricular (LV) dimensions, and evidence of inducible ischemia. The electrocardiographic reporting system (MUSE CV System, GE Healthcare, Milwaukee, Wisconsin) is a database containing reports from 2000 onward, as well as stress variables, such as baseline electrocardiographic rhythm and morphology, baseline and peak heart rates, target heart rate achieved (85% maximal predicted heart rate, calculated as 220 age), blood pressure, and rate pressure product. Stress electrocardiographic reports also contain baseline characteristics, such as patient age, gender, race, indication for stress test, and medications. Given that our electrocardiographic reporting system has retrievable stress data beginning only on January 1, 2000, we searched the echocardiographic reporting system for all pharmacologic stress echocardiograms performed from January 1, 2000, to December 31, Fourteen hundred forty-nine studies were identified. Studies were excluded if they were repeated in the same patients during 2000 (n 41), were exercise stress echocardiograms incorrectly identified as dobutamine stress echocardiograms (n 21), had incomplete stress data (n 14), were listed in the system twice (n 20), or were Persantine echocardiograms (n 3). Studies were also excluded if the patients had preexisting ventricular ectopy on baseline electrocardiography (n 57), previous heart transplantation (n 23), previous placement of implantable cardiac defibrillators (n 3), or a history of ventricular tachyarrhythmias (n 1). After all exclusions, there were 1,266 patients with complete dobutamine stress data for review. NSVT, defined /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

123 1294 The American Journal of Cardiology ( Table 1 Baseline characteristics Characteristic NSVT p Value No (n 1,201) Yes (n 65) Age (yrs) Men 520 (43%) 37 (57%) 0.04 Caucasian 943 (79%) 49 (75%) 0.54 Inpatient 547 (46%) 26 (40%) 0.44 Medications ECASA 370 (31%) 21 (32%) 0.78 Beta blocker 481 (40%) 17 (26%) 0.03 Calcium channel blocker 252 (21%) 15 (23%) 0.64 ACE inhibitor/arb 337 (28%) 23 (35%) 0.21 Digoxin 70 (6%) 12 (18%) Diuretic 269 (22%) 20 (31%) 0.13 Nitrates 160 (13%) 6 (9%) 0.45 Antilipid 273 (23%) 9 (14%) 0.12 Antiarrhythmic 10 (1%) Smoker 437 (36%) 22 (34%) 0.79 Hypertension 914 (76%) 55 (84%) 0.13 Diabetes mellitus 362 (30%) 23 (35%) 0.41 Hyperlipidemia 531 (44%) 24 (37%) 0.30 Prior coronary artery 444 (37%) 32 (49%) 0.05 disease Prior myocardial infarction 209 (17%) 10 (15%) 0.87 ACE angiotensin-converting enzyme; ARB angiotensin II receptor blocker; CAD coronary artery disease; ECASA enteric-coated acetylsalicylic acid; MI myocardial infarction. as the presence of 3 consecutive ventricular contractions 100 beats/min, was identified in 65 patients by stress electrocardiographic reports. Patients without ventricular ectopy, or those with less malignant ventricular ectopy, such as isolated premature ventricular contractions, bigeminy, trigeminy, or couplets, were considered to have no NSVT. There were 1,201 patients in the no NSVT group. Hospital records were reviewed for the assessment of classic cardiac risk factors: smoking history, hypertension, hyperlipidemia, and diabetes mellitus. Smoking history was defined as a 10 pack-year history of cigarette use and active tobacco use within the preceding 10 years. Hypertension, hyperlipidemia, and diabetes mellitus were taken as documented evidence of those diseases with current medical therapy (antihypertensives, oral hypoglycemics or insulin, or antilipid medication). Documented evidence of previous myocardial infarction and history of obstructive coronary artery disease, defined as a 70% epicardial stenosis (or 50% left main coronary artery stenosis) or a history of percutaneous transluminal coronary intervention, was also recorded. The study was conducted from March 2003 to December The protocol for data collection was approved by the institutional review board of Wake Forest University Baptist Medical Center before collection and analysis. The primary outcome measured in the study was allcause mortality. Patient mortality over 3 years was assessed using the Social Security Death Index. The Social Security Table 2 Stress data and baseline electrocardiographic and echocardiographic data Characteristic NSVT p Value No (n 1,201) Yes (n 65) Baseline heart rate (beats/min) Baseline SBP (mm Hg) Baseline DBP (mm Hg) Peak HR (beats/min) Peak SBP (mm Hg) Peak DBP (mm Hg) BP HR product % maximum HR 946 (79%) 60 (92%) achieved Baseline electrocardiogram Sinus rhythm 1147 (96%) 52 (80%) Atrial fibrillation 25 (2%) 7 (11%) Paced 27 (2%) 5 (8%) 0.02 Other 2 ( 1%) 1 (1%) 0.15 Atrioventricular block 59 (5%) 3 (5%) 1.0 IVCD, BBB, hemiblock 157 (13%) 5 (8%) 0.25 Anterior or septal infarct 112 (9%) 7 (11%) 0.66 Inferior or lateral infarct 51 (4%) 4 (6%) 0.52 Any prior infarct 163 (14%) 11 (17%) 0.46 LV hypertrophy 56 (5%) 2 (3%) 0.76 Echocardiographic data EF LV hypertrophy 260 (22%) 13 (20%) 0.88 Dilated left ventricle 70 (6%) 7 (11%) 0.11 Resting LV score Stress LV score Positive results for inducible ischemia 119 (10%) 11 (17%) 0.09 BBB bundle branch block; BP blood pressure; DBP diastolic blood pressure; HR heart rate; IVCD intraventricular conduction delay; SBP systolic blood pressure. Death Index, available through a variety of Internet resources, is a sensitive and specific method of identifying patient death. 9 Results are expressed as mean SD. Statistical analysis (GraphPad Prism, version 4.0 for Windows, Graphpad Software, San Diego, California) was performed using chisquare and Fisher s exact tests for categorical variables and unpaired Student s t tests for continuous variables. Survival curves were generated using the Kaplan-Meier method, starting from the day of DSE. Differences between survival curves were assessed using the log-rank method. NSVT occurred in 65 of 1,266 patients (5.1%). Baseline risk factors and cardiac history are identified in Table 1. Patients with NSVT had significantly higher rates of being men and significantly more coronary artery disease. Betablocker use was significantly greater in the no NSVT group, and digoxin use was significantly greater in the NSVT group. Table 2 lists stress data from the 2 groups. A significantly higher peak heart rate was achieved in the NSVT group. Patients in the no NSVT group were more likely to be in normal sinus rhythm at baseline and less likely to be in atrial fibrillation or paced rhythm than those in the NSVT group.

124 Arrhythmias and Conduction Disturbances/NSVT During Dobutamine Stress Echocardiography 1295 Figure 1. All-cause mortality over 3 years in patients with NSVT versus those with no NSVT. HR hazard ratio. Patients in the NSVT group had significantly smaller baseline EFs and significantly greater baseline and peak stress wall motion scores. Figure 1 shows that there was no significant difference in survival over 3 years after DSE in the 2 groups. Overall survival at the end of 3 years was 51 of 65 patients (78%) in the NSVT group and 991 of 1,201 patients (83%) in the no NSVT group (p 0.15). There was a trend toward more inducible ischemia in the NSVT group (17% NSVT vs 10% no NSVT, p 0.09). When all studies with positive results for inducible ischemia were excluded, there were 1,082 patients in the no NSVT group and 54 patients in the NSVT group. In this subgroup, there remained similar differences in baseline characteristics, medications, stress echocardiographic, and electrocardiographic data compared with the overall groups. Figure 2 shows that there was no significant difference in survival over 3 years after DSE in the 2 groups when the stress echocardiographic results were negative for inducible ischemia (hazard ratio 1.39, 95% confidence interval 0.75 to 2.90, p 0.26). Figures 3 and 4 show survival between the no NSVT and NSVT groups when all stress echocardiograms with positive results were excluded and baseline EFs were stratified to 0.45 (NSVT: 40 patients; no NSVT: 944 patients) or between 0.35 and 0.45 (NSVT: 8 patients; no NSVT: 89 patients). For mildly reduced to normal baseline EFs with negative stress echocardiograms, there was no significant difference in survival between the NSVT and no NSVT groups; however, for moderately reduced baseline EFs, there was a significantly higher rate of death in the NSVT group. The absolute risk for death in the groups with moderately reduced EFs at the end of 3 years was 5 of 8 (63%) in the NSVT group and 27 of 89 (30%) in the no NSVT group (p 0.11). In these groups, 63% of the NSVT group and 55% of the no NSVT group had a history of coronary artery disease. Of the patients with coronary artery disease and moderately reduced EFs, the absolute risk for death was 4 of 5 (80%) in the NSVT group and 15 of 49 (31%) in the no NSVT group (p 0.05). There were 6 patients with severely reduced LV function (EF 0.35) and stress echocardiograms with negative results who had NSVT during DSE and 47 without NSVT. The absolute risk for death in these groups at the end of 3 years was 1 of 6 patients (17%) in the NSVT group and 22 of 47 patients (47%) in the no NSVT group (p 0.22), and there was no difference in survival curves. This study confirms previously published data that suggest that there is no difference in all-cause mortality between patients with and without NSVT during DSE after a median follow-up of 3 years. 8 Perhaps more important, NSVT that occurred during DSE when there was no evidence of inducible ischemia did not confer increased all-cause mortality in

125 1296 The American Journal of Cardiology ( Figure 2. All-cause mortality over 3 years in patients with NSVT versus those with no NSVT and negative stress echocardiographic results. Abbreviation as in Figure 1. Figure 3. All-cause mortality over 3 years in patients with NSVT versus those with no NSVT, mildly reduced to normal LV function, and negative stress echocardiographic results. Abbreviation as Figure 1.

126 Arrhythmias and Conduction Disturbances/NSVT During Dobutamine Stress Echocardiography 1297 Figure 4. All-cause mortality over 3 years in patients with NSVT versus those with no NSVT, moderately reduced LV function (EF 0.35 to 0.45), and negative stress echocardiographic results. HR hazard ratio. this study. NSVT that occurs during a stress test with positive results for inducible ischemia would likely be due to ischemic factors, which would be addressed further with coronary angiography in the clinical setting. The results of this study are reassuring for clinicians who may be concerned about the presence and prognosis of NSVT during DSE when there is no evidence of inducible ischemia. However, the presence of NSVT during DSE in patients without inducible ischemia and moderately reduced LV function conferred increased all-cause mortality over 3 years compared with similar patients without NSVT. There are some major limitations to this study, notably, its retrospective nature and limited follow-up. Many of the patients included were referred for DSE and never returned to our institution in the ensuing 3 years of follow-up. Consequently, cause of death was difficult to determine accurately. The evaluation of secondary end points, such as death from cardiovascular causes, the development of ventricular dysrhythmia, or the development of myocardial infarction, was also difficult to pursue. Also, all results were unadjusted for baseline characteristics; however, there was no difference in survival in the overall groups, and it is unlikely that adjusting for baseline characteristics would have shifted the survival curve of the NSVT groups significantly from the no NSVT group, because the NSVT group already had more underlying coronary artery disease, smaller EFs, and worse wall motion scores. The only subgroup to show a difference in survival between the NSVT and the no NSVT groups was that of patients with EFs from 0.35 to 0.45 and underlying inducible ischemia. Baseline characteristics between the NSVT and no NSVT groups of these patients were not significantly different; however, the numbers in these groups were relatively small, and larger numbers of patients would be needed to adequately assess differences between these patient groups. Therefore, we contend that these results need to be further validated with a prospective, controlled study. Furthermore, patients with moderately reduced LV function (EF 0.35 to 0.45) and NSVT during DSE with negative results for inducible ischemia may also require further risk stratification (e.g., ambulatory monitoring, T-wave alternans, or electrophysiologic testing) to identify high-risk subgroups. Acknowledgment: We gratefully acknowledge the previous work of Wesley Haisty, MD, Greg Hundley, MD, and Dalane Kitzman, MD, in their establishment of the databases from which our data were obtained. 1. Geleijnse ML, Fioretti PM, Roelandt JRTC. Methodology, feasibility, safety, and diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 1997;30:

127 1298 The American Journal of Cardiology ( 2. Mertes H, Sawada SG, Ryan T, Segar DS, Kovacs R, Foltz J, Feigenbaum H. Symptoms, adverse effects and complications associated with dobutamine stress echocardiography: experience in 1118 patients. Circulation 1993;88: Picano E, Mathias W Jr, Pingitore A, Bigi R, Previtali M. Safety and tolerability of dobutamine-atropine stress echocardiography: a prospective multicenter study. Lancet 1994;344: Secknus MA, Marwick TH. Evolution of dobutamine echocardiography protocols and indications: safety and side effects in 3011 studies over 5 years. J Am Coll Cardiol 1997;29: Elhendy A, Domburg RT, Jeroen JB, Roelandt JRTC. Relation between the extent of coronary artery disease and tachyarrhythmias during dobutamine stress echocardiography. Am J Cardiol 1999;83: Chauvel C, Cohen A, Khireddine M. Safety of dobutamine stress echocardiography: a 24 hour Holter monitoring study. Eur Heart J 1996;17: Bigi R, Partesana N, Verzoni A, Bandini P, Maffi M, Longoni A, Occhi G, Fiorentini C. Incidence and correlates of complex ventricular arrhythmias during dobutamine stress echocardiography after acute myocardial infarction. Eur Heart J 1995;16: Sutter JD, Poldermans D, Vourvouri E, Donburg RV, Elhendy A, Bax J, Sozzi F, Jordaens L, Buyzere M, Roelandt J. Long-term prognostic significance of complex ventricular arrhythmias during dobutamine stress echocardiography. Am J Cardiol 2003;91: Schisterman EF, Whitcomb BW. Use of the Social Security Administration Death Master File for ascertainment of mortality status. Population Health Metrics 2004;2:2.

128 Analysis of Left Ventricular Systolic Function Using Midwall Mechanics in Patients >60 Years of Age With Hypertensive Heart Disease and Heart Failure Craig S. Vinch, MD, Gerard P. Aurigemma, MD*, Helge U. Simon, MD, Jeffrey C. Hill, RDCS, Dennis A. Tighe, MD, and Theo E. Meyer, MD, DPhil Normal ejection fraction (EFs) is often equated with normal systolic function. However, midwall mechanics reveal systolic dysfunction in hypertensive heart disease accompanied by hypertrophic remodeling. Midwall mechanics are unstudied in patients with acute diastolic heart failure (HF). This study analyzed left ventricular (LV) midwall stress-shortening relations in 61 patients aged >60 years with hypertensive heart disease, HF, and normal EF. Sixty-one hypertensive patients (mean age years) who presented with HF, each with an EF >50%, underwent echocardiography. Midwall mechanics were compared with those of 79 controls (mean age 75 8 years) without structural heart disease. Relative wall thickness ( vs mm) and LV mass ( vs g) were significantly greater in patients with HF compared with controls. Mean EFs were similar in patients with HF and controls (64 9% vs 67 9%). Although mean endocardial fractional shortening (35 7% vs 37 7%) was not significantly different, midwall shortening in patients with HF was significantly less compared with controls (16 2% vs 19 3%, p <0.05). Eighteen of the 61 patients with HF (30%) had midwall shortening that was <95% confidence intervals of the normal midwall stress-shortening relations. By this criterion, these patients had systolic dysfunction despite normal EF; they had smaller LV chambers (in dimension and volume), greater relative wall thickness, and smaller stroke volumes. In conclusion, almost 1/3 of patients hospitalized with diastolic HF had systolic dysfunction, characterized by abnormal midwall stress-shortening relations Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) We studied indexes of left ventricular (LV) systolic function, including midwall shortening, in 61 patients 60 years of age admitted with heart failure (HF) to determine whether there were demonstrable systolic function abnormalities. Methods Study population: The study population with hypertensive heart disease and HF comprised 61 patients (41 women, 20 men) 60 years old who were identified by reviewing the billing records and the echocardiographic database over a period of 18 months in a large community hospital in Worcester, Massachusetts. The medical records of all patients who were admitted for HF and underwent echocardiography were screened and reviewed. Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. Manuscript received April 13, 2005; revised manuscript received and accepted June 24, * Corresponding author: Tel: ; fax: address: aurigemg@ummhc.org (G.P. Aurigemma). We sought patients with extreme concentric geometry, as denoted by relative wall thickness on 2-dimensional directed M-mode echocardiography. For a patient to be included in the analysis, the following clinical characteristics had to be present: (1) history of hypertension; (2) evidence of HF by clinical examination and chest x-ray at presentation to hospital; (3) the presence of concentric LV remodeling by echocardiography, with relative wall thickness 0.45; (4) LV ejection fraction (EF) by 2-dimensional echocardiography of 50%; (5) the absence of significant valvular abnormalities, defined as greater than mild aortic regurgitation, greater than mild aortic stenosis, greater than moderate mitral regurgitation, or greater than mild mitral stenosis; and (6) no clinical evidence of myocardial ischemia (by serial electrocardiograms and creatine phosphokinase measurements) as the precipitating cause for the episode of congestive HF. Control group: We included echocardiographic data on 79 patients (39 women, 40 men; mean age 75 8 years) who underwent echocardiography for clinical indications and whose echocardiographic results were interpreted as normal (control group) /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

129 1300 The American Journal of Cardiology ( Echocardiography: M-mode, 2-dimensional, and Doppler echocardiography were performed by experienced sonographers using commercially available equipment (Hewlett- Packard series 5500, Hewlett-Packard Company, Palo Alto, California). Ventricular minor axis dimensions were obtained in diastole and systole at the level of the chordal apparatus according to American Society of Echocardiography conventions. 1 Septal and posterior wall thicknesses were obtained in diastole from the parasternal window. Diastolic relative wall thickness was calculated as previously described. 2 LV mass was computed using the method of Devereux et al. 3 Pulsed Doppler recordings of the early (E) and late (A) mitral valve inflow velocities at the level of the leaflet tips were obtained, and the E/A ratio was calculated as previously described. 4 LV chamber and myocardial function: Standard echocardiographic chamber volumes and functional parameters such as the EF and stroke volume were calculated using Teichholz s formula, 5 and cardiac output was calculated as the product of stroke volume and heart rate. LV volumes, mass, stroke volume, and cardiac output were indexed to body surface area. Endocardial and midwall fractional shortening were computed using previously described methods. 6 End-systolic circumferential stress was calculated. 7 We estimated end-systolic pressure as the mean arterial pressure, using the method described by Rozich et al. 8 Circumferential wall stress was related to midwall fractional shortening to assess myocardial function corrected for afterload. 9,10 Statistical analysis: The control group was used to establish 95% confidence intervals for midwall stress-shortening relations. We subdivided the HF group on the basis of normal versus subnormal midwall stress-shortening relations (Figure 1). Those whose values were within the 95% confidence interval were designated as group A (n 43). Those whose midwall stress-shortening relations were below the lower 95% confidence interval of the normal values were designated as group B (n 18). The 2 groups were compared with respect to structural and functional variables, as well as symptom class. Data are expressed as mean SD. Continuous variables were compared between groups by the unpaired Student s t test and by 1-way analysis of variance with post hoc Bonferroni adjustment. Linear regression analysis was performed to establish relations between clinical parameters. Categorical variables were compared between groups by chi-square tests. A p value 0.05 was considered statistically significant. Results Clinical data: Clinical data for the HF study population are listed in Table 1. Most patients (80%) were in normal sinus rhythm at the time of their echocardiograms, and most Figure 1. Midwall fractional shortening and circumferential wall stress. Compared with the 95% confidence interval of the normal group, about 1/3 of all patients with HF with hypertensive hypertrophy had reduced systolic function on the basis of the stress-shortening relation. (67%) were women. All patients had received treatment for HF at the time their echocardiograms were performed, and as can be seen, blood pressure was controlled. Patients with HF with reduced myocardial function, according to midwall stress-shortening analysis (group B), were older than those with normal midwall stress shortening (group A) (82 8vs years, p 0.05). Symptom status: Patients in group B had similar symptom classes compared with those in group A (13 of 18 were New York Heart Association class III or IV vs 29 of 43 in group A, chi-square 0.05). Medication use: The use of blockers and/or calcium channel receptor antagonists was not related to reduced systolic function in patients with HF. LV structure and function: As expected, study patients tended to have concentric hypertrophy, with smaller LV Table 1 Clinical characteristics of patients with hypertensive hypertrophy and HF Clinical Data Value Age (yrs) Women 41 (67%) Men 20 (33%) Body mass index (kg/m 2 ) Body surface area (m 2 ) blocker use 27 (44%) Angiotensin-converting enzyme inhibitor 46 (75%) Diuretics 45 (74%) Digoxin 18 (30%) Calcium channel blocker 22 (36%) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Data are presented as mean SD or number (percentage).

130 Systemic Hypertension/Systolic Function in Diastolic HF 1301 Table 2 LV structure Variable Patients With HF Controls Entire Group (n 61) Normal Midwall Stress Relations Depressed Midwall Stress Relations (n 79) (n 43) (n 18) LV end-diastolic dimension (mm) 44 7* * 47 7 Posterior wall thickness (mm) LV mass (g) * * LV mass index (g/m 2 ) * * Relative wall thickness * * * LV end-diastolic volume (ml) 91 32* * LV end-diastolic volume index (ml/m 2 ) 51 18* * LV end-systolic volume (ml) LV end-systolic volume index (ml/m 2 ) *p 0.05 compared with control group; p 0.05 group A versus group B; analyses by 1-way analysis of variance with post hoc Bonferroni adjustment. cavity size, greater relative wall thickness, and greater LV mass compared with controls (Table 2). The group with reduced systolic function by stress shortening (group B) was characterized by smaller LV cavity volumes, smaller dimensions, and greater relative wall thickness. Group B patients had significantly smaller EFs and lower endocardial fractional shortening than group A and the control group (Table 3). Midwall shortening, however, was significantly less in the HF group than in controls (16 2% vs 19 3% p 0.05), although LV afterload was less in patients with HF than in controls (59 26 vs g/m 2,p 0.05). The cardiac index was in the low normal range in the HF group as a whole but did not differ significantly from that in controls ( vs L/min/m 2,p 0.05). There was a close relation between diastolic chamber dimension and stroke volume (r 0.90, p 0.001). Compared with group A patients, group B patients had greater relative wall thickness ( vs , p 0.05), smaller LV end-diastolic dimensions (39 5vs46 6 mm, p 0.05), but similar LV mass indexes ( vs g/m 2,p 0.05). Not surprisingly, in view of the small chamber size, the cardiac index in group B was significantly less than in group A and control patients ( vs vs L/min/m 2, respectively, p 0.05). Doppler assessment of LV filling: Group B s mean and stratified E/A ratios (ranges 0.7, 0.7 to 1.7, and 1.5) were not significantly dissimilar to those of group A, as listed in Table 3. A large proportion of patients had restrictive filling patterns on their transmitral valve inflow Doppler profiles; however, the E/A ratio varied widely in the HF group (Table 3). Discussion The principal finding of this study is that a small but substantial proportion of patients with acute HF and LV hyper- Table 3 Systolic and diastolic functional parameters Variable Patients With HF Controls Entire Group (n 61) Normal Midwall Stress Relations Depressed Midwall Stress Relations (n 79) (n 43) (n 18) Systolic function LV ejection fraction (%) * 67 9 Midwall fractional shortening (%) 16 2* 17 2* 13 1* 19 3 Endocardial fractional shortening (%) * 37 7 Circumferential wall stress (g/m 2 ) 59 26* 60 30* 58 14* Stroke volume index (ml/m 2 ) 32 10* * Diastolic function Mitral Doppler E/A ratio Mitral Doppler E/A ratio /61 (21%) 7/43 (16%) 6/18 (33%) Mitral Doppler E/A ratio /61 (48%) 21/43 (49%) 8/18 (44%) Mitral Doppler E/A ratio /61 (16%) 7/43 (16%) 3/18 (17%) Percentages may not total 100% because of missing values. *p 0.05 compared with control group; p 0.05 group A versus group B, analyses by 1-way analysis of variance with post hoc Bonferroni adjustment.

131 1302 The American Journal of Cardiology ( trophy in association with hypertension have demonstrable abnormalities in LV systolic function. These findings extend our previous observations in other subpopulations with hypertensive heart disease that systolic function is abnormal in a substantial portion of patients with hypertrophic remodeling who have normal EFs. 7,9 12 Similar findings have been more recently observed by others using magnetic resonance imaging tagging 13 and tissue Doppler imaging. 14 In 1985, Topol et al 15 described a series of 21 hypertensive patients (mean age 73 years) with a distinct clinical syndrome characterized by recurrent admission to the hospital for HF who had an intolerance to vasodilatory agents. At the time, the finding that LV systolic function, as denoted by the EF, was supranormal (mean 79%) was considered remarkable. It is now a well recognized fact that many, if not most, older patients hospitalized with HF have normal EF, and it seems reasonable to observe that the mechanisms underlying the clinical syndrome of HF are likely more complex than originally appreciated. We performed this study because there have been few studies to date on LV function in patients with extreme concentric geometry who present with signs and symptoms of HF. The LV concentric remodeling in our patients is similar but not as extreme as that described by Topol et al. 15 The relative wall thickness of patients in their report was greater (1.0 vs in our patients with HF), and the LV end-diastolic diameter was smaller (36 vs 44 7mminour patients with HF). Structurally, patients in our group B are more representative of the patients in Topol et al s 15 report. Midwall fractional shortening (derived from mean echocardiographic values) in Topol et al s 15 group was 17% (vs 16 2 in our HF group B); circumferential wall stress was 23 g/cm 2, compared with g/cm 2 in our patients. In all likelihood, therefore, the patients described in Topol et al s 15 study would have had abnormal midwall mechanics. It appears that Topol et al s 15 group represents an extreme group on a continuous scale of concentric LV remodeling, but it is similar to our group B in the aforementioned respects. The finding of systolic dysfunction in patients with normal (or supranormal) EF is consistent with recent echocardiographic and magnetic resonance imaging data. The 2 techniques have yielded data showing that equating a normal EF with normal systolic function in patients with such large values for relative wall thickness is incorrect. 6,7,9 13 Abnormal myocardial function (reduced midwall shortening in relation to stress) is clearly evident, and in patients with more extreme relative wall thickness, abnormal pump function (reduced cardiac output) is also evident. These findings emphasize the malefic consequences of extreme concentric remodeling on systolic function. It is not immediately clear how reduced systolic function was related to the pathogenesis of HF. Our group has previously demonstrated reduced systolic function in older patients with normal EFs and abnormally large relative wall thicknesses but without overt HF. 7 Using tissue Doppler imaging, others have demonstrated that reduced long-axis shortening is present in many patients with diastolic HF We observed similar systolic dysfunction in this symptomatic group with more extreme alterations in LV geometry. In the group with the higher values for relative wall thicknesses, we observed small stroke volumes that were not offset by increases in heart rate, resulting in reduced cardiac indexes. It is attractive to speculate that the same mechanisms that may trigger neurohumoral activation in patients with reduced stroke volumes due to systolic dysfunction with reduced EFs may be operative in our subset of patients with reduced stroke volumes associated with normal EFs. Increased brain natriuretic peptide has been shown to be associated with development of LV hypertrophy and reduced midwall shortening 22 and to be correlated with parameters of diastolic dysfunction in hypertensive patients with LV hypertrophy Brain natriuretic peptide is also abnormal in patients with asymptomatic diastolic dysfunction. 24 In our judgment, it is more likely that the pulmonary and peripheral venous congestion in these patients is more closely related to abnormal diastolic properties of the left ventricle than to these systolic function abnormalities. We believe that systolic and diastolic abnormalities develop in parallel. We and others have shown that subtle systolic function abnormalities exist in hypertensive patients without HF and argue that these abnormalities occur pari passu with the structural changes that cause diastolic dysfunction. 6,7,9,11,12,25,26 In our patients, the transmitral LV inflow data were not particularly helpful in elucidating whether diastolic dysfunction was present. It is well known that the filling ratio is sensitive to loading conditions, and it is likely that by the time the echocardiographic studies were performed, these might have changed substantially. As has been well described, the correlation between Doppler indexes of filling and LV filling pressures in patients with normal EFs is not good. 27 This attests to the multiplicity of factors influencing diastolic function in the clinical setting. Even when the Doppler mitral inflow data are obtained within a few hours of hospital presentation, these Doppler data do not necessarily demonstrate classic findings of elevated left atrial pressure The assessment of midwall mechanics and afterload took place after treatment (i.e., on day 2 or 3 of the hospitalization) in many patients. Therefore, treatment potentially altering LV mechanics was already instituted. It remains unclear how much those variables change during the course of treatment. This may explain the reduced wall stress in the HF group and leads to the question of whether the EF and endocardial fractional shortening were reduced acutely at the time of presentation to the emergency room. Of potential relevance in this regard are 3 studies that did not demonstrate differences in the EF during acute episodes of HF with afterload excess compared with the EF after stabilization and lower afterload

132 Systemic Hypertension/Systolic Function in Diastolic HF Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58: Savage DD, Garrison RJ, Kannel WB, Levy D, Anderson SJ, Stokes J, Feinleib M, Castelli WP. The spectrum of left ventricular hypertrophy in a general population sample: the Framingham Study. Circulation 1987;75: Devereux RB, Alonso DR, Lutas EM, Gottlieb GJ, Campo E, Sachs I, Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings. Am J Cardiol 1986;57: Rakowski H, Appleton C, Chan KL, Dumesnil JG, Honos G, Jue J, Koilpillai C, Lepage S, Martin RP, Mercier LA, et al. Canadian consensus recommendations for the measurement and reporting of diastolic dysfunction by echocardiography: from the Investigators of Consensus on Diastolic Dysfunction by Echocardiography. J Am Soc Echocardiogr 1996;9: Teichholz LE, Kreulen T, Herman MV, Gorlin R. Problems in echocardiographic volume determinations: echocardiographic-angiographic correlations in the presence of absence of asynergy. Am J Cardiol 1976;37: Shimizu G, Hirota Y, Kita Y, Kawamura K, Saito T, Gaasch WH. Left ventricular midwall mechanics in systemic arterial hypertension. Myocardial function is depressed in pressure-overload hypertrophy. Circulation 1991;83: Aurigemma GP, Silver KH, Priest MA, Gaasch WH. Geometric changes allow normal ejection fraction despite depressed myocardial shortening in hypertensive left ventricular hypertrophy. J Am Coll Cardiol 1995;26: Rozich JD, Carabello BA, Usher BW, Kratz JM, Bell AE, Zile MR. Mitral valve replacement with and without chordal preservation in patients with chronic mitral regurgitation. Mechanisms for differences in postoperative ejection performance. 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133 Effect of Dynamic Left Ventricular Dyssynchrony on Dynamic Mitral Regurgitation in Patients With Heart Failure Due to Coronary Artery Disease Patrizio Lancellotti, MD, PhD, Pierre-Yves Stainier, MD, Florence Lebois, MD, and Luc A. Piérard, MD, PhD* In patients with heart failure, exercise-induced increases in mitral regurgitation (MR), which convey a poor prognosis, are related to the dynamic distortion of mitral valve geometry. It was hypothesized that dynamic MR may also be related to intermittent changes in left ventricular synchronicity during exercise Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Ischemic mitral regurgitation (MR) is characteristically dynamic and sensitive to changes in ventricular size, shape, and loading that increase leaflet tethering and/or reduce mitral valve closing force. 1 Exercise echocardiography has recently emerged as a method well suited to quantitating the dynamic component of ischemic MR 2 and to unmasking patients at high risk for poor outcomes. 3 Exercise-induced changes in the degree of MR are related to changes in mitral valve geometry at both ends of tethered leaflets. 4 The strongest determinant of dynamic MR is an exercise-induced increase in valvular deformation, as measured by systolic tenting area. We hypothesized that dynamic left ventricular (LV) dyssynchrony intermittent changes in LV synchronicity during exercise may be a determinant of dynamic MR. Such LV dyssynchronization could be caused by exercise-induced ischemia. The present study concerned 35 consecutive patients in sinus rhythm with chronic ischemic LV dysfunction (ejection fraction 45%) and at least mild functional MR who underwent simultaneous quantitative exercise Doppler echocardiography and technetium-99m sestamibi single photonemission computed tomography. All patients had been stable for 2 months, and none met the following exclusion criteria: technically inadequate echocardiogram, organic mitral valve disease, more than trivial aortic regurgitation, and atrial fibrillation. All patients gave their informed consent, and the protocol was approved by the local ethics committee. Beta blockers were discontinued 24 hours before the test. A symptom-limited graded bicycle exercise test was performed on a tilting exercise table. After an initial workload of 25 W maintained for 3 minutes, the workload was increased every 2 minutes by 25 W. Blood pressure and a 12-lead electrocardiogram were recorded every 2 minutes. Two-dimensional and Doppler echocardiographic recordings were available throughout the test. Department of Cardiology, University Hospital of Liège, Liège, Belgium. Manuscript received April 1, 2005; revised manuscript received and accepted June 14, * Corresponding author: Tel: ; fax: address: lpierard@chu.ulg.ac.be (L.A. Piérard). Echocardiographic examinations were performed using a Vivid 7 system (GE Healthcare, Little Chalfont, United Kingdom). All echocardiographic and Doppler data were obtained in digital format and stored on optical disks for off-line analysis. The quantitation of MR was performed by the quantitative Doppler method, using mitral and aortic stroke volumes, and the proximal isovelocity surface area method, as previously described. 2 The results of the 2 methods were averaged, allowing the calculation of the effective regurgitant orifice (ERO). The LV dp/dt was estimated from the steepest increasing segment of the continuous-wave Doppler regurgitant jet, as previously described. 5 Valvular tenting area was obtained from the parasternal long-axis view at midsystole and measured the area enclosed between the annular plane and the mitral leaflets. 4 Color-tissue Doppler imaging was performed in the apical views (2, 3, and 4 chamber) to assess longitudinal myocardial regional function. The sector size and depth were optimized to obtain the highest possible frame rate. Regional pulse-wave Doppler velocity profiles were reconstituted and computer analyzed offline. Cardiac synchronicity was assessed from measurements of time intervals, obtained in 6 basal LV segments and the basal lateral right ventricular segment, between the onset of the QRS complex and the peak myocardial sustained systolic velocity. 6 LV dyssynchrony was determined as the difference, among the 6 LV walls, between the longest and the shortest times to peak myocardial sustained systolic velocity, 6 referred to as LV dispersion. Interventricular dyssynchrony was determined as the difference between the time interval in the basal lateral segment of the right ventricle and of the left ventricle. LV and interventricular dyssynchrony were calculated at rest and at peak exercise. Quantitative single photon-emission tomography was performed as previously described. 7 Briefly, technetium-99m sestamibi 20 mci was injected at peak exercise, and tomographic imaging was performed 60 to 90 minutes after injection using a 90 dual-head camera (Sopha DST, General Electric Medical Systems Benelux). A study at rest was acquired on a separate day. To detect the presence and location of ischemic perfusion changes, exercise and resting tomograms were compared using quantitative analysis software. In abnormally perfused areas, a hypoperfusion index was calculated (hypo /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

134 Heart Failure/Dynamic LV Dyssynchrony 1305 Table 1 Clinical characteristics (n 35) Variable Value Age (yrs) Men 22 (63%) Smoker 22 (63%) Diabetes mellitus 7 (20%) Hypertension 15 (43%) Infarct site: inferior/anterior/both 21/9/5 New York Heart Association class I/II/III 3/21/11 Coronary bypass 4 (11%) Pulmonary edema 6 (17%) Beta-blocker use 24 (69%) Furosemide use 14 (40%) Angiotensin-converting enzyme inhibitor use 28 (80%) Nitrate use 11 (31%) Spironolactone use 7 (20%) perfusion defect surface mean severity), which reflects the fractional mass of hypoperfused myocardium in percentage of the total extrapolated myocardial mass. 7 Ischemia was considered significant when the difference between the stress and resting indexes was 10%. 8 Data are expressed as mean SD. Student s t test was used to assess differences between mean values, and categorical variables were compared with Fisher s exact test. A p value 0.05 was considered significant. Linear regression analysis was applied to study the correlation between changes in ERO and stroke volume during exercise and different variables. To determine independent predictors of exercise-induced changes in ERO, a stepwise multiple linear regression was performed. The clinical characteristics of the 35 patients are listed in Table 1. The QRS duration was ms. During testing, heart rate and systolic blood pressure increased significantly from at rest to peak exercise (75 12 vs beats/min and vs mm Hg, respectively, p ; Table 2). None of the included patients had chest pain, significant ST-segment depression, or echocardiographic evidence of ischemia during exercise. All patients had abnormal perfusion single photon-emission computed tomographic results at rest. At exercise, the hypoperfusion index severity changed from 19 9% to 20 10% (p 0.69); only 3 patients had 10% increases in index severity, corresponding to ischemia in the apical area in 2 patients and in the inferior wall in 1. Interventricular dyssynchrony (36 30 ms at rest to ms at peak exercise) did not change significantly during exercise (p 0.79). LV dispersion increased by 10 ms (range 10 to 140) in 16 patients (Figure 1), remained stable in 4, and decreased by 10 ms (range 10 to 70) in the remaining 15 patients (Figure 1). During exercise, ERO increased from 12 6mm 2 (range 3 to 27) to mm 2 (range 2.8 to 43) (p ). ERO increased by 13 mm 2 in 12 patients, increased by 13 mm 2 in 23, and decreased in 1. None of the 3 patients with ischemia as determined by perfusion scintigraphy had 13 mm 2 increases in ERO. In these 3 patients, ERO increased by mm 2. Exercise-induced changes in ERO were not Table 2 Hemodynamic and Doppler echocardiographic changes during exercise (n 35) Variable Value Rest Heart rate (beats/min) Systolic arterial pressure (mm Hg) ERO (mm 2 ) 12 6 LV end-diastolic volume (ml/m 2 ) LV end-systolic volume (ml/m 2 ) LV ejection fraction (%) 32 6 Stroke volume (ml/beat) Transtricuspid pressure gradient (mm Hg) 28 8 Tenting area (cm 2 ) LV dp/dt (mm Hg/s) LV dispersion (ms) Left-right ventricular dyssynchrony (ms) Hypoperfusion index (%) Wall motion score index Difference between exercise and rest Heart rate (beats/min) Systolic arterial pressure (mm Hg) ERO (mm 2 ) 9 10 LV end-diastolic volume (ml/m 2 ) LV end-systolic volume (ml/m 2 ) 11 9 LV ejection fraction (%) 6 5 Stroke volume (ml/beat) Transtricuspid pressure gradient (mm Hg) Tenting area (cm 2 ) LV dp/dt (mm Hg/s) LV dispersion (ms) 6 48 Left-right ventricular dyssynchrony (ms) Hypoperfusion index (%) Wall motion score index correlated with changes in heart rate, blood pressure, LV volumes, and ejection fractions. Such ERO changes were strongly correlated with changes in the systolic tenting area (r 0.78, p ), a determinant of tethering force, but not with changes in LV dp/dt (r 0.18, p NS), a marker of mitral valve closing force. Larger changes in ERO were also related to greater exercise-induced increases in LV dispersion (r 0.61, p ) (Figure 2), whereas no relation was found with changes in interventricular dyssynchrony (r 0.06, p NS). Changes in LV dispersion were significantly associated with changes in systolic tenting area (r 0.52, p ). In multivariate analysis, an increase in systolic tenting area and in LV dispersion emerged as independent determinants of ERO changes during exercise (r , p ). Exercise-induced changes in LV dispersion were not correlated with changes in heart rate, blood pressure, LV volumes, and ejection fractions. Larger increases in LV dispersion were inversely correlated with changes in stroke volume (r 0.80, p ; Figure 3), whereas no relation was found with changes in transtricuspid pressure gradient (r 0.15, p NS) and changes in LV dp/dt (r 0.074, p NS). Functional MR and LV dyssynchrony are frequently observed in heart failure patients with systolic LV dysfunction. 9,10 Each is associated with a dismal prognosis. 3,9,10

135 1306 The American Journal of Cardiology ( Figure 1. Tissue Doppler imaging echocardiograms depicting exercise-induced changes in LV dyssynchrony as estimated by the differences in time to peak velocities between 2 basal segments: (A) a patient with an increase in LV dyssynchrony and (B) a patient with normalized LV synchronicity. Figure 2. Correlation between changes in ERO and changes in LV dispersion during exercise. During exercise, MR varies dynamically with loading conditions that modulate LV volume and mitral valve geometry. 11 We hypothesized that exercise-induced LV dyssynchrony could be a determinant of dynamic MR and forward stroke volume response. The present study showed important changes in LV synchronicity during exercise in most patients, with these dynamic changes varying substantially Figure 3. Correlation between changes in stroke volume and changes in LV dispersion during exercise. from patient to patient. Exercise-induced changes were adverse increased LV dyssynchrony in 16 of the 35 patients. In contrast, exercise improved the synchronicity of the left ventricle in 15 patients. According to our hypothesis, exercise-induced changes in LV dyssynchrony strongly correlated with those in MR and in forward stroke volume but were not caused by inducible ischemia.

136 Heart Failure/Dynamic LV Dyssynchrony 1307 Under basal conditions, the degree of functional MR is related to mitral valvular deformation that is dependent on local rather than global LV remodeling. 12 In patients with ischemic heart failure, tethering (the restriction of leaflet closure) is compounded by LV dysfunction, which decreases the force needed to close the leaflets. 13,14 During exercise, the dynamic changes in MR are correlated to changes in mitral valve configuration and mitral apparatus geometry at both ends of the tethered leaflets. 4 To the best of our knowledge, the present study is the first to demonstrate that the asynchronous activation of basal LV segments during exercise may occur in the absence of detectable ischemia and may contribute to exercise-induced changes in MR. The increase in LV dyssynchronization during exercise strongly correlated with the increase in MR severity and with the increased systolic tenting area. This suggests that systolic displacement of the mitral leaflet body into the LV cavity can be accentuated at least in part by the disturbed activation sequence of the basal left ventricle. Intermittent increases in MR as a result of dynamic LV dyssynchrony may progressively increase myocardial stiffness and accelerate local and global LV remodeling. 15 Dynamic MR is also a determinant of rapid QRS widening 16 and may subsequently lead to permanent electromechanical dyssynchronization, which can be treated by cardiac resynchronization therapy. 17,18 Several limitations should be acknowledged. Patients in New York Heart Association class IV were excluded. Dynamic LV dyssynchrony can be more severe in these patients. The assessment of dynamic changes in LV synchronicity was based on the measurements of time intervals between basal LV segments using off-line tissue Doppler imaging analysis. No evaluation of strain and strain rate parameters was performed to differentiate passive from active motion. 17 However, tissue Doppler imaging has been shown to be superior to strain rate imaging in clinical practice. 19 The estimation of LV dp/dt by the continuous Doppler wave of MR tends to underestimate true LV dp/dt max because it calculates the mean increase in LV pressure during the isovolumic contraction phase rather than the true maximum instantaneous pressure increase. 5 Despite this small discrepancy, the method is reproducible and represents a robust approach for estimating mitral closing forces. 20 Although Doppler methods performed to quantify MR have some pitfalls, 21 the 2 quantitative methods used in this study have been validated at rest and during exercise in our institution He S, Fontaine AA, Schwammenthal E, Yoganathan AP, Levine RA. Integrated mechanism for functional mitral regurgitation: leaflet restriction versus coapting force: in vitro studies. Circulation 1997;96: Lebrun F, Lancellotti P, Piérard LA. Quantitation of functional mitral regurgitation during bicycle exercise in patients with heart failure. J Am Coll Cardiol 2001;38: Lancellotti P, Troisfontaines P, Toussaint A-C, Piérard LA. Prognostic importance of exercise-induced changes in mitral regurgitation in patients with chronic ischemic left ventricular dysfunction. Circulation 2003;108: Lancellotti P, Lebrun F, Piérard LA. Determinants of exercise-induced changes in mitral regurgitation in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2003;42: Kolias TJ, Aaronson KD, Armstrong WF. Doppler-derived dp/dt and dp/dt predict survival in congestive heart failure. J Am Coll Cardiol 2000;36: Yu CM, Chau E, Sanderson JE, Fan K, Tang M-O, Fung W-H, Liu H, Kong S-L, Lam Y-M, Hill MRS, et al. Tissue Doppler echocardiographic evidence of reverse remodeling and improved synchronicity by simultaneously delaying regional contraction after biventricular pacing therapy in heart failure. Circulation 2002;105: Benoît T, Vivegnis D, Foulon J, Rigo P. Quantitative evaluation of myocardial single-photon emission tomographic imaging: application to the measurement of perfusion defect size and severity. Eur J Nucl Med 1996;23: Lancellotti P, Benoit T, Rigo P, Piérard LA. Dobutamine stress echocardiography versus quantitative technetium-99m sestamibi SPECT for detecting residual stenosis and multivessel disease after myocardial infarction. Heart 2001;86: Grigioni F, Enriquez-Sarano M, Zehr KJ, Bailey KR, Tajik AJ. Ischemic mitral regurgitation: long-term outcome and prognostic implications with quantitative Doppler assessment. Circulation 2001;103: Bader H, Garrigue S, Lafitte S, Reuter S, Jaïs P, Haïssaguerre M, Bonnet J, Clementy J, Roudaut R. Intra-left ventricular electromechanical asynchrony: a new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol 2004;43: Levine RA, Hung J. Ischemic mitral regurgitation, the dynamic lesion: clues to the cure. J Am Coll Cardiol 2003;42: Yiu SF, Enriquez-Sarano M, Tribouilloy C, Seward JB, Tajik AJ. Determinants of the degree of functional mitral regurgitation in patients with systolic left ventricular dysfunction: a quantitative clinical study. Circulation 2000;102: Otsuji Y, Handschumacher MD, Schwammenthal E, Jiang L, Song JK, Guerrero JL, Vlahakes GJ, Levine RA. Insights from three-dimensional echocardiography into the mechanism of functional mitral regurgitation: direct in vivo demonstration of altered leaflet tethering geometry. Circulation 1997;96: Kaul S, Pearlman JD, Touchstone DA, Esquival L. Prevalence and mechanisms of mitral regurgitation in the absence of intrinsic abnormalities of the mitral leaflets. Am Heart J 1989;118: Conti JB, Mills RM. Mitral regurgitation and death while awaiting cardiac transplantation. Am J Cardiol 1993;71: Lancellotti P, Kulbertus HE, Piérard LA. Predictors of rapid QRS widening in patients with coronary artery disease and left ventricular dysfunction. Am J Cardiol 2004;93: Breithardt OA, Stellbrink C, Herbots L, Claus P, Sinha AM, Bijnens B, Hanrath P, Sutherland GR. Cardiac resynchronization therapy can reverse abnormal myocardial strain distribution in patients with heart failure and left bundle branch block. J Am Coll Cardiol 2003;42: Lancellotti P, Mélon P, Sakalihasan N, Waleffe A, Dubois C, Bertholet M, Piérard LA. Effect of cardiac resynchronization therapy on functional mitral regurgitation in heart failure. Am J Cardiol 2004;94: Yu C-M, Fung JW-H, Zhang Q, Chan C-K, Chan Y-S, Lin H, Kum LCC, Kong S-L, Zhang Y, Sanderson JE. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation 2004;110: Breithardt OA, Sinha AM, Schwammenthal E, Bidaoui N, Markus KU, Franke A, Stellbrink C. Acute effects of cardiac resynchronization therapy on functional mitral regurgitation in advanced systolic heart failure. J Am Coll Cardiol 2003;41: Enriquez-Sarano M, Seward JB, Bailey KR, Tajik AJ. Effective regurgitant orifice area: a noninvasive Doppler development of an old hemodynamic concept. J Am Coll Cardiol 1994;23:

137 Differences in Diagnostic Value of Four Electrocardiographic Voltage Criteria for Hypertrophic Cardiomyopathy in a Genotyped Population Tetsuo Konno, MD*, Masami Shimizu, MD, Hidekazu Ino, MD, Noboru Fujino, MD, Kenshi Hayashi, MD, Katsuharu Uchiyama, MD, Tomoya Kaneda, MD, Masaru Inoue, MD, Takashi Fujita, MD, Eiichi Masuta, MD, Akira Funada, MD, and Hiroshi Mabuchi, MD The diagnostic value of various classic electrocardiographic (ECG) voltage criteria for hypertrophic cardiomyopathy (HC) has not been established in a genotyped population. This study aimed to determine the most accurate diagnostic definition of classic ECG voltage criteria for detecting carriers of HC. ECG and echocardiographic findings were analyzed in 161 genotyped subjects (97 genetically affected, 64 unaffected) from 20 families with disease-causing mutations in 4 genes. The diagnostic value of 4 voltage criteria (Cornell, Sokolow-Lyon, Romhilt-Estes, and 12-lead QRS voltage) for detecting carriers of HC was investigated. In all subjects, the Romhilt- Estes (point score >4) criterion and 12-lead QRS voltage (>240 mm) were most sensitive (37% and 36%, respectively), with high specificity (95% each), resulting in the greatest accuracy (60% and 59%, respectively). Using these criteria, in subjects without echocardiographic evidence of left ventricular hypertrophy, voltage abnormalities were found in 22.6% of carriers and 4.7% of noncarriers (p <0.01). In conclusion, these findings suggest that the Romhilt-Estes and the 12-lead QRS voltage criteria may be the most accurate diagnostic definitions for HC on the basis of molecular genetic diagnoses. Furthermore, this study demonstrated that voltage abnormalities may be found in prehypertrophic carriers. Even when genetic testing becomes widely available, it will be difficult to make genetic diagnoses in all patients with HC because of its genetic heterogeneity. Therefore, understanding the diagnostic value of classic ECG voltage criteria may be important in detecting carriers, including those without left ventricular hypertrophy Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) In clinical practice, classic electrocardiographic (ECG) voltage criteria have been applied to the detection of left ventricular hypertrophy in patients with hypertrophic cardiomyopathy (HC). However, differences in the diagnostic value of various voltage criteria for HC have not yet been clarified. Recent molecular genetic studies in HC have shown that some genetic carriers of the disease may have no demonstrable hypertrophy on 2-dimensional echocardiography. 1 Previous studies have demonstrated that ECG abnormalities may be observed before the appearance of left ventricular hypertrophy in carriers with disease-causing mutations for HC. 2,3 The first goal of the present study was to determine the most accurate diagnostic definition of classic ECG voltage criteria for HC on the basis of molecular genetic diagnoses, and the second goal was to apply classic Molecular Genetics of Cardiovascular Disorders, Division of Cardiovascular Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. Manuscript received January 26, 2005; revised manuscript received and accepted June 15, * Corresponding author: Tel: ; fax: address: kontetsu@im2.m.kanazawa-u.ac.jp (T. Konno). ECG voltage criteria to the identification of prehypertrophic carriers in clinically healthy subjects. Methods Subjects: Twenty families with HC in which the disease-causing mutation was identified were studied. After the mutation was identified in the proband with HC, the family members were studied by 12-lead electrocardiography and echocardiography, and blood samples were obtained for genetic analysis. A total of 173 subjects were included in this study. Twelve subjects were excluded because of 1of the following reasons: a history of old anterior myocardial infarction, preexcitation, hypertension, and conduction disturbance. Consequently, 161 subjects were analyzed. Informed consent was obtained from all subjects or their guardians in accordance with the guidelines of the Bioethical Committee on Medical Researches, School of Medicine, Kanazawa University. Detection of mutations: Deoxyribonucleic acid of the probands was isolated from peripheral white blood cells, as previously described. 4 The amplification of genomic de /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

138 Cardiomyopathy/Voltage Criteria for Hypertrophic Cardiomyopathy 1309 oxyribonucleic acid was performed using a polymerase chain reaction. Oligonucleotide primers were used to amplify exons of the cardiac myosin-binding protein C gene, -myosin heavy chain gene, cardiac troponin T gene, and cardiac troponin I gene, as previously reported. 5 8 Singlestrand conformational polymorphism analysis of amplified deoxyribonucleic acid was then performed. For abnormal single-strand conformational polymorphism patterns, the nucleotide sequences of the cloned polymerase chain reaction products were determined on the 2 strands by the dye terminator cycle sequencing method using an automated fluorescent sequencer (ABI PRISM 310 Genetic Analyzer, PE Biosystems, Foster City, California). The sequence variations were confirmed by restriction enzyme digestion. Definition of classic ECG voltage criteria: Standard 12-lead electrocardiograms were recorded in all subjects in the supine position during quiet respiration. The ECG voltage criteria were defined as follows on the basis of previous studies: Cornell voltage criterion: R avl SV 3,with8mm added in women, 28 mm 9 ; Sokolow-Lyon voltage criterion: SV 1 RV 5 or RV 6, whichever is larger, 35 mm 10 ; Romhilt-Estes voltage criterion: point score, described previously, 11 4; and sum of QRS voltages in all 12 leads 175 mm. 12 ECG abnormalities other than classic ECG voltage criteria were defined as follows: Q wave 3 mmin depth and/or 0.04 seconds in duration in 2 leads except avr 13 ; ST-segment depression of an upsloping type 0.1 mv at 0.08 seconds after the J point, or those of horizontal or downsloping type 0.05 mv 2,13 ; and T-wave inversion 0.1 mv except avr and V 1 to V 2 leads in the absence of conduction disturbance. 2,13 Echocardiographic criteria: Standard M-mode and 2- dimensional echocardiographic studies were performed to identify and quantify morphologic features of the left ventricle. Left ventricular dimensions and the thickness of the septum and posterior wall were measured at the level of the tips of the mitral valve leaflets. Left ventricular maximum wall thickness 13 mm in adults and 95% confidence interval of the theoretic value in children were considered the diagnostic criteria for HC. 14 Electrocardiography and echocardiography were performed at the time of genotyping and were analyzed without knowledge of the genetic status. Statistical analysis: Sensitivity was defined in percentage as true-positive results/(true-positive results falsenegative results) 100, specificity as true-negative results/ (true-negative results false-positive results) 100, positive predictive value as true-positive results/(true-positive results false-positive results) 100, negative predictive value as true-negative results/(true-negative results false-negative results) 100, and accuracy as (true-positive results true-negative results)/(true-positive results truenegative results false-positive results false-negative results) Continuous data are expressed as mean SD and were analyzed with Student s unpaired, 2-tailed t test. Table 1 Demographic and clinical characteristics of the study groups Characteristic Carriers (n 97) Noncarriers (n 64) Age (yrs) Men/Women 45/52 28/36 Genes TNNI TNNT MYBPC MYH7 5 2 Echocardiography MWT (mm) * IVST (mm) * PWT (mm) * LVDd (mm) LVDs (mm) FS (%) LAD (mm) Voltage criteria Sokolow-Lyon 33 (34%) 15 (23%) Cornel 29 (30%)* 3 (4.9%) Romhilt-Estes 36 (37%)* 3 (4.9%) 12-lead QRS 76 (78%)* 20 (31%) *p ; p 0.01; p FS fractional shortening; IVST interventricular wall thickness; LAD left atrial dimension; LVDd left ventricular end-diastolic dimension; LVDs left ventricular end-systolic dimension; MYBPC3 cardiac myosin-binding protein C; MYH7 cardiac -myosin heavy chain; MWT maximal wall thickness; PWT left ventricular posterior wall thickness; TNNI3 cardiac troponin I; TNNT2 cardiac troponin T. Categorical data were compared with the chi-square test. Differences were considered to be statistically significant at p Results Genetic results and characteristics of subjects: Ten different mutations were identified in 20 families. Genetic analysis revealed that 97 of the 161 subjects enrolled were genetically affected, and 64 subjects were genetically unaffected. Of the 97 genetically affected subjects, 30 were associated with the cardiac myosin-binding protein C gene mutation (Del593C, n 4; Int21DSG 1A, n 14; Arg820Gln, n 12), 5 were associated with the -myosin heavy chain gene mutation (Ala26Val, n 3; Glu935Lys, n 2), 21 were associated with the cardiac troponin T gene mutation (Arg92Trp, n 8; Lys273Glu, n 10; Val85Leu, n 1; Phe110Ile, n 2), and 41 were associated with the cardiac troponin I gene mutation (Lys183Del, n 41). All mutations have been previously identified and described elsewhere. 4,16 21 The demographics and clinical characteristics of the study population are listed in Table 1. There were no statistically significant differences in the mean age and gender distribution between carriers and noncarriers. The frequency of voltage abnormalities assessed by the Cornell, Romhilt-Estes, and 12-lead QRS voltage criteria was significantly greater in carriers than noncarriers.

139 1310 The American Journal of Cardiology ( Table 2 Diagnostic value of various classic ECG voltage criteria for detecting carriers of HC Criterion Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) Age 30 yrs (n 51) Sokolow-Lyon Cornell lead QRS Romhilt-Estes Age 30 yrs (n 110) Sokolow-Lyon Cornell lead QRS Romhilt-Estes All subjects (n 161) Sokolow-Lyon Cornell lead QRS Romhilt-Estes NPV negative predictive value; PPV positive predictive value. Table 3 Diagnostic value of various classic ECG voltage criteria for detecting carriers of HC (with specificity adjustment) Criterion Sensitivity (%) Specificity (%) PPV (%) NPV (%) Accuracy (%) Age 30 yrs (n 51) Sokolow-Lyon ( 45 mm) Cornell lead QRS ( 235 mm) Romhilt-Estes Age 30 yrs (n 110) Sokolow-Lyon ( 50 mm) Cornell lead QRS ( 275 mm) Romhilt-Estes All subjects (n 161) Sokolow-Lyon ( 48 mm) Cornell lead QRS ( 240 mm) Romhilt-Estes Abbreviations as in Table 2. Diagnostic value of various ECG voltage criteria: Table 2 lists the diagnostic value of the various ECG voltage criteria for carriers with disease-causing mutations. In the young and adult populations, the 12-lead QRS voltage criterion showed the greatest sensitivity but the least specificity. All 4 criteria showed greater diagnostic values in the adult population than in the young population, with greater sensitivity and greater specificity, resulting in greater accuracy. Comparison of sensitivity of various ECG voltage criteria: Table 3 lists the diagnostic value of the various ECG voltage criteria for carriers with disease-causing mutations, with adjustment of the specificity to compare the sensitivity. In the young population, the 12-lead QRS voltage criterion showed the greatest sensitivity of the 4 voltage criteria. In the adult population, the Romhilt-Estes criterion showed the greatest sensitivity of the 4 voltage criteria. In all subjects, the sensitivities of the 12-lead QRS voltage and Romhilt-Estes criteria were greater than those of the Cornell and Sokolow-Lyon criteria. Age-related frequency of major ECG abnormalities: Figure 1 shows the ratio of major ECG abnormalities in different decades of life in carrier subjects. In teens, abnormal Q waves were most frequently found, gradually decreasing after 20 years of age. In contrast, ST-T abnormalities were the most frequently observed of the 3 major ECG abnormalities after 20 years of age. The frequency of left ventricular hypertrophy assessed by the Romhilt-Estes criterion increased after 20 years of age but decreased after 60 years of age. Voltage abnormalities in prehypertrophic carriers: The Romhilt-Estes (point score 4) and the 12-lead QRS voltage ( 240 mm) criteria, which showed the greatest diagnostic value in all subjects at a specificity of 95%, were

140 Cardiomyopathy/Voltage Criteria for Hypertrophic Cardiomyopathy 1311 Figure 1. Age-related frequencies of abnormal Q waves, voltage abnormalities assessed by the Romhilt-Estes criterion, and ST-T abnormalities. Open bars, the percentage of carriers with abnormal Q waves, hatched bars, the percentage of carriers with voltage abnormalities, and solid bars, the percentage of carriers with ST-T abnormalities. applied to the identification of prehypertrophic carriers in clinically healthy subjects without echocardiographic evidence of left ventricular hypertrophy. Of the 97 genetically affected subjects, 31 did not manifest left ventricular hypertrophy on echocardiography, and they were defined as prehypertrophic carriers. The frequency of voltage abnormalities assessed by the Romhilt-Estes and 12-lead QRS voltage criteria was significantly greater in prehypertrophic carriers than noncarriers (22.6% in prehypertrophic carriers, n 31; 4.7% in noncarriers, n 64; p 0.01). Maximal wall thickness and age were not significantly different between prehypertrophic carriers and noncarriers (maximal wall thickness mm in prehypertrophic carriers, mm in noncarriers, p NS; age years in prehypertrophic carriers, years in noncarriers, p NS). Five of 31 prehypertrophic carriers showed wall thickness of 12 to 13 mm, whereas 2 of 64 noncarriers exhibited this level of hypertrophy. In screening for prehypertrophic carriers in clinically healthy subjects without left ventricular hypertrophy, the sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the Romhilt-Estes and 12-lead QRS voltage criteria were 23%, 95%, 70%, 72%, and 72%, respectively. Discussion In patients with HC, the Romhilt-Estes criterion is conventionally applied to the detection of left ventricular hypertrophy in clinical practice, although its use has not been based on the evidence established. In this study, we demonstrated that the Romhilt-Estes and 12-lead QRS voltage criteria were most accurate for the diagnosis of carriers of HC and that voltage abnormalities may be observed, even in prehypertrophic carriers. The Romhilt-Estes criterion is a unique ECG voltage criterion, which is calculated by its original point-score system. 11 Interestingly, the definition of not only QRScomplex amplitude but also the ST-T segment is included in the point-score system, in contrast with the Cornell and Sokolow-Lyon criteria. Probable left ventricular hypertrophy is defined as 4 of a maximum total of 13 points. Of note, 3 points will be given if the typical ST-T pattern of left ventricular strain is present without the use of digitalis. That is to say, patients with ST-T segment abnormalities tend to be diagnosed as positive by the Romhilt-Estes criterion. In the present study, ST-T abnormalities were commonly observed in carrier subjects after 20 years of age (Figure 1), which could have contributed to a high sensitivity for the Romhilt-Estes criterion, especially in the adult population. It was previously demonstrated that the 12-lead QRS voltage criterion shows the greatest sensitivity for HC in necropsy patients. 12 Actually, using 175 mm as the cutoff point, the 12-lead QRS voltage criterion showed excellent sensitivity for HC in the genotyped population studied here (Table 2). Of note, the 12-lead QRS voltage criterion showed preferable sensitivity, even when the cutoff point was set to 240 mm to provide a specificity of 95% (Table 3). Our data may provide evidence of the clinical use of the Romhilt-Estes and 12-lead QRS voltage criteria as standard voltage criteria for HC on the basis of molecular genetic diagnoses. Establishing a clinical diagnosis in prehypertrophic carriers is of major importance, because sudden death occurs in young, asymptomatic patients with HC even in the absence of left ventricular hypertrophy. 22,23 In our population, voltage abnormalities assessed by the Romhilt-Estes and 12- lead QRS voltage criteria were observed at a significantly higher rate in prehypertrophic carriers than in noncarriers (22.6% in preclinical carriers, 4.7% in noncarriers, p 0.01). These findings suggest that voltage abnormalities may be a useful predictor for prehypertrophic carriers in clinically healthy subjects. A simple, cheap, accessible, sensitive, and specific diagnostic test for HC is not available at present, 24 especially for detecting prehypertrophic carriers. Ho et al 25 reported that diastolic dysfunction assessed by tissue Doppler imaging may predict the genetic status in subjects without left ventricular hypertrophy. In their report, the diagnostic value of a combination of Ea velocity ( 13.5 cm/s) and the left ventricular ejection fraction ( 68%) shows a preferable sensitivity of 44%, with a specificity of 100%. However, in clinical practice, tissue Doppler techniques have not yet been widely used for screening prehypertrophic carriers because of their relatively complicated procedures and cost-related problems. From this point of view, electrocardiography is a clinically accessible method for the diagnosis of HC. 13 Although voltage abnormalities assessed by the Romhilt-Estes and 12-lead QRS voltage criteria showed lower sensitivity for prehypertrophic carriers (23%) compared with the tissue Doppler techniques described previously, we suggest that ECG voltage criteria may still be useful in

141 1312 The American Journal of Cardiology ( detecting prehypertrophic carriers, because of their excellent specificity, simplicity, and cost-effectiveness. 1. Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux AC, Isnard R, Hagege A, Langlard JM, Bonne G, et al. Diagnostic value of electrocardiography and echocardiography for familial hypertrophic cardiomyopathy in a genotyped adult population. Circulation 1997;96: Shimizu M, Ino H, Yamaguchi M, Terai H, Hayashi K, Kiyama M, Sakata K, Hayashi T, Inoue M, Kaneda T, et al. Chronologic electrocardiographic changes in patients with hypertrophic cardiomyopathy associated with cardiac troponin I mutation. Am Heart J 2002;143: Ryan MP, Cleland JG, French JA, Joshi J, Choudhury L, Chojnowska L, Michalak E, al-mahdawi S, Nihoyannopoulos P, Oakley CM. The standard electrocardiogram as a screening test for hypertrophic cardiomyopathy. Am J Cardiol 1995;76: Kokado H, Shimizu M, Yoshio H, Ino H, Okeie K, Emoto Y, Matsuyama T, Yamaguchi M, Yasuda T, Fujino N, et al. Clinical features of hypertrophic cardiomyopathy caused by a Lys183 deletion mutation in the cardiac troponin I gene. Circulation 2000;102: Carrier L, Bonne G, Bahrend E, Yu B, Richard P, Niel F, Hainque B, Cruaud C, Gary F, Labeit S, et al. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy. Circ Res 1997;80: Jaenicke T, Diederich KW, Haas W, Schleich J, Lichter P, Pfordt M, Bach A, Vosberg HP. The complete sequence of the human betamyosin heavy chain gene and a comparative analysis of its product. Genomics 1990;8: Thierfelder L, Watkins H, MacRae C, Lamas R, McKenna W, Vosberg HP, Seidman JG, Seidman CE. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere. Cell 1994;77: Kimura A, Harada H, Park JE, Nishi H, Satoh M, Takahashi M, Hiroi S, Sasaoka T, Ohbuchi N, Nakamura T, et al. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy. Nat Genet 1997;16: Okin PM, Roman MJ, Devereux RB, Kligfield P. Electrocardiographic identification of increased left ventricular mass by simple voltageduration products. J Am Coll Cardiol 1995;25: Sokolow M, Lyon TP. The ventricular complex in left ventricular hypertrophy as obtained by unipolar precordial and limb leads. Am Heart J 1949;37: Romhilt DW, Estes EH. A point-score system for the ECG diagnosis of left ventricular hypertrophy. Am Heart J 1968;75: Dollar AL, Roberts WC. Usefulness of total 12-lead QRS voltage compared with other criteria for determining left ventricular hypertrophy in hypertrophic cardiomyopathy: analysis of 57 patients studies at necropsy. Am J Med 1989;87: Konno T, Shimizu M, Ino H, Yamaguchi M, Terai H, Uchiyama K, Oe K, Mabuchi T, Kaneda T, Mabuchi H. Diagnostic value of abnormal Q waves for identification of preclinical carriers of hypertrophic cardiomyopathy based on a molecular genetic diagnosis. Eur Heart J 2004;25: Charron P, Dubourg O, Desnos M, Bennaceur M, Carrier L, Camproux AC, Isnard R, Hagege A, Langlard JM, Bonne G, et al. Clinical features and prognostic implications of familial hypertrophic cardiomyopathy related to the cardiac myosin binding protein C gene. Circulation 1998;97: Grimes DA, Schulz KF. Uses and abuses of screening tests. Lancet 2002;359: Konno T, Shimizu M, Ino H, Matsuyama T, Yamaguchi M, Terai H, Hayashi K, Mabuchi T, Kiyama M, Sakata K, et al. A novel missense mutation in the myosin binding protein-c gene is responsible hypertrophic cardiomyopathy with left ventricular dysfunction and dilation in elderly patients. J Am Coll Cardiol 2003;41: Konno T, Shimizu M, Ino H, Terai H, Fujino N, Sakata K, Inoue M, Mabuchi H. A novel mutation (Int21DSG 1A) in the cardiac myosin binding protein-c gene is responsible for hypertrophic cardiomyopathy with severe left ventricular hypertrophy and a high degree of penetrance (abstr). Circulation 2003; Nishi H, Kimura A, Harada H, Koga Y, Adachi K, Matsuyama K, Koyanagi T, Yasunaga S, Imaizumi T, Toshima H, et al. A myosin missense mutation, not a null allele, causes familial hypertrophic cardiomyopathy. Circulation 1995;91: Nishi H, Kimura A, Harada H, Adachi K, Koga Y, Sasazuki T, Toshima H. Possible gene dose effect of a mutant cardiac beta-myosin heavy chain gene on the clinical expression of familial hypertrophic cardiomyopathy. Biochem Biophys Res Commun 1994;200: Fujino N, Shimizu M, Ino H, Okeie K, Yamaguchi M, Yasuda T, Kokado H, Mabuchi H. Cardiac troponin T Arg92Trp mutation and progression from hypertrophic to dilated cardiomyopathy. Clin Cardiol 2001;24: Fujino N, Shimizu M, Ino H, Yamaguchi M, Yasuda T, Nagata M, Konno T, Mabuchi H. A novel mutation Lys273Glu in the cardiac troponin T gene shows high degree of penetrance and transition from hypertrophic to dilated cardiomyopathy. Am J Cardiol 2002;89: McKenna WJ, Stewart JT, Nihoyannopoulos P, McGinty F, Davies MJ. Hypertrophic cardiomyopathy without hypertrophy: two families with myocardial disarray in the absence of increased myocardial mass. Br Heart J 1990;63: Maron BJ, Kragel AH, Roberts WC. Sudden death in hypertrophic cardiomyopathy with normal left ventricular mass. Br Heart J 1990; 63: Sigwart U. The diagnosis of familial hypertrophic cardiomyopathy in children. Eur Heart J 1998;19: Ho CY, Sweitzer NK, McDonough B, Maron BJ, Casey SA, Seidman JG, Seidman CE, Solomon SD. Assessment of diastolic function with Doppler tissue imaging to predict genotype in preclinical hypertrophic cardiomyopathy. Circulation 2002;105:

142 Usefulness of Magnetic Resonance Angiography for Diagnosis of Scimitar Syndrome in Early Infancy Muhammad A. Khan, MD a, Alejandro J. Torres, MD a, Beth F. Printz, MD a,b, and Ashwin Prakash, MD a,b, * This study evaluated the feasibility and accuracy of the magnetic resonance angiography (MRA) evaluation of scimitar syndrome in early infancy in 4 subjects. MRA imaging was successful, with excellent imaging quality to evaluate the main and lobar pulmonary artery branches, lobar pulmonary veins, scimitar vein, and systemicpulmonary collateral arteries in all subjects. There was good agreement between findings with MRA, x-ray angiography (n 3), surgical inspection (n 3), and autopsy (n 1) Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Scimitar syndrome is a rare and complex congenital anomaly characterized by partial anomalous pulmonary venous drainage to the inferior vena cava, pulmonary hypoplasia, and pulmonary sequestration. It may occur either in isolation or in association with other congenital cardiac defects. 1,2 Cardiac catheterization is considered the reference standard for confirmation of the diagnosis and is also used for the coil embolization of systemic-pulmonary collateral arteries. However, catheterization is an invasive technique involving exposure to ionizing radiation and has a significant risk for complications, especially in infants. 3 Magnetic resonance angiography (MRA) is a newer modality that has been shown to be accurate in the diagnosis of pulmonary and systemic venous anomalies and in the identification of aortopulmonary collateral arteries in children and adults. 4 7 However, there are several technical limitations to its use in young infants, and its accuracy in the diagnosis of scimitar syndrome in this patient population is unknown. The aim of this study was to evaluate the feasibility, accuracy, and technical aspects of MRA in the diagnosis of scimitar syndrome in infancy compared with cardiac catheterization and/or surgical inspection. The records of all 4 consecutive infants (median age 39 days, range 3 to 68; 1 male and 3 female infants) with diagnoses of scimitar syndrome who underwent clinically indicated cardiac magnetic resonance imaging studies before surgical or catheter-based intervention at Morgan Stanley Children s Hospital of New York Presbyterian from March to August 2004 were retrospectively reviewed. a Division of Pediatric Cardiology and b Department of Radiology, Columbia University College of Physicians and Surgeons and Morgan Stanley Children s Hospital of New York Presbyterian, New York, New York. Manuscript received April 13, 2005; revised manuscript received and accepted June 22, * Corresponding author: Tel: ; fax: address: ap493@columbia.edu (A. Prakash). All subjects had undergone echocardiography before MRA. MRA studies were performed using a 1.5-T whole-body scanner (Signa EXCITE, GE Healthcare, Milwaukee, Wisconsin), using a commercially available head-imaging coil with 4 receiver channels. All infants were intubated and were being mechanically ventilated during the studies. Sedation and paralysis were induced with intravenous fentanyl 2 g/kg and vecuronium 0.1 mg/kg after placement into the scanner and just before imaging. After 3-plane spoiled gradient-recalled echo localizer images, 3-dimensional MRA was performed in the coronal orientation using the following imaging parameters: field of view 200 mm, matrix 192 (phase) and 256 (frequency), slice thickness 2 mm, echo time 1.1 ms, repetition time 3.4 to 3.7 ms, flip angle 40, number of signal averages 1, sequential phase ordering, number of dynamics 3, and acquisition time 25 to 35 s/dynamic. Gadopentetate dimeglumine (Magnevist, Berlex Laboratories, Seattle, Washington; 0.4 to 0.5 mmol/kg) followed by a normal saline flush (1 ml/kg) were manually injected in a peripheral or central vein at a rate of 0.5 to 1 ml/s. After the suspension of mechanical ventilation, imaging was initiated approximately 5 to 10 seconds after the start of the injection using the best estimate method. Three sets of images (dynamics) were obtained, with ventilator breaths delivered for approximately 5 to 10 seconds between each set. Oxygen saturation, respirations, heart rate, and blood Table 1 Grading for MRA image quality Score Description 1 Structure not seen at all due to poor image quality 2 Structure seen with indistinct margins, insufficient for diagnosis or measurement 3 Structure seen with indistinct margins, sufficient for diagnosis but not for measurement 4 Structure seen with distinct margins, sufficient for diagnosis and measurement A Structure absent with otherwise good imaging quality /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

143 1314 The American Journal of Cardiology ( Table 2 Anatomic and clinical profile of subjects Lung Volume: Right/Left (ml) Associated Extracardiac Anomalies Cardiac Position Systemic Pulmonary Collateral Arteries Pulmonary Venous Anomaly Gender Other Cardiac Defects Weight (kg) Subject Age (days) Rt-lung hypoplasia, horseshoe lung Dextrocardia 28/69 Abdominal aorta to rt lower lung M None Rt upper vein to IVC-RA junction 78/23 Lt-lung hypoplasia Extreme levocardia Rt veins to IVC Abdominal aorta to rt lower lung and lt lower lung F Tricuspid atresia, ASD, VSD Rt-lung hypoplasia Dextrocardia 19/104 Abdominal aorta to rt lower lung Lt veins to SVC-RA junction, rt middle and lower lobe veins to IVC-RA junction F ASD, mixed TAPVR Dextrocardia 24/ F ASD, VSD Rt veins to IVC-RA junction None Rt-lung hypoplasia, lt PA sling, tracheal stenosis, bowel malrotation, duodenal atresia, Meckel s diverticulum ASD atrial septal defect; IVC inferior vena cava; lt left; PA pulmonary artery; RA right atrium; rt right; SVC superior vena cava; TAPVR total anomalous pulmonary venous return; VSD ventricular septal defect. pressure were monitored noninvasively throughout the procedure. Magnetic resonance image analysis was performed on a computer workstation (Advantage Windows 4.1, GE Healthcare). Cardiac and extracardiac vascular anatomy was defined by constructing user-defined subvolume maximalintensity projections and multiplanar reformatted images. In addition, right and left lung volumes were calculated using a stack of images reconstructed in the axial plane from 3-dimensional MRA. Using commercially available software (MASS, MEDIS Medical Imaging Systems, Leiden, The Netherlands) and methods similar to that described for the measurement of ventricular chamber volumes, the borders of each lung were traced manually and the volume of each lung calculated. Cardiac catheterization data were available for 3 of 4 subjects. MRA and x-ray angiographic images were analyzed by separate blinded observers to determine the locations and sizes of the anomalous pulmonary vein, branch pulmonary artery size and architecture, the locations and sizes of aortopulmonary collaterals, and the presence of dual blood supply to sequestered lung segments. Each structure was measured at the same location on MRA and x-ray angiographic images. In addition, for each subject, the quality of MRA imaging of the main, proximal branch, and lobar pulmonary arteries; lobar pulmonary veins; scimitar vein; and aortopulmonary collateral arteries was graded on a scale ranging from 1 to 4 (Table 1). Anatomic measurements made with MRA and x-ray angiography were compared using correlation and Bland-Altman analysis. Surgical and autopsy reports were analyzed when available. Clinical and anatomic characteristics of the subjects and details of associated cardiac and systemic anomalies are listed in Table 2. Examples of maximal-intensity projections reconstructed from MRA images are shown in Figures 1 to 3. On blinded analysis of MRA images, partial anomalous pulmonary venous connection to the inferior vena cava was identified in all subjects, and systemic-pulmonary collateral arteries from the abdominal aorta were seen in 3 of 4 subjects. Of the subjects with systemic-pulmonary collateral arteries, additional native pulmonary artery branches to the involved lung lobe ( dual supply) were seen in 2 of 3 subjects. Right and left lung volumes are listed in Table 2. All subjects had unilateral lung hypoplasia, which was right sided in 3 subjects and left sided in 1 subject. Overall MRA image quality was adequate in all subjects, without imaging artifacts. The imaging quality score (graded 1 to 4) for the main and proximal branch pulmonary arteries, scimitar vein, and systemic-pulmonary collateral arteries was 4 (excellent) for every analyzed structure in every subject. The median imaging quality score was 3.7 (range 2 to 4, n 18) for lobar pulmonary artery branches and 3.9 (range 2 to 4, n 19) for lobar pulmonary veins. The median total duration of magnetic resonance imaging was 7 minutes (range 2 to 11). Cardiac catheterization was performed in 3 of 4 subjects (subjects 2 to 4), all after MRA imaging. The indications for

144 Congenital Heart Disease/MRA of Infants With Scimitar Syndrome 1315 Figure 1. Coronal maximal-intensity projection MRA image from subject 2 showing a right-sided scimitar vein draining into the inferior vena cava with stenosis at its entry. catheterization were the coil embolization of systemicpulmonary collateral arteries in 2 (subjects 2 and 3) and the measurement of pulmonary artery pressure in 1 (subject 4). There was complete agreement between MRA and x-ray angiography in identifying the location and drainage of the scimitar vein (2 of 2 subjects) and the location and drainage of systemic-pulmonary collateral arteries (2 of 2 subjects). There was close correlation (r 0.95) and agreement (mean difference mm) between MRA and x-ray angiography in the measurement of the size of proximal pulmonary artery branches, the scimitar vein, and systemicpulmonary collateral arteries, as shown in Figures 4 and 5. Figure 3. Axial maximal-intensity projection MRA image from subject 4 showing marked hypoplasia of the right pulmonary artery (RPA) and right lung. LPA left pulmonary artery. Cardiac surgery was performed in 3 of 4 infants (subjects 1 to 3) for the repair of associated cardiac defects. One infant (subject 2) also underwent baffling of the scimitar vein to the left atrium. Findings at surgical inspection were in agreement with findings on MRA in all patients. An autopsy was performed on 1 infant (subject 4), and the results were in complete agreement with the findings on MRA. The results of this study demonstrate that the rapid and complete anatomic evaluation of scimitar syndrome in early infancy is possible using MRA. In this small group of patients with this rare congenital anomaly, the results of MRA were in close agreement with the results of cardiac catheterization and surgical or pathologic inspection. The quality of MRA images was excellent for the evaluation of Figure 2. Coronal maximal-intensity projection MRA image from subject 2 showing a systemic-pulmonary collateral artery (arrowhead) from the abdominal descending aorta to the lower lobe of the right lung. Figure 4. Correlation plot of measurements made on MRA and x-ray angiography.

145 1316 The American Journal of Cardiology ( within a few minutes while avoiding the risks of invasive catheterization, which may be limited to infants in whom the embolization of systemic-pulmonary artery collateral vessels or measurement of pulmonary arterial pressure is indicated. This study was limited by its retrospective design, small number of study subjects, and absence of gold-standard imaging in all subjects. The results should be validated and expanded by additional studies. Figure 5. Bland-Altman plot of measurements made on MRA and x-ray angiography. the main and lobar pulmonary artery branches, lobar pulmonary veins, scimitar vein, and systemic-pulmonary artery collateral arteries in all subjects. In addition, right and left lung volumes could also be calculated. The diagnosis of scimitar syndrome in early infancy can be usually made on echocardiography, which can demonstrate anomalous pulmonary venous drainage to the inferior vena cava. However, cardiac catheterization is frequently performed to define the peripheral pulmonary arterial architecture and the presence and location of systemic-pulmonary artery collateral arteries, especially when surgery is indicated. The diagnostic accuracy of MRA in the anatomic delineation of pulmonary artery architecture and anomalies of pulmonary venous drainage has previously been demonstrated. 4 7 There are also several single-case reports of the successful use of MRA in the anatomic delineation of scimitar syndrome in adult patients However, the feasibility and accuracy of MRA in small infants with scimitar syndrome has not been previously described. The use of MRA in small infants poses several challenges because of a relatively low signal-to-noise ratio and respiratory motion artifacts. These difficulties can be overcome with the appropriate modification of imaging parameters and by suspending respirations during image acquisition. 12 The evaluation of scimitar syndrome in infancy by MRA offers several advantages. It allows the angiographic evaluation of the entire extracardiac vasculature 1. Halasz N, Halloran KH, Liebow AA. Bronchial and arterial anomalies with drainage of the right lung into the inferior vena cava. Circulation 1956;14: Huddleston CB, Exil V, Canter CE, Mendeloff EN. Scimitar syndrome presenting in infancy. Ann Thorac Surg 1999;67: Brown DW, Gauvreau K, Moran AM, Jenkins KJ, Perry SB, del Nido PJ, Colan SD. Clinical outcomes and utility of cardiac catheterization prior to superior cavopulmonary anastomosis. J Thorac Cardiovasc Surg 2003;126: Greil GF, Powell AJ, Gildein HP, Geva T. Gadolinium-enhanced three-dimensional magnetic resonance angiography of pulmonary and systemic venous anomalies. J Am Coll Cardiol 2002;39: Geva T, Greil GF, Marshall AC, Landzberg M, Powell AJ. Gadolinium-enhanced 3-dimensional magnetic resonance angiography of pulmonary blood supply in patients with complex pulmonary stenosis or atresia: comparison with x-ray angiography. Circulation 2002;106: Prasad SK, Soukias N, Hornung T, Khan M, Pennell DJ, Gatzoulis MA, Mohiaddin RH. Role of magnetic resonance angiography in the diagnosis of major aortopulmonary collateral arteries and partial anomalous pulmonary venous drainage. Circulation 2004;109: Masui T, Seelos KC, Kersting-Sommerhoff BA, Higgins CB. Abnormalities of the pulmonary veins: evaluation with MR imaging and comparison with cardiac angiography and echocardiography. Radiology 1991;181: Gilkeson RC, Lee JH, Sachs PB, Clampitt M. Gadolinium-enhanced magnetic resonance angiography in scimitar syndrome: diagnosis and postoperative evaluation. Tex Heart Inst J 2000;27: Marco de Lucas E, Canga A, Sadaba P, Martin-Duran R, Otero M, Cerezal L. Scimitar syndrome: complete anatomical and functional diagnosis with gadolinium-enhanced and velocity-encoded cine MRI. Pediatr Radiol 2003;33: Puvaneswary M, Leitch J, Chard RB. MRI of partial anomalous pulmonary venous return (scimitar syndrome). Australas Radiol 2003; 47: Kramer U, Dornberger V, Fenchel M, Stauder N, Claussen CD, Miller S. Scimitar syndrome: morphological diagnosis and assessment of hemodynamic significance by magnetic resonance imaging. Eur Radiol 2003;13(suppl):L147 L Tsai-Goodman B, Geva T, Odegard KC, Sena LM, Powell AJ. Clinical role, accuracy, and technical aspects of cardiovascular magnetic resonance imaging in infants. Am J Cardiol 2004;94:69 74.

146 Echocardiographic Doppler Assessment of the Biophysical Properties of the Aorta in Pediatric Patients With the Marfan Syndrome Timothy J. Bradley, MBChB*, James E. Potts, PhD, Mary T. Potts, RDCS, Astrid M. DeSouza, BSc, and George G.S. Sandor, MB, ChB In the Marfan syndrome (MS), aortic root involvement is usually clinically monitored according to the aortic sinus of Valsalva dilation. Using an echocardiographic Doppler method in this cross-sectional study, abnormal biophysical properties of the ascending aorta were found in pediatric patients with MS compared with healthy controls but not consistently in association with the aortic sinus of Valsalva dilation Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Pulse-wave velocity (PWV) is an indirect measure of elastic arterial stiffness. Increased arterial (primarily aortic) stiffness increases PWV. 1 The arterial pressure-strain elastic modulus (Ep) 2 and the arterial wall stiffness index 3 are direct measures of arterial stiffness that assess the relation between pulsatile changes in arterial diameter and pressure. The aortic impedance spectrum expresses the ratio of pressure to flow harmonics that exists in the aortic root. Characteristic impedance (Zc) is determined by physical properties of the artery being considered (e.g., viscoelasticity, dimension). Input impedance (Zi) is determined by reflected pressure and flow waves generated in the more distal arterial tree that produce local frequency-dependent oscillations around the characteristic value. 4 Changes in arterial stiffness affect impedance by altering the physical and wavereflective properties of the aorta and the arterial system. These biophysical properties can be derived in the ascending aorta noninvasively using an echocardiographic Doppler method. 5 The aims of this study were to (1) determine whether early changes in these biophysical properties of the aorta were present in pediatric patients with the Marfan syndrome (MS) compared with controls and (2) evaluate the correlates of these indexes with patient characteristics (gender, age, height, weight, body surface area, body mass index) and a surrogate measure of aortic root involvement (aortic sinus of Valsalva dimension). Thirty-one pediatric patients being followed for MS in our cardiology clinic were screened. Only 26 who strictly met the diagnostic criteria for MS according to the Gent nosology 6 were included. Healthy children and adolescents were Division of Cardiology, Department of Pediatrics, British Columbia Children s Hospital and The University of British Columbia, Vancouver, British Columbia, Canada. Manuscript received February 9, 2005; revised manuscript received and accepted June 21, This work was supported in part by a grant from the Canadian Marfan Association, Mississauga, Ontario, and the Temerty Family Foundation, Toronto, Ontario, Canada. * Corresponding author: Tel: ; fax: address: timothy.bradley@sickkids.ca (T.J. Bradley). recruited from volunteers to make up the control group (n 69). No participant had a history of renal disease, hypertension, or either congenital heart disease or connective tissue disease other than MS. Patients in the 2 groups had clinical and echocardiographic evidence of mild mitral valve prolapse, but no participant had significant associated mitral regurgitation. No participant had significant aortic regurgitation or a bicuspid aortic valve. Six of the MS group were on -blocker medications at the time of assessment. The remaining 20 from the MS group and the entire control group were not on cardiac medication when assessed. Informed consent was obtained from each subject or their parents/guardians. The study protocol was approved by our institutional research review board. All participants had complete echocardiographic assessment with electrocardiographic monitoring. Standard M-mode and 2-dimensional echocardiography were performed to exclude additional congenital heart disease. The aortic stiffness and impedance indexes were derived using an echocardiographic Doppler method. 5 In a standard parasternal long-axis view using 2-dimensional echocardiography, the aortic root diameters (annulus, sinus of Valsalva, and sinotubular junction) were measured. In a high left or right parasternal view, a M-mode recording was made at a right angle and the ascending aortic diameter measured at end-diastolic and at maximum systolic dimensions (Figure 1). All measurements were made on 2-dimensional and M-mode images using the trailing to leading edge method. In a standard suprasternal long-axis view (Figure 1), an ascending aortic pulse-wave Doppler tracing was recorded, and the peak aortic velocity was measured. The time from the QRS to the onset of the ascending aortic Doppler envelope (time 1) was measured (Figure 1). Maintaining the same transducer position, the pulse-wave Doppler sample volume was immediately placed as distal as possible in the descending aorta, and the time from the QRS to the onset of the descending aorta Doppler envelope (time 2) was measured (Figure 1). Using the same 2-dimensional image, the aortic arch length between these 2 sample volume positions was obtained by summing serial measurements made with electronic calipers along the central axis of /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

147 1318 The American Journal of Cardiology ( Table 1 Clinical characteristics Characteristic Patients With MS (n 26) Controls (n 69) p Value Age (yrs) Male:female 14:12 29: Height (cm) Weight (kg) Body surface area (m 2 ) Body mass index (kg/m 2 ) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) Table 2 Echocardiographic measurements Variable Patients With MS (n 26) Controls (n 69) p Value Figure 1. Echocardiographic Doppler method. (A) M-mode recording of the ascending aortic diameters. (B) Standard suprasternal long-axis view. The pulse-wave Doppler tracing recordings were made in the ascending aorta and descending aorta, and the length between these 2 sample volume positions was measured. (C) Spectral Doppler trace in the ascending aorta. (D) Spectral Doppler trace in the descending aorta. Ao aortic; Dd end-diastolic ascending aortic diameter; Ds maximum systolic ascending aortic diameter; RPA right pulmonary artery; T1 time 1; T2 time 2. Aortic root diameters Annulus (cm) Sinus of Valsalva (cm) Normalized for body surface area Normalized for aortic annulus Sinotubular junction (cm) Ascending aortic diameters Maximum systolic (cm) End-diastolic (cm) Peak aortic velocity (cm/s) this curved segment of the aorta. All echocardiographic measurements were averaged over 3 consecutive cardiac cycles. The following calculations were used: pulse pressure systolic blood pressure diastolic blood pressure (mm Hg); peak aortic flow peak aortic velocity aortic annulus cross-sectional area (cubed centimeters per second); transit time time 2 time 1 (seconds); PWV aortic arch length/transit time (centimeters per second); Ep pulse pressure/[(maximum systolic ascending aortic diameter enddiastolic ascending aortic diameter)/end-diastolic ascending aortic diameter] (mm Hg) 2 ; stiffness index ln(systolic blood pressure/diastolic blood pressure)/[(maximum systolic ascending aortic diameter end-diastolic ascending aortic diameter)/ end-diastolic ascending aortic diameter] 3 ;Zi pulse pressure/ peak aortic flow (dyne s/cm 5,1mmHg 1,333 dyne/cm 2 ); and Zc PWV /aortic annulus cross-sectional area (dyne s/cm 5, blood density 1.06 g/cm 3, 1 dyne 1 g cm/s 2 ). 2 The aortic sinus of Valsalva measurement was normalized for body surface area by dividing the observed dimension by the predicted dimension based on age and body surface area using the established regression formula 7,8 and for aortic annulus by dividing the observed dimension by the observed dimension for the aortic annulus. 9,10 To assess the reproducibility of the echocardiographic Doppler method, 5 patients were examined on 4 occasions. To assess interobserver variability, the first and second occasions were performed consecutively by different echocardiographers. To assess within-subject short-term intersessional variability, the third occasion was performed 20 to 30 minutes after the first occasion by the same echocardiographer. To assess within-subject longer term intersessional variability, the fourth occasion was performed 2 to 4 weeks after the first occasion by the same echocardiographer. Finally, to assess interreviewer variability, 2 different reviewers performed the measurements on the first occasion. Summary statistics are expressed as mean SD. Frequency tables were calculated for all categorical variables, and group differences were determined using the chi-square test or, if necessary, Fisher s exact test. Univariate analyses were performed on all continuous variables, and group differences were determined using analysis of variance. Post hoc comparisons were made using the Newman- Keuls procedure. Linear modeling, including linear regression and analysis of covariance, was used to evaluate the independent effect(s) of selected variables in explaining group differences in ascending aortic stiffness and impedance indexes. A p value 0.05 was considered statistically significant. To assess reproducibility within

148 Congenital Heart Disease/Aortic Stiffness in Pediatric Marfan Syndrome 1319 Table 3 Biophysical properties of the ascending aorta Variable Patients with MS (n 26) Controls (n 69) p Value PWV (cm/s) Ep (mm Hg) Stiffness index Zi (dyne s/cm 5 ) Zc (dyne s/cm 5 ) Table 4 Estimated gender, age-, and height-independent differences Variable Estimated Difference in Pediatric Patients with MS for a Given Gender, Age, and Height SEE Pr t PWV (cm/s) 129 greater Ep (mm Hg) 34 greater Stiffness index 0.68 greater Zi (dyne s/cm 5 ) 23 less Zc (dyne s/cm 5 ) 17 greater each potential source of variability, coefficients of variation (mean/sd [percent]) were calculated for all of the dependent variables. All statistical analyses were performed with SAS version 8.2 software (SAS Institute Inc., Cary, North Carolina). The 2 groups were well matched for age and gender, but as expected, patients with MS were taller than controls (Table 1). Aortic root diameters and normalized sinus of Valsalva dimensions, again as expected, were all greater in patients with MS, but ascending aortic dimensions were similar in the 2 groups (Table 2). Systolic blood pressure and peak aortic velocity were less in patients with MS and remained less even when comparing only the 20 patients with MS not receiving -blocker medications ( mm Hg, p 0.003, and cm/s, p , respectively) with the controls. PWV, stiffness index, and Ep were all greater in patients with MS, consistently indicating increased stiffness in the wall of the ascending aorta (Table 3). Zi was less in the MS group, but Zc was similar in the 2 groups. After adjustment for gender, age, and height to control for potential interactions between these parameters and the effect of height on arterial reflective waves, only PWV and the stiffness index remained greater, Zi remained less, and Zc was marginally greater in patients with MS. The estimated difference for each of the indexes for a pediatric patient with MS independent of gender, age, and height based on these data is listed in Table 4. Again, when considering only the 20 patients with MS not receiving -blocker medications, PWV ( cm/s, p ) and the stiffness index ( , p 0.02) remained greater, and the Zi ( dyne s/cm 5, p 0.002) was less in the nonmedicated MS group compared with controls. Univariate analysis of the 2 groups combined suggested positive correlations between central PWV and our Figure 2. Univariate correlations between PWV and sinus of Valsalva normalized for body surface area. Table 5 Reproducibility Coefficient of Variation Interobserver Intersessional Interreviewer Short Term Longer Term PWV (cm/s) 4% 2% 2% 12% Ep (mm Hg) 12% 12% 16% 7% Stiffness index 4% 5% 6% 3% Zi (dyne s/cm 5 ) 10% 12% 10% 7% Zc (dyne s/cm 5 ) 5% 2% 2% 9% surrogate measure of aortic root involvement, sinus of Valsalva (r 0.52, p ), even when normalized for body surface area (r 0.46, p ) and the aortic annulus (r 0.46, p ). However, although plotting the data demonstrated a clear demarcation of increased PWV 440 cm/s in patients with MS (Figure 2), aortic root dilation was not consistently found, even with normalized sinus of Valsalva measurements to account for any age-related variation. For the 5 patients who had repeat echocardiographic Doppler assessment of the biophysical properties of their aortas on 4 occasions, the coefficients of variation calculated for the interobserver, intersessional, and inter-reviewer comparisons ranged from 2% to 16% (Table 5). Increased aortic stiffness and decreased aortic distensibility have been reported previously in patients with MS using echocardiographic, magnetic resonance imaging, and invasive techniques. 20 Jondeau et al, 15 finding arterial distensibility to be less in the abdominal aortas of adults with MS compared with control subjects, but not in the common carotid, common femoral, and radial arteries, concluded that increased arterial stiffness was confined to the aorta. They also concluded that central pulse pressure was a major determinant of ascending aortic dilation in adults with MS. However, in their methods, they actually stated that the

149 1320 The American Journal of Cardiology ( largest diameter, always at the level of the sinus of Valsalva, was taken as the ascending aorta for this study, so in actuality, central pulse pressure was a major determinant of the sinus of Valsalva diameter. As in the present study, some of their adult patients with MS were receiving long-term -blocker treatment. They found no significant differences compared with controls in systolic, diastolic, and pulse pressure when measured at the brachial artery level. In our cohort, systolic blood pressure was less than in controls, even when considering only patients not receiving blockers, but diastolic and pulse pressures were similar. Although it is likely that measures of arterial stiffness and vascular impedance are susceptible to changes in distending pressure, it was not possible for us to correct for blood pressure without autocorrelation, because it was already contained in most of our calculations. The increased PWV around the aortic arch in pediatric patients with MS was similar to that previously found in a smaller group of pediatric patients with MS using the same echocardiographic Doppler method 5 and to that previously found in adults with MS by echocardiography using a formula derived from Young s modulus, 11 by dual carotid and femoral pulse-wave monitoring, 13 and by magnetic resonance imaging. 19 PWV values were greater in the 2 groups in these adult studies consistent with age, and the assessment of PWV along the entire aorta with pulse-wave acceleration peripherally. However, there was considerable overlap in the measured PWV between adults with MS and controls, 11,13,19 potentially because of adult-onset arterial disease of different causes. It is interesting to note that there was a clear demarcation in PWV between pediatric patients with MS and controls in our study. If further studies using this technique confirm our results in pediatric patients with MS, PWV may become useful to assist in the clinical diagnosis of pediatric patients with MS with an atypical phenotype. The increased Ep and stiffness index in pediatric patients with MS was similar to that we had previously found 5 and consistent with regard to other reports of an increase in the purportedly less load dependent stiffness index in adult and pediatric patients with MS from invasive, 20 echocardiographic, and magnetic resonance imaging studies. In pediatric patients with MS, we found lower Zi. From our formulas, Zi is inversely proportional to aortic annulus cross-sectional area and peak aortic velocity, and the derived decrease in Zi appears to be due to the increased aortic annulus dimensions in MS. The decreased peak aortic velocity in pediatric patients with MS, which incidentally was not as significantly decreased in patients receiving -blocker medications, may suggest an adaptive response to the left ventricle to lower Zi. The similar Zc found in the 2 groups has been previously demonstrated invasively at cardiac catheterization using fast-fourier transform of aortic pressure and flow waves by Yin et al. 20 The explanation for this appears to be that the Zc embodies the counterbalancing effects of alterations in stiffness and size of the proximal aorta, because it is directly related to aortic stiffness and inversely related to its diameter. 20 The finding of normal ascending aortic diameters in the MS group is consistent with our observed clinical pattern of aortic root involvement in pediatric patients with MS, with initial sinus of Valsalva dilation followed by sinotubular junction dilation and relative sparing of the ascending aorta. To gauge the interaction between the severity of aortic root involvement and the arterial stiffness and vascular impedance indexes in the ascending aorta and around the aortic arch, we therefore used the measured sinus of Valsalva dimension, after normalization for body surface area and for aortic annulus dimension. Aortic root dimensions in normal children and adults have been found to be strongly influenced by age and body surface area. The observed sinus of Valsalva dimension has been normalized to the predicted dimension for body surface area, according to established regression formulas, 7 which has been shown to have some predictive value for aortic root complications in long-term follow-up. 8 Other investigators have argued that the relation between aortic growth and body surface area is nonlinear and have suggested normalizing the sinus of Valsalva dimension to the aortic annulus dimension. 9,10 Using these surrogate measures of aortic root disease, in this cohort, we were unable to determine any consistent relations between the measured arterial stiffness and vascular impedance indexes and sinus of Valsalva dilation. Although this may represent a sampling error, it may also reflect considerable phenotypic variability within MS. Limitations of this study include technical considerations of the echocardiographic Doppler method for deriving PWV, which required measurement of the rapid transit time of the central pulsewave and the inability of current echocardiographic machines to accurately measure the curved length around the aortic arch. The blood pressures used to derive the indexes were obtained from the brachial artery rather than centrally. The measurements of impedance have been simplified but could be augmented by Fourier analysis of simultaneous carotid pulse tracings and ascending aortic Doppler waveforms to look for correlation. The small number of patients receiving blockers and the study design also meant that we were unable to assess the effect of therapy. The coefficients of variation obtained demonstrated acceptable reproducibility for testing physiologic measures. Although the potential sources of variability assessed did not apply to this crosssectional study, they would need to be addressed if this echocardiographic Doppler method is used to serially monitor disease progression and effect of therapy in patients with MS. 1. Dart AM, Kingwell BA. Pulse pressure a review of mechanisms and clinical relevance. J Am Coll Cardiol 2001;37: Merillon JP, Motte G, Fruchaud J, Masquet C, Gourgon R. Evaluation of the elasticity and characteristic impedance of the ascending aorta in man. Cardiovasc Res 1978;12: Hirai T, Sasayama S, Kawasaki T, Yagi S. Stiffness of systemic arteries in patients with myocardial infarction. A noninvasive method to predict severity of coronary atherosclerosis. Circulation 1989;80:78 86.

150 Congenital Heart Disease/Aortic Stiffness in Pediatric Marfan Syndrome Milnor WR. Arterial impedance as ventricular afterload. Circ Res 1975;36: Sandor GG, Hishitani T, Petty RE, Potts MT, Desouza A, Desouza E, Potts JE. A novel Doppler echocardiographic method of measuring the biophysical properties of the aorta in pediatric patients. JAmSoc Echocardiogr 2003;16: De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996;62: Roman MJ, Devereux RB, Kramer-Fox R, O Loughlin J. Two-dimensional echocardiographic aortic root dimensions in normal children and adults. Am J Cardiol 1989;64: Legget ME, Unger TA, O Sullivan CK, Zwink TR, Bennett RL, Byers PH, Otto CM. Aortic root complications in Marfan s syndrome: identification of a lower risk group. Heart 1996;75: Sheil ML, Jenkins O, Sholler GF. Echocardiographic assessment of aortic root dimensions in normal children based on measurement of a new ratio of aortic size independent of growth. Am J Cardiol 1995; 75: Mart CR, Khan SA, Smith FC, Kavey RE. A new on-line method for predicting aortic root dilatation during two-dimensional echocardiography in pediatric patients with Marfan syndrome using the sinus of Valsalva to annulus ratio. Pediatr Cardiol 2003;24: Jeremy RW, Huang H, Hwa J, McCarron H, Hughes CF, Richards JG. Relation between age, arterial distensibility, and aortic dilatation in the Marfan syndrome. Am J Cardiol 1994;74: Reed CM, Fox ME, Alpert BS. Aortic biomechanical properties in pediatric patients with the Marfan syndrome, and the effects of atenolol. Am J Cardiol 1993;71: Hirata K, Triposkiadis F, Sparks E, Bowen J, Wooley CF, Boudoulas H. The Marfan syndrome: abnormal aortic elastic properties. J Am Coll Cardiol 1991;18: Franke A, Muhler EG, Klues HG, Peters K, Lepper W, von Bernuth G, Hanrath P. Detection of abnormal aortic elastic properties in asymptomatic patients with Marfan syndrome by combined transoesophageal echocardiography and acoustic quantification. Heart 1996;75: Jondeau G, Boutouyrie P, Lacolley P, Laloux B, Dubourg O, Bourdarias JP, Laurent S. Central pulse pressure is a major determinant of ascending aorta dilation in Marfan syndrome. Circulation 1999;99: Haouzi A, Berglund H, Pelikan PC, Maurer G, Siegel RJ. Heterogeneous aortic response to acute beta-adrenergic blockade in Marfan syndrome. Am Heart J 1997;133: Savolainen A, Keto P, Hekali P, Nisula L, Kaitila I, Viitasalo M, Poutanen VP, Standertskjold-Nordenstam CG, Kupari M. Aortic distensibility in children with the Marfan syndrome. Am J Cardiol 1992; 70: Adams JN, Brooks M, Redpath TW, Smith FW, Dean J, Gray J, Walton S, Trent RJ. Aortic distensibility and stiffness index measured by magnetic resonance imaging in patients with Marfan s syndrome. Br Heart J 1995;73: Groenink M, de Roos A, Mulder BJ, Spaan JA, van der Wall EE. Changes in aortic distensibility and pulse wave velocity assessed with magnetic resonance imaging following beta-blocker therapy in the Marfan syndrome. Am J Cardiol 1998;82: Yin FC, Brin KP, Ting CT, Pyeritz RE. Arterial hemodynamic indexes in Marfan s syndrome. Circulation 1989;79:

151 Prospective Evaluation of Aggressive Medical Therapy for Atherosclerotic Renal Artery Stenosis, With Renal Artery Stenting Reserved for Previously Injured Heart, Brain, or Kidney George Hanzel, MD a, Helena Balon, MD b, Oliver Wong, MD, PhD b, Daniel Soffer, MD c, Daniel Taehee Lee, MD d, and Robert David Safian, MD a, * Sixty-six patients with atherosclerotic renal artery stenosis (RAS) and serum creatinine <2.0 mg/dl were treated with antihypertensive therapy, a statin, and aspirin. Renal stenting was reserved for patients with injuries to the heart, brain, or kidneys. The primary end point was stenotic kidney glomerular filtration rate (GFR) at 21 months; secondary end points included major adverse clinical events, serum creatinine, total GFR, and blood pressure (BP). After baseline evaluation, 26 of 66 patients underwent renal stenting because of injuries to the heart, brain, or kidneys. After 21 months, 6 medical patients required renal stenting, and 5 patients experienced late clinical events (2 medical patients, 3 stent patients). There was no difference in final BP between groups. Whereas medical patients experienced 6% and 8% decreases in total and stenotic kidney GFR, stent patients experienced 7% and 11% increases in total kidney (p 0.006) and stenotic kidney (p 0.02) GFR. There was no difference in final serum creatinine. In conclusion, patients with atherosclerotic RAS and baseline creatinine <2.0 mg/dl can be safely managed with aggressive medical therapy, with a small decrease in GFR. For patients who develop injuries to the heart, brain, or kidneys, renal artery stenting may further reduce hypertension and improve renal function Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Atherosclerotic renal artery stenosis (RAS) is a common manifestation of generalized atherosclerosis and is the most common disorder of the renal arterial circulation. 1 8 Despite the frequent association of RAS with hypertension and excretory dysfunction, it has been difficult to establish a direct cause-and-effect relation. Currently available studies have failed to demonstrate a clear benefit of renal artery revascularization on hypertension, renal function, and survival This study prospectively evaluated a strategy of aggressive medical therapy and risk factor modification for all patients with atherosclerotic RAS, reserving renal artery stenting for patients with objective evidence for injuries to the heart, brain, or kidneys. Methods Eligibility criteria: We evaluated and prospectively followed 66 patients with angiographically confirmed unilateral or bilateral atherosclerotic RAS (diameter stenosis 70% involving the ostium or proximal 2 cm of the main Divisions of a Cardiology and b Nuclear Medicine, William Beaumont Hospital, Royal Oak, Michigan; c Lenox Hill Hospital, New York, New York; and d Michigan Cardiovascular Institute, Saginaw, Michigan. Manuscript received January 25, 2005; revised manuscript received and accepted June 14, * Corresponding author: Tel: ; fax: address: rsafian@beaumont.edu (R.D. Safian). renal artery) and baseline serum creatinine 2.0 mg/dl. Written informed consent was obtained in accordance with the Human Investigations Committee at William Beaumont Hospital. Patients were excluded if there was known renal parenchymal disease, proteinuria 1.0 g in 24 hours, severe peripheral arterial disease precluding safe access to the central arterial circulation, or anticipated life expectancy 2 years. Noninvasive evaluation: All patients underwent baseline histories and physical examinations, basic metabolic panels, urinalysis, and nuclear scintigraphy. Patients with 1 proteinuria underwent 24-hour urine collection. Nuclear scintigraphy included total glomerular filtration rate (GFR) using iodine-125 iothalamate and fractional renal blood flow with technetium 99m labeled diethylenetriaminepentaacetic acid, and single-kidney GFR was calculated. Treatment protocol: All patients received aspirin 325 mg/day and a statin to achieve a low-density lipoprotein cholesterol level 100 mg/dl. Antihypertensive therapy was initiated with an angiotensin-converting enzyme inhibitor or angiotensin receptor antagonist, and other agents were added as necessary. Renal artery stenting was performed using the standard protocol (activated clotting time 250 to 300 seconds). After intervention, patients received ticlopidine 250 mg twice daily or clopidogrel 75 mg/day for 30 days. Procedural success was defined as final diameter /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

152 Miscellaneous/Treatment Strategy for Renal Artery Stenosis 1323 Table 1 Baseline characteristics of 66 patients with atherosclerotic RAS Characteristic Medical Group (n 40) Stent Group (n 26) p Value Figure 1. Management algorithm for 66 patients with atherosclerotic RAS. *End-organ injuries of the heart, brain, or kidneys defined as an increase in serum creatinine 1.0 mg/dl, stenotic kidney with 40% of total GFR, and hypertensive crisis associated with acute neurologic impairment (n 4) or nonischemic pulmonary edema (n 5). Six patients treated medically underwent late renal artery stenting because of progressive decreases in single-kidney GFR. Age (yrs) Coronary artery disease 85% 77% 0.52 Congestive heart failure 25% 46% Peripheral vascular disease 65% 58% 0.55 Stroke 20% 27% 0.51 Smoking status Current 2.6% 27% Previous 75% 65% 0.40 Hypertension 100% 100% 1.06 Hyperlipidemia 88% 88% 1.00 Diabetes mellitus 27.5% 27% 0.96 Antihypertensive medication Beta blocker 77% 73% 0.72 ACEI/ARB 64% 73% 0.45 Calcium antagonist 33% 69% Diuretic 36% 58% Vasodilator 2.6% 27% Centrally acting agent 2.6% 19% ACEI angiotensin-converting enzyme inhibitor; ARB angiotensin receptor blocker. stenosis 20% and normal distal flow. Patients were considered to have injuries to the heart, brain, or kidneys on the basis of increases in serum creatinine 1.0 mg/dl, stenotic kidneys with 40% of total GFR, and hypertensive crisis associated with acute neurologic impairment or nonischemic acute pulmonary edema. All patients underwent aggressive risk factor modification, whereas those with endorgan injury also underwent renal artery stenting. Patients were followed up every 3 to 6 months (blood pressure [BP], lipid profile, clinical status; Figure 1), and nuclear studies were obtained yearly. Patients in the medical arm who developed manifestations of end-organ impairment were treated with renal artery stenting (renal impairment was defined as a decrease in stenotic kidney GFR 25% compared with baseline). Patients in the medical arm who underwent renal artery stenting were analyzed in the medical arm before revascularization and in the stent arm after revascularization. Refractory hypertension was not an indication for revascularization in the absence of end-organ injury. End points of the study: The primary end point of this study was the stenotic kidney GFR. Predefined secondary end points included BP; total GFR; serum creatinine; and the combined incidence of renal replacement therapy, stroke, transient ischemic attack, myocardial infarction, pulmonary edema, and death. Statistical analysis: Continuous variables are reported as mean SE. Categorical variables were analyzed using the chi-square or Fisher s exact test. The Wilcox rank-sum test was used for continuous variables. Logistic regression (SAS version 8.0, SAS Institute Inc., Cary, North Carolina) was used to identify predictors of improvement in BP and GFR. Variables included age, gender, coronary artery disease, previous myocardial infarction, congestive heart failure, claudication, transient ischemia attack, stroke, diabetes mellitus, hyperlipidemia, smoking status, proteinuria, previous nephrectomy, a single functioning kidney, baseline creatinine, and baseline BP. A p value 0.05 was considered statistically significant. Results Baseline characteristics: The study group consisted of 66 patients with atherosclerotic RAS; 26 underwent renal artery stenting, and 40 were treated medically (Table 1). RAS was classified as unilateral (32 in the medical group, 13 in the stent group), bilateral (7 in the medical group, 5 in the stent group), and stenosis of a solitary kidney (1 in the medical group, 8 in the stent group). At the time of baseline evaluation, antihypertensive therapy was prescribed in 63 patients (95.5%), but 3 were intolerant because of progressive increases in serum creatinine. Manifestations of endorgan impairment were identified in 26 patients (progressive increases in serum creatinine in 9, unilateral RAS with fractional GFR 40% in 8, and hypertensive crisis in 9; Figure 1). Clinical outcomes: Twenty-six patients underwent renal artery stenting with 100% procedural success; blood transfusion was required in 1 patient (3.8%). No patients developed periprocedural renal failure. During median follow-up of 21 months, 5 patients (6.9%) experienced major adverse events, including stroke in 3 (1 in the medical group, 2 in the stent group) and myocardial infarction in 2 (1 in each group). No patients died or required renal replacement therapy. Six patients (15%) in the medical arm developed progressive decreases in single-kidney GFR (1 had stenosis of

153 1324 The American Journal of Cardiology ( Figure 2. BP (left panel) and number of antihypertensive medications (right panel) at baseline and follow-up. Solid lines, the medical group (p 0.03 for systolic BP [SBP], p 0.01 for diastolic BP [DBP]); dashed lines, the stent group (p 0.01 for SBP, p 0.03 for DBP). a solitary kidney, and 5 had unilateral RAS); all underwent successful stenting without complications. BP response: The 2 groups experienced a significant decrease in BP, although the magnitude of improvement was greater in the stent group (Figure 2). In the medical group, systolic BP decreased from to mm Hg (p 0.03), and diastolic BP decreased from to mm Hg (p 0.01). In the stent group, systolic BP decreased from to mm Hg (p 0.008), and diastolic BP decreased from to mm Hg (p 0.03). The 9% decrease in systolic BP in the stent group was significantly greater than the 5% decrease in the medical group (p 0.016), but the final systolic and diastolic BPs were similar (Figure 3). At baseline, medical patients were taking fewer medications than those in the stent group ( vs , p 0.002). At follow-up, there was no change in medication requirements in the medical group ( , p NS) and there was a nonsignificant decrease in medication requirements in the stent group ( , p NS). There was no difference in medication requirements between groups (Figure 2). Renal function: The baseline ( mg/dl in the medical group, mg/dl in the stent group) and final ( mg/dl in the medical group, mg/dl in the stent group) creatinine concentrations were similar in the 2 groups. However, there was a 7% increase in serum creatinine concentration in the medical group (p 0.021) and a 3.8% decrease in creatinine in the stent group (p NS) (Figure 3). In the medical group, there was a significant decrease in total kidney ( to ml/min/1.73 m 2,p 0.03) and stenotic kidney ( to ml/min/1.73 m 2,p 0.006) GFR. In contrast, total kidney ( to ml/min/1.73 m 2,p NS) and stenotic kidney ( to ml/min/1.73 m 2,p 0.07) GFR increased in the stent group (Figure 4). Whereas patients in the medical group experienced a 6% decrease in total GFR and an 8% decline in stenotic kidney GFR, stent patients experienced a 7% improvement in total GFR (p 0.02 compared with the medical group) and an 11% improvement in stenotic kidney GFR (p compared with the medical group). Interestingly, the single-kidney GFR for the nonstenotic kidney decreased by 3.2% ( to ml/min/1.73 m 2 ) in the medical group and by 9.7% ( to ml/min/1.73 m 2 ) in the stent group (Figure 3). Predictors of outcome: By multivariate analysis, renal artery stenting was the only independent predictor of a 10% increase in total GFR (odds ratio 7.94, 95% confidence interval 2.29 to 27.6). The only independent predictor of a

154 Miscellaneous/Treatment Strategy for Renal Artery Stenosis 1325 Figure 3. Percentage changes from baseline to follow-up in patients with atherosclerotic RAS. White bars, the stent group; black bars, the medical group. Cr serum creatinine concentration (mg/dl); NSK nonstenotic kidney; SBP systolic blood pressure (mm Hg); SK stenotic kidney. decrease in systolic BP 20 mm Hg or diastolic BP 10 mm Hg was the initial systolic BP (odds ratio 0.96, 95% confidence interval 0.92 to 0.99). Discussion The principal finding of this study is that elderly patients with atherosclerotic RAS and baseline creatinine concentrations 2.0 mg/dl should be treated with aggressive medical therapy, reserving renal artery stenting for injuries to the heart, brain, or kidneys. This finding is important because the indications for renal revascularization, and the impact of revascularization on BP, renal function, and survival, remain controversial The precise relation between BP and atherosclerotic RAS is not clear. Surgery and percutaneous techniques cure hypertension in only 1% to 21% of such patients, suggesting that hypertension and atherosclerotic RAS are not causally related Despite low cure rates, improvements in BP and medication requirements after renal revascularization are corroborated by our study Nevertheless, our study suggests that aggressive medical therapy results in significant BP improvement, even in patients referred for refractory hypertension, and that percutaneous revascularization is not clearly superior to medical therapy for BP control The lack of cure of hypertension in any patient and the need for multiple medications in all stent patients strongly suggests that these patients did not have pure renovascular hypertension. In contrast, stent patients had greater baseline systolic BP, required more medications, and had a greater decrease in BP than medically treated patients. These observations suggest that patients with atherosclerotic RAS and end-organ impairment may have an incremental component of renovascular hypertension, superimposed on essential hypertension. 27 The relation between RAS and excretory function is poorly understood. Because RAS due to fibromuscular dysplasia does not cause ischemic nephropathy despite highgrade stenoses similar in severity to atherosclerotic RAS, 28 atherogenic factors must play an important role in renal dysfunction. 29 Several studies suggest stabilization or improvement in renal function after renal revascularization Our study is consistent with these observations, because nuclear scintigraphy confirms an absolute improvement of 13% and 19% for total and stenotic kidney GFR, respectively, in the stent group compared with the medical group. Despite the favorable impact of stenting on nuclear GFR and BP, the frequency of late clinical events was low and was similar for medical and stent patients. The low frequency of adverse events in our study was probably due to an aggressive medical regimen to limit atherosclerosis, close medical follow-up, and the presence of normal or mildly impaired baseline renal function. There are several limitations of this study. First, this

155 1326 The American Journal of Cardiology ( Figure 4. Total kidney (left panel) and stenotic kidney (right panel) GFR at baseline and follow-up. Solid lines, the medical group (p 0.03 for total GFR, p 0.01 for single kidney GFR); dashed lines, the stent group (p NS for total GFR, p 0.07 for single-kidney GFR). study was not randomized but was designed to prospectively evaluate a strategy using aggressive medical therapy in all patients and renal stenting for patients with end-organ injury. Second, this study cannot be applied to patients with creatinine elevations. Third, the inclusion of fractional GFR 40% as an index of renal dysfunction is arbitrary, but we used it as an objective measure of impaired flow to the stenotic kidney. Finally, this study was not adequately powered to evaluate late major cardiac events. It is not clear whether modest improvement in GFR will be durable or prevent renal failure and other clinical events. A large multicenter randomized trial (Cardiovascular Outcomes in Renal Atherosclerotic Lesions) funded by the National Institutes of Health will address these important considerations. In conclusion, atherosclerotic RAS can be managed with aggressive medical therapy to limit atherosclerosis and reduce BP. In patients with injuries to the heart, brain, and kidneys, renal artery stenting may result in further improvement in BP and renal function. Acknowledgment: We wish to gratefully acknowledge Darcie Brunette for manuscript preparation; Staci Barnhart RN, BSN, and Jim Colar RN, BSN, for data collection; and the technicians and nurses in our nuclear medicine section for performing the nuclear studies. 1. Tollefson DF, Ernst CB. Natural history of atherosclerotic renal artery stenosis associated with aortic disease. J Vasc Surg 1991;14: Scoble JE, Maher ER, Hamilton G, Dick R, Sweny P, Moorhead JF. Atherosclerotic renovascular disease causing renal impairment-a case for treatment. Clin Nephrol 1989;31: O Neill EA, Hansen KJ, Canzanello VJ, Pennell TC, Dean RH. Prevalence of ischemic nephropathy in patients with renal insufficiency. Am Surg 1992;58: Harding MB, Smith LR, Himmelstein SI, Harrison K, Phillips HR, Schwab SJ, Hermiller JB, Davidson CJ, Bashore TM. Renal artery stenosis: prevalence and associated risk factors in patients undergoing routine cardiac catheterization. J Am Soc Nephrol 1992;11: Olin JW, Melia M, Young JR, Graor RA, Risius B. Prevalence of atherosclerotic renal artery stenosis in patients with atherosclerosis elsewhere. Am J Med 1990;88:46N 51N. 6. Rihal CS, Textor SC, Breen JF, McKusick MA, Grill DE, Hallett JW, Holmes DR Jr. Incidental renal artery stenosis among a prospective cohort of hypertensive patients undergoing coronary angiography. Mayo Clin Proc 2002;77: Khosla S, Kunjummen B, Manda R, Khaleel R, Kular R, Gladson M, Razminia M, Guerrero M, Trivedi A, Vidyarthi V, et al. Prevalence of renal artery stenosis requiring revascularization in patients initially referred for coronary angiography. Cathet Cardiovasc Intervent 2003; 58: Buller CE, Nogareda JG, Ramanathan K, Ricci DR, Djurdjev O, Tinckam KJ, Penn IM, Fox RS, Stevens LA, Duncan JA, et al. The profile of cardiac patients with renal artery stenosis. J Am Coll Cardiol 2004;43: Webster J, Marshall F, Abdalla M, Dominiczak A, Edwards R, Isles CG, Loose H, Main J, Padfield P, Russell IT, et al. Randomized

156 Miscellaneous/Treatment Strategy for Renal Artery Stenosis 1327 comparison of percutaneous angioplasty vs continued medical therapy for hypertensive patients with atheromatous renal artery stenosis. J Hum Hypertens 1998;12: Plouin PF, Chatellier G, Darné B, Raynaud A. Blood pressure outcome of angioplasty in atherosclerotic renal artery stenosis. Hypertension 1998;31: van Jaarsveld BC, Krijnen P, Pieterman H, Derkx FH, Deinum J, Postma CT, Dees A, Woittiez AJ, Bartelink AK, Man in t Veld AJ, et al. The effect of balloon angioplasty on hypertension in atherosclerotic renal-artery stenosis. N Engl J Med 2000;342: Nordmann AJ, Woo K, Parkes R, Logan AG. Balloon angioplasty or medical therapy for hypertensive patients with atherosclerotic renal artery stenosis? A meta-analysis of randomized controlled trials. Am J Med 2003;114: Weinrauch LA, D Elia JA. Renal artery stenosis: fortuitous diagnosis, problematic therapy. J Am Coll Cardiol 2004;43: Butterly DW, Schwab SJ. Renal artery stenosis: the case for conservative management. Mayo Clin Proc 2000;75: Romero JC, Feldstein AE, Rodriguez-Porcel MG, Cases-Amenos A. New insights into the pathophysiology of renovascular hypertension. Mayo Clin Proc 1997;72: Canzanello VJ, Millan VG, Spiegel JE, Ponce PS, Kopelman RI, Madias NE. Percutaneous transluminal renal angioplasty in management of atherosclerotic renovascular hypertension: results in 100 patients. Hypertension 1989;13: Blum U, Krumme B, Flugel P, Gabelmann A, Lehnert T, Buitrago- Tellez C, Schollmeyer P, Langer M. Treatment of ostial renal-artery stenoses with vascular endoprotheses after unsuccessful balloon angioplasty. N Engl J Med 1997;336: van de Ven PJ, Kaatee R, Beutler JJ, Beek FJ, Woittiez AJ, Buskens E, Koomans HA, Mali WP. Arterial stenting and balloon angioplasty in ostial atherosclerotic renovascular disease: a randomized trial. Lancet 1999;353: Dorros G, Jaff M, Mathiak L, Dorros II, Lowe A, Murphy K, He T. Four-year follow-up of Palmaz-Schatz stent revascularization as treatment for atherosclerotic renal artery stenosis. Circulation 1998;98: Burket MW, Cooper CJ, Kennedy DJ, Brewster PS, Ansel GM, Moore JA, Venkatesan J, Henrich WL. Renal artery angioplasty and stent placement: predictors of a favorable outcome. Am Heart J 2000;139: Dorros G, Jaff M, Mathiak L, He T. Multicenter Palmaz stent renal artery stenosis revascularization registry report; four-year follow-up of 1,058 successful patients. Cathet Cardiovasc Intervent 2002;55: Radermacher J, Chavan A, Bleck J, Vitzthum A, Stoess B, Gebel MJ, Galanski M, Koch KM, Haller H. Use of Doppler ultrasound to predict the outcome of therapy for renal-artery stenosis. N Engl J Med 2001; 344: Zeller T, Frank U, Muller C, Burgelin K, Sinn L, Bestehorn HP, Cook-Bruns N, Neumann FJ. Predictors of improved renal function after percutaneous stent-supported angioplasty of severe atherosclerotic ostial renal artery stenosis. Circulation 2003;108: Rocha-Singh K, Ahuja R, Sung C-H, Rutherford J. Long-term renal function preservation after renal artery stenting in patients with progressive ischemic nephropathy. Cathet Cardiovasc Intervent 2002;57: Watson PS, Hadjipetrou P, Cox SV, Piemonte TC, Eisenhauer AC. Effect of renal artery stenting on renal function and size in patients with atherosclerotic renovascular disease. Circulation 2000;102: Harden PN, MacLeod MJ, Rodger RS, Baxter GM, Connell JM, Dominiczak AF, Junor BJ, Briggs JD, Moss JG. Effect of renal-artery stenting on progression of renovascular renal failure. Lancet 1997;349: Khosla S, White CJ, Collins TJ, Jenkons JS, Shaw D, Ramee SR. Effects of renal artery stent implantation in patients with renovascular hypertension presenting with unstable angina or congestive heart failure. Am J Cardiol 1997;80: Morganti A. Angioplasty of the renal artery: antihypertensive and renal effects. J Nephrol 2000;13(suppl):S28 S Chade AR, Rodriguez-Porcel M, Grande JP, Krier JD, Lerman A, Romero JC, Napoli C, Lerman LO. Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 2002;106:

157 Chronotropic Incompetence as a Predictor of Death Among Patients With Normal Electrograms Taking Beta Blockers (Metoprolol or Atenolol) Mohammed N. Khan, MD, Claire E. Pothier, MA, and Michael S. Lauer, MD* Chronotropic incompetence, or an inability to increase heart rate during exercise, independently predicts death in patients not taking blockers. Whether it predicts death in patients taking blockers is not known. Consecutive patients (n 3,736; mean age years; 68% men), who were taking either metoprolol tartrate or atenolol and were referred for symptom-limited exercise testing from 1990 to 2002 at a major academic medical center, formed the prospective study cohort. None had heart failure, pacemakers, atrial fibrillation, or any electrocardiographic abnormalities. Patients were followed for a median of 4.5 years for all-cause mortality. Chronotropic response was defined as the percentage of heart rate reserve used. A value of <62%, which was noted in 813 patients (22%), was considered abnormal, meaning that chronotropic incompetence was present. There were 173 deaths. After adjusting for age, gender, heart rate at rest, standard risk factors, other medications, Duke treadmill score, and heart rate recovery, chronotropic incompetence predicted death (adjusted hazard ratio 1.94, 95% confidence interval 1.43 to 2.64, p <0.0001). The association of chronotropic incompetence with death was present, irrespective of which drug was taken or the number of half-lives that had elapsed since the last dose. In conclusion, in patients taking blockers, chronotropic incompetence is independently predictive of death Elsevier Inc. All rights reserved. (Am J Cardiol 2005;96: ) Chronotropic incompetence, or an attenuated heart rate response to exercise, has been recognized as an independent prognostic marker in patients not taking blockers. 1 9 The importance of chronotropic incompetence in patients taking blockers is unclear. A recent intriguing report described a greater prevalence of angiographic coronary disease in patients taking blockers with chronotropic incompetence compared with those without chronotropic incompetence. 10 We therefore decided to determine whether chronotropic incompetence predicts all-cause mortality in patients taking blockers. Department of Cardiovascular Medicine, Cleveland Clinic Foundation, Cleveland, Ohio. Manuscript received March 17, 2005; revised manuscript received and accepted June 13, Dr. Lauer was supported by Grants R01 HL072771, P50 HL77107, and HL from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Ms. Pothier was supported by Grant HL from the National Heart, Lung, and Blood Institute, Bethesda, Maryland. * Corresponding author: Tel: ; fax: address: lauerm@ccf.org (M.S. Lauer). Methods Patients: All Cleveland Clinic Foundation patients who were referred for symptom-limited exercise testing from September 1990 to December 2002 for the evaluation of known or suspected coronary disease were eligible for inclusion in this retrolective analysis of a prospectively collected database. Patients were excluded for age 30 years, diagnoses of heart failure or cardiomyopathy, known severe left ventricular systolic dysfunction, a history of valvular disease, the use of digoxin, the placement of a pacemaker, a history of atrial fibrillation, end-stage renal disease, previous heart or renal transplantation, a history of congenital heart disease or Wolff-Parkinson-White syndrome, or any baseline electrocardiographic abnormalities. We chose to limit our study population to those patients who had normal electrocardiographic results at rest to control for the left ventricular ejection fraction (EF). Several large cohorts have found that normal electrocardiographic results at rest predict normal left ventricular EFs Normal electrocardiographic results at rest had a 96% positive predictive value for normal left ventricular EFs, whereas no clinical predictor was found to have a positive predictive value 87%. 13 As part of our routine protocol, chronically used medications are prospectively recorded into a computerized database immediately before exercise testing. Information on medication doses is not recorded, however. Because most patients receiving blockers from 1990 to 2002 were taking either metoprolol tartrate or atenolol, patients not taking either of these 2 blockers were excluded. The Cleveland Clinic Foundation Institutional Review Board has approved the performance of research based on /05/$ see front matter 2005 Elsevier Inc. All rights reserved. doi: /j.amjcard

158 Miscellaneous/Chronotropic Incompetence and Beta Blockers 1329 Table 1 Baseline and exercise characteristics according to abnormal chronotropic response Variable Normal Chronotropic Response (n 2,923) Abnormal Chronotropic Response (n 813) p Value Age (yrs) (means SD) Men 1,992 (68%) 545 (67%) 0.55 Black 345 (12%) 96 (12%) 1.0 Clinical history (no [%]) Diabetes mellitus, insulin-treated 67 (2%) 33 (4%) Diabetes mellitus, not insulin-treated 266 (9%) 95 (12%) Hypertension 2,175 (74%) 610 (75%) 0.75 Tobacco use 451 (15%) 208 (26%) Known coronary artery disease 1,366 (47%) 485 (60%) Previous coronary artery bypass grafting 559 (19%) 209 (26%) Previous percutaneous coronary intervention 835 (29%) 273 (34%) Previous myocardial infarction 639 (22%) 262 (32%) Family history of coronary artery disease 1,076 (37%) 302 (37%) 0.87 Previous peripheral vascular disease 50 (2%) 41 (5%) Previous carotid disease 92 (3%) 52 (6%) Known COPD 35 (1%) 23 (3%) Previous cerebral vascular accident 43 (1%) 17 (2%) 0.21 Angiotensin-converting enzyme inhibitor use 445 (16%) 142 (17%) 0.12 Aspirin use 1,698 (58%) 485 (60%) 0.44 Diltiazem or verapamil use 191 (7%) 102 (13%) Dihydropyridine use 306 (10%) 123 (15%) Nitrate use 731 (25%) 283 (35%) Statin use 1,014 (35%) 320 (39%) 0.01 Thiazide diuretic use 367 (13%) 133 (16%) Metoprolol use 1,230 (42%) 355 (44%) 0.42 Heart rate at rest (beats/min) Blood pressure at rest (mm Hg) Systolic Diastolic Reason for test (other than suspected or chronic coronary artery disease) Recent percutaneous coronary intervention 129 (4%) 33 (4%) 0.70 Recent myocardial infarction 59 (1%) 41 (5%) Cardiac rehabilitation entrance 86 (3%) 41 (5%) Type of test requested Nuclear imaging 1,415 (48%) 365 (45%) 0.08 Echocardiographic imaging 899 (31%) 249 (31%) 0.97 Abnormal ST-segment change 417 (14%) 104 (13%) 0.30 Very abnormal ST change 240 (8%) 63 (8%) 0.72 Abnormal heart rate recovery 584 (18%) 394 (42%) Duke score Intermediate-risk score 799 (27%) 364 (45%) High-risk score 30 (1%) 27 (3%) Frequent ventricular ectopy after exercise 170 (6%) 39 (5%) 0.30 Test-terminating angina 34 (1%) 34 (4%) the computerized clinical database of the exercise stress laboratory. The requirement for informed consent was waived. Clinical data: All patients referred to the exercise laboratory during the study period underwent a standarized, prospective, computer-recorded clinical evaluation by personnel unaware of this study s hypothesis. Exercise testing: Patients underwent symptom-limited exercise testing using standard exercise protocols with continuous electrocardiographic monitoring. Heart rate and blood pressure were obtained at rest (after 2 minutes in the supine position) and at the end of each stage of exercise and during the first 5 minutes of recovery. All patients were told to continue exercising until they could no longer do so because of limitations by symptoms. Data were also routinely recorded on symptoms, electrocardiographic changes, and arrhythmias. Heart rate recovery was defined as the difference between heart rate at peak exercise and 1 minute later; values of 12 or 18 beats/min for patients who underwent stress echocardiography were considered abnormal. 14,15 Frequent ventricular ectopy after exercise has been previously defined. 16 Chronotropic response: The chronotropic response to exercise was assessed on the basis of the percentage of heart rate reserve used at peak exercise. 6 Heart rate reserve is the difference between maximal age-predicted heart rate (i.e.,

159 1330 The American Journal of Cardiology ( Figure 1. Kaplan-Meier curves showing the association of chronotropic incompetence with overall survival. Chronotropic incompetence was defined as failure to use 62% of heart rate reserve; that is, heart rate reserve used (peak heart rate heart rate at rest)/(220 age heart rate at rest) Figure 2. Kaplan-Meier plot showing overall survival according to chronotropic response (CR) and functional capacity (FC). Chronotropic incompetence was defined as failure to use 62% of heart rate reserve; that is, heart rate reserve used (peak heart rate heart rate at rest)/(220 age heart rate at rest) FC was considered impaired if fair or poor for age and gender. 220 age) and heart rate at rest. We and others have shown previously that the proportion of heart rate reserve used is a stronger predictor of risk then the percentage of age-predicted heart rate achieved. 6,8,9 In patients not taking blockers, this value ([peak heart rate heart rate at rest]/ heart rate reserve) is considered abnormal if it is 80%. 1,6 In patients taking blockers, however, the optimal cutoff for an abnormal value is not known. Therefore, we performed a procedure by which we constructed Kaplan-Meier plots for all possible cut-off values of chronotropic response between the 10th and 90th percentiles and determined which cut-off value had the largest log-rank chi-square statistic. 17 In this way, chronotropic incompetence in this population of patients taking metoprolol or atenolol was considered present if 62% of heart rate reserve was used by peak exercise. End points: The primary end point was all-cause death as assessed by query of the Social Security Death Index. As others and we have argued previously, all-cause death, unlike cardiac or cardiovascular death, is a clinically relevant, objective, and unbiased end point. 18,19 The very high specificity and sensitivity of the Social Security Death Index in our stress laboratory patients has been previously documented. 15,20 Statistical analyses: For descriptive purposes, patients were divided into 2 groups according to the presence or absence of chronotropic incompetence. Comparisons of continuous variables were made using Wilcoxon s ranksum test, and comparisons of categorical variables were made using the chi-square or Fisher s exact test as appropriate. Survival analyses were performed by the construction of Kaplan-Meier plots, the calculation of log-rank chi-square statistics, and the construction of Akaike information criterion optimized, multivariate Cox-proportional hazards models. Potential confounders included all variables listed in Table 1. The Cox proportional-hazards assumption was confirmed by the inspection of scaled Schoenfeld residuals. Nonlinear associations of continuous variables (including chronotropic response) were allowed by means of restricted cubic splines. Model discrimination was assessed by the calculation of an optimism-corrected c statistic for censored data based on 200 bootstrap resamplings. Accurate model calibration was ensured by creating an additional 200 bootstrap resamples and comparing predicted 5-year survival rates to actual Kaplan-Meier mortality rates. Prespecified stratified analyses were performed to test for potential interactions. We modeled chronotropic response as the proportion of heart rate reserve used and did not separate the numerator and the denominator. The reason for this is based on the physiology of this measurement, which has been shown to successfully factor out effects of metabolic function and heart rate at rest. 4,6 Analyses were performed using the SAS version 8.2 system(sas Institute Inc., Cary, North Carolina) and S-Plus version 6.2 software (Insightful Inc., Seattle, Washington). Regression analyses used the Design and HMisc libraries of Harrell. 21