HEART FAILURE IS A PROGRESsive

Transcription

1 ORIGINAL CONTRIBUTION Progression of Left Ventricular Diastolic Dysfunction and Risk of Heart Failure Garvan C. Kane, MD, PhD Barry L. Karon, MD Douglas W. Mahoney, MS Margaret M. Redfield, MD Veronique L. Roger, MD, MPH John C. Burnett Jr, MD Steven J. Jacobsen, MD, PhD Richard J. Rodeheffer, MD HEART FAILURE IS A PROGRESsive condition that increases in incidence with advancing age There is an emerging emphasis on understanding the progression from heart failure risk factors to asymptomatic ventricular dysfunction and eventually to symptomatic heart failure and death. 6,7 Therefore, it is important to have population-based information on changes in cardiac function over time. Heart failure may develop with reduced or preserved left ventricular ejection fraction (LVEF), each form accounting for approximately half of cases. 4,7,10-15 Echocardiographic classification of diastolic function in crosssectional community studies has shown diastolic dysfunction to be highly prevalent and associated with heart failure However, little is known about time-dependent changes in diastolic function or their relationship to clinical heart failure. We randomly selected a cohort of 2042 persons 45 years or older, the Olmsted County Heart Function Study (OCHFS). 11 A cross-sectional evaluation of diastolic function in examination 1 ( ) has been reported. 11 We report now a reevaluation of this cohort, examination 2 (2001- Context Heart failure incidence increases with advancing age, and approximately half of patients with heart failure have preserved left ventricular ejection fraction. Although diastolic dysfunction plays a role in heart failure with preserved ejection fraction, little is known about age-dependent longitudinal changes in diastolic function in community populations. Objective To measure changes in diastolic function over time and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure. Design, Setting, and Participants Population-based cohort of participants enrolled in the Olmsted County Heart Function Study. Randomly selected participants 45 years or older (N=2042) underwent clinical evaluation, medical record abstraction, and echocardiography (examination 1 [ ]). Diastolic left ventricular function was graded as normal, mild, moderate, or severe by validated Doppler techniques. After 4 years, participants were invited to return for examination 2 ( ). The cohort of participants returning for examination 2 (n=1402 of 1960 surviving [72%]) then underwent follow-up for ascertainment of new-onset heart failure ( ). Main Outcome Measures Change in diastolic function grade and incident heart failure. Results During the 4 (SD, 0.3) years between examinations 1 and 2, diastolic dysfunction prevalence increased from 23.8% (95% confidence interval [CI], 21.2%- 26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P.001). Diastolic function grade worsened in 23.4% (95% CI, 20.9%-26.0%) of participants, was unchanged in 67.8% (95% CI, 64.8%-70.6%), and improved in 8.8% (95% CI, 7.1%-10.5%). Worsened diastolic dysfunction was associated with age 65 years or older (odds ratio, 2.85 [95% CI, ]). During 6.3 (SD, 2.3) years of additional follow-up, heart failure occurred in 2.6% (95% CI, 1.4%-3.8%), 7.8% (95% CI, 5.8%-13.0%), and 12.2% (95% CI, 8.5%-18.4%) of persons whose diastolic function normalized or remained normal, remained or progressed to mild dysfunction, or remained or progressed to moderate or severe dysfunction, respectively (P.001). Diastolic dysfunction was associated with incident heart failure after adjustment for age, hypertension, diabetes, and coronary artery disease (hazard ratio, 1.81 [95% CI, ]). Conclusions In a population-based cohort undergoing 4 years of follow-up, prevalence of diastolic dysfunction increased. Diastolic dysfunction was associated with development of heart failure during 6 years of subsequent follow-up. JAMA. 2011;306(8): ). After examination 2, the cohort was followed passively and incident heart failure events ascertained ( ). The objectives were to measure changes in diastolic function over time, to identify factors predictive of change in diastolic function, and to determine the relationship between diastolic dysfunction and the risk of subsequent heart failure. Author Affiliations: Division of Cardiovascular Diseases, Departments of Internal Medicine (Drs Kane, Karon, Redfield, Roger, Burnett, and Rodeheffer) and Health Science Research (Mr Mahoney and Dr Roger), Mayo Clinic and Medical School, Rochester, Minnesota; and Department of Preventive Medicine, University of Southern California Keck School of Medicine and Southern California Permanente Medical Group, Los Angeles (Dr Jacobson). Corresponding Author: Richard J. Rodeheffer, MD, Division of Cardiovascular Diseases, Mayo Clinic, 200 First St SW, Rochester, MN JAMA, August 24/31, 2011 Vol 306, No American Medical Association. All rights reserved.

2 METHODS The institutional review boards of Mayo Clinic and Olmsted Medical Center approved this study. Participants provided written informed consent for evaluation and medical record follow-up. Participants In 2000 the population of Olmsted County, Minnesota, was ; 90% were white, 81% urban, and 11% 65 years or older. Characteristics of this community and its use in populationbased research (the Rochester Epidemiology Project) have been described. 16 In 1997 a random sample of county residents 45 years or older was identified by applying a sampling fraction of 7% within each sex- and age-specific (5 years) stratum. Of the 4203 persons invited, 2042 participated in examination 1. A comparison of invited participants and nonparticipants was performed. 17 Examination 1 ( ) included physical examination, echocardiography, and medical record abstraction. Four years later, all participants were invited to return, and 1402 participated in examination 2 ( ). All data collected at examination 1 were recollected at examination 2. Incident heart failure between examinations 1 and 2 was diagnosed by the Framingham criteria. 2,11 Diabetes was based on physician diagnosis and treatment. Myocardial infarction and hypertension were diagnosed according to criteria from the World Health Organization and the Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, respectively. 11,18 After examination 2, long-term surveillance for incident heart failure was accomplished by methodology previously validated in Olmsted County. 9 From examination 2 to November 2010, incident heart failure was identified using code 428 from the International Classification of Diseases, Ninth Revision, Clinical Modification, which identifies 90% of Framingham criteria validated cases. 9 Codes were assigned by trained coders according to physician diagnoses in outpatient and inpatient records (not by hospital billing records). Healthy Subgroup At examination 1, a subset of participants was identified without heart failure, hypertension, coronary artery disease, diabetes, or use of cardiovascular medications. Echocardiograms Ejection fraction was measured by quantitative 2-dimensional echocardiography, as previously reported. 11 Systolic dysfunction was defined as LVEF less than 50%. Decreased LVEF was defined as a decrease of more than 7.5% (ie, 1-SD decrease). Diastolic function was assessed by pulse-wave Doppler examination of mitral flow (before and during Valsalva maneuver), pulmonary venous flow, and Doppler imaging of the medial mitral annulus. 11,19,20 Diastolic dysfunction was graded on a 4-point ordinal scale: (1) normal; (2) mild diastolic dysfunction (abnormal relaxation without increased left ventricular enddiastolic filling pressure [decreased ratio of early to late ventricular filling velocity {E:A ratio} 0.75]); (3) moderate or pseudonormal diastolic dysfunction (abnormal relaxation with increased left ventricular end-diastolic filling pressure [E:A ratio of and deceleration time 140 ms, plus 2 other Doppler indices of elevated enddiastolic filling pressure]); (4) or severe diastolic dysfunction (advanced reduction in compliance [ie, markedly increased stiffness], with restrictive filling [E:A ratio 1.5 and deceleration time 140 ms, plus Doppler indices of elevated left ventricular end-diastolic filling pressure]). For participants with atrial fibrillation, diastolic function was classified as indeterminate unless restrictive physiology (E:A ratio 1.5, deceleration time 140 ms) was present. Valvular heart disease was assigned for moderate to severe echocardiographic valvular stenosis or regurgitation. Figure 1. Study Flow 4203 Individuals randomly invited to participate 2161 Excluded (Did not participate in examination 1) 2042 Participated in examination 1 ( ) 640 Excluded 558 Did not return for examination 2 82 Died before examination Returned for examination 2 ( ) 1151 Classifiable diastolic function 139 Indeterminate diastolic function 112 Diastolic dysfunction, indeterminate grade Echocardiogram Reading Agreement Echocardiograms at examinations 1 and 2 were performed by the same 3 echocardiographers according to standardized protocols and reviewed by an echocardiologist (B.L.K., M.M.R.). 11 Echocardiographers and echocardiologists were masked to clinical and examination 1 echocardiogram findings. Interreader agreement was assessed for the echocardiologists, who independently reviewed sets of echocardiograms chosen to represent a range of ventricular function, and was comparable. Nonreturning Participants To assess for examination 2 participation bias, characteristics of examination 1 participants who returned for examination 2 were compared with those who did not. Statistical Analysis Comparisons between categorical variables at examinations 1 and 2 were made using the McNemar test; continuous variables were compared using the Wilcoxon signed-rank test. Ordinal logistic regression was used to adjust the association of clinical variables with the progression of diastolic dysfunction for age and sex. Cox proportional hazards regression models were used to identify factors associ American Medical Association. All rights reserved. JAMA, August 24/31, 2011 Vol 306, No

3 Table 1. Clinical and Echocardiographic Characteristics of Participants (N = 1402) Characteristic Examination 1 ( ) No. (%) Examination 2 ( ) P Value Demographic Men 692 (49.4) 692 (49.4) Age, y Mean (SD) 61.0 (9.5) 65.2 (9.5) , No. (%) 924 (65.9) 744 (53.1) 65, No. (%) 478 (34.1) 658 (46.9) Clinical BMI, mean (SD) a 28.3 (5.1) 28.5 (5.2) (25.3) 367 (26.2) (43.4) 594 (42.4) (31.2) 441 (31.5) Blood pressure, mean (SD), mm Hg Systolic (19.8) (19.1).001 Diastolic 73.4 (9.9) 69.5 (10.4).001 Hypertension b 361 (25.8) 594 (42.4).001 Diabetes mellitus b 88 (6.3) 145 (10.3).001 Coronary artery disease b 148 (10.6) 234 (16.7).001 Myocardial infarction b 48 (3.4) 50 (3.6).16 Heart failure (Framingham criteria) b 16 (1.1) 31 (2.2).001 Cardiovascular medication use ACE inhibitor/arb 123 (8.7) 251 (17.9).001 -Blocker 190 (13.6) 303 (21.6).001 Calcium channel blocker 81 (5.8) 105 (7.5).07 Lipid-lowering agent 245 (17.5) 431 (30.7).001 Other cardiovascular medication 463 (33.0) 614 (43.8).001 Echocardiography c LVEF, mean (SD), % d 63.9 (6.6) 65.9 (7.5).001 LVEF category, No. (%), % 40 5 (0.5) 5 (0.5) (1.8) 18 (1.9) (97.7) 924 (97.6) LVEDD/height, mean (SD), mm/m 26.1 (2.9) 26.1 (2.8).12 LAVI, mean (SD) 24.3 (7.5) 24.7 (8.5).05 Ventricular filling, mean (SD) E, m/s 0.67 (0.15) 0.73 (0.18).001 e, m/s 0.09 (0.04) 0.08 (0.05).001 E:e ratio 8.5 (2.8) 10.7 (4.5) (58.4) 589 (42.0) (25.7) 788 (56.2) Diastolic function e Normal 981 (70.0) 688 (49.1) Mild dysfunction 213 (15.2) 271 (19.3) Moderate dysfunction 87 (6.2) 190 (13.6) Severe dysfunction 3 (0.2) 2 (0.1).001 Dysfunction, indeterminate grade 26 (1.9) 112 (8.0) Indeterminate function insufficient data 77 (5.5) 120 (8.6) Indeterminate function arrhythmia 15 (1.1) 19 (1.4) Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blocker; BMI, body mass index; BSA, body surface area; E, mitral peak velocity of early filling; e, medial mitral annulus tissue velocity; LAVI, left atrial volume index; LVEDD, left ventricular end-diastolic dimension; LVEF, left ventricular ejection fraction. a Calculated as weight in kilograms divided by height in meters squared. b Ascertained by chart abstraction. c Could be measured in 1148 and 1078 participants at examinations 1 and 2, respectively, for LVEDD/height; in 1316 and 1352 for LAVI; in 138 and 1389 for E; in 1182 and 1387 for e ; and in 1178 and 1377 for E:e ratio. d Could be measured in 947 participants. e Could be measured in 1310 and 1263 participants at examinations 1 and 2, respectively. ated with incident heart failure after examination 2. Models were developed using stepwise techniques with consideration of clinically relevant variables having P.10 by univariate analysis: age, sex, hypertension, diabetes, coronary disease, incident myocardial infarction, LVEF, diastolic dysfunction, left atrial volume index, and ratio of mitral peak velocity of early filling to medial mitral annular tissue velocity (E:e ). For persons with incomplete data, additional categorical variables (test performed, test not performed) were included. Time-varying effects of covariates were assessed using 2 models: the first censored all participants at the median event time (3.5 years), and the second involved only those at risk beyond 3.5 years. Long-term follow-up is based on the Kaplan-Meier productlimit method and compared between groups using the log-rank test. Analyses were performed using SAS versions 8.0 and 9.2 and JMP version 8.0 (SAS Institute Inc, Cary, North Carolina). Analyses were 2-sided; P.05 was used to indicate statistical significance. RESULTS Cohort Characteristics Of the 4203 eligible Olmsted County residents invited to participate in examination 1, 2042 (49%) participated. Analysis of potential participation bias in examination 1 has been reported in 500 randomly selected participants and 500 nonparticipants; there was no significant difference in the prevalence of cardiovascular disease. 17 Cross-sectional analyses of examination 1 participants have been reported. 7,11,19-25 Eighty-two examination 1 participants died before examination 2, and 1402 of the 1960 surviving examination 1 participants (72%) returned for examination 2. These 1402 participants are the focus of the present analysis. (FIGURE 1) The mean age of the 1402 study participants at examination 1 was 61 (SD, 9.5) years, with 34.1% 65 years or older. 858 JAMA, August 24/31, 2011 Vol 306, No American Medical Association. All rights reserved.

4 Examination 2 was performed 4.0 (SD, 0.3) years after examination 1, by which time 46.9% of participants were 65 years or older. At examination 2 there was an increase in the prevalence of comorbid conditions: hypertension increased from 25.8% (361/1402) to 42.4% (594/1402) (P.001), diabetes from 6.3% (88/1402) to 10.3% (145/ 1402) (P.001), and heart failure from 1.1% (16/1402) to 2.2% (31/1402) (P=.03). Despite the increased number of participants fulfilling diagnostic criteria for hypertension, mean systolic blood pressure decreased from (SD, 19.8) mm Hg at examination 1 to (SD, 19.1) mm Hg at examination 2 (P.001). Concomitantly, use of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers increased from 8.7% (123/1402) to 17.9% (251/1402) (P.001) and use of -blockers from 13.6% (190/1402) to 21.6% (303/ 1402) (P.001). Changes in Diastolic Function Diastolic function grade could be assigned in 1058 of 1402 participants (75.5%) at both examinations 1 and 2. At examination 2, diastolic dysfunction was present but not gradable in 112 persons, and diastolic function could not be measured in 139 persons because of arrhythmia or incomplete echocardiographic data (TABLE 1). From examination 1 to examination 2, the prevalence of diastolic dysfunction of any degree increased from 23.8% (95% confidence interval [CI], 21.2%-26.4%) to 39.2% (95% CI, 36.3%-42.2%) (P.001). Moderate or severe diastolic dysfunction increased from 6.4% (95% CI, 4.9%-7.9%) to 16.0% (95% CI, 13.7%-18.2%) (P.001). Within-individual changes are depicted in TABLE 2. Over 4 years, 23.4% (95% CI, 20.9%-26.0%) of participants experienced worsening of diastolic function, 67.8% (95% CI, 64.8%- 70.6%) remained unchanged, and 8.8% (95% CI, 7.1%-10.5%) experienced improved diastolic function. Elevated ventricular filling pressure (E:e ratio 10) increased from 30.6% (95% CI, 27.9%- 33.6%) to 57.2% (95% CI, 54.6% %) (P.001). Factors Predictive of Worsening Diastolic Function Age was predictive of the development of diastolic dysfunction, especially ages 65 years or older (odds ratio [OR], 2.85 [95% CI, ]), as was E:e ratio at examination 1 (OR, 1.14 [95% CI, ]) (TABLE 3). Diastolic Function in Healthy Participants Five hundred thirty-one participants were without hypertension, diabetes, coronary artery disease, heart failure, Table 2. Within-Individual Changes in Diastolic Function Classification From Examination 1 to Examination 2 in All Participants a Diastolic Dysfunction, Examination 1 Diastolic Dysfunction, Examination 2 Normal Mild Moderate Severe Total Normal Mild Moderate Severe Total a Diastolic function could be classified at both examinations in 1058 of 1402 participants. Values in bold indicate participants with no change in diastolic function grade at examination 2; values above the diagonal defined by the values in bold indicate participants with improved grade; values below the diagonal indicate participants with worse grade. Table 3. Factors Predictive of the Development of Diastolic Dysfunction From Examination 1 to Examination 2 a Factor Development of Diastolic Dysfunction (n = 319) b Diastolic Function Remains Normal (n = 573) Unadjusted OR (95% CI) Adjusted for Age and Sex Age, y Mean (IQR), y 65.4 (57-73) 60.6 (55-65) 2.06 ( ) c Group, No. (%) (52) 430 (75) 1 [Reference] (48) 143 (25) 2.85 ( ) Women, No. (%) 179 (56) 285 (50) 1.06 ( ) 1.05 ( ) Body mass index, mean (IQR) d 28.1 ( ) 28.1 ( ) 0.99 ( ) 1.0 ( ) Hypertension, examination 1, No. (%) 74 (23) 92 (16) 1.58 ( ) 1.23 ( ) Diabetes mellitus, examination 1, No. (%) 17 (5) 22 (4) 0.71 ( ) 0.83 ( ) LVEF, examination 1, median (IQR), % 64.2 ( ) 59.9 ( ) 0.99 ( ) e 0.97 ( ) e E:e ratio, examination ( ) 7.5 ( ) 1.19 ( ) 1.14 ( ) Hypertension, examination 2, No. (%) 140 (44) 165 (29) 1.93 ( ) 1.54 ( ) Incident myocardial infarction, No. (%) 3 (0.90) 3 (0.05) 1.17 ( ) 1.04 ( ) Abbrevations: CI, confidence interval; IQR, interquartile range; LVEF, left ventricular ejection fraction; OR, odds ratio. a n=892 in whom diastolic function was normal at examination 1 and could be classified as normal or diastolic dysfunction of any degree at examination 2. b Comprising 99 persons with mild and 134 with moderate or severe diastolic dysfunction and 86 with diastolic dysfunction that could not be confidently assisgned a grade. c Per 10 years of age. d Calculated as weight in kilograms divided by height in meters squared. e Per 5% change in LVEF American Medical Association. All rights reserved. JAMA, August 24/31, 2011 Vol 306, No

5 or use of cardiovascular medications. Incidence of diastolic dysfunction of any degree increased from 11.3% (60/531 [95% CI, 8.6%-14.0%]) at examination 1 to 29.8% (158/531 [95% CI, 25.9%-33.7%]) at examination 2 (P.001) (etable, available at http: // In 423 of the 531 healthy participants (79.7%), diastolic function grade could be classified at both examinations. Among 423 healthy participants, 84 (19.9% [95% CI, 16.0%-23.7%]) showed worsening diastolic function, 318 (75.2% [95% CI, 70.8%-79.1%]) remained the same, and 21 (5.0% [95% CI, 2.9%-7.0%]) improved (TABLE 4). Consistent with these findings, prevalence of elevated ventricular filling pressure (E:e ratio 10) increased from 17.9% (95/531 [95% CI, 14.6%-21.2%]) to 45.0% (239/531 [95% CI, 40.8%-49.3%]) (P.001) (etable). Change in Systolic Function Ejection fraction could be measured using 2-dimensional echocardiography in 947 of 1402 participants (67.5%) at both examinations. Table 4. Within-Individual Changes in Diastolic Function Classification From Examination 1 to Examination 2 in 423 (of 531) Healthy Participants Whose Diastolic Function Grade Could Be Classified at Both Examinations Diastolic Dysfunction, Examination 1 Diastolic Dysfunction, Examination 2 Normal Mild Moderate Severe Total Normal Mild Moderate Severe Total Healthy participants defined as those without hypertension, diabetes, coronary artery disease, heart failure, or use of cardiovascular medications. Values in bold indicate participants with no change in diastolic function grade at examination 2; values above the diagonal defined by the values in bold indicate participants with improved grade; values below the diagonal indicate participants with worse grade. Within-individual decrease in LVEF, defined as a decrease of more than 7.5% (ie, 1 SD), occurred in 76 of 947 participants in whom LVEF could be measured (8.0%). However, LVEF less than 50% was unchanged in 24 of 1402 participants (2.3%) at examination 1 and 23 of 1402 (2.4%) at examination 2 (Table 1). Incident Heart Failure Between Examination 1 and Examination 2 Among participants without heart failure at examination 1, Framingham criteria heart failure developed by examination 2 in 12 of 1386 participants (0.9%). Among these, 83% (5/6 with gradable diastolic function) had diastolic dysfunction at examination 1, compared with 24% (310/1289) who did not develop heart failure between examinations (P.001). Consistent with this observation, left atrial volume index was greater in participants with heart failure (36 [SD, 12.9] cc/ m 2 ) vs those without heart failure (24 [SD, 6.8] cc/m 2 ) (OR, 1.73 [95% CI, ]). Table 5. Baseline Factors Predictive of the Development of Incident Heart Failure After Examination 2 Heart Failure, No. (%) a HR (95 CI) Variable Yes No (n = 81) b (n = 1277) Unadjusted Adjusted for Age and Sex Multivariable Model c Clinical variables Age, y Mean (IQR) 75.0 ( ) 64.2 ( ) 3.1 ( ) d 2.53 ( ) (14) 726 (57) 1 [Reference] (86) 551 (43) 8.38 ( ) Women 43 (53) 648 (51) 1.10 ( ) Hypertension (examination 2) 59 (73) 505 (40) 4.10 ( ) 2.66 ( ) 2.21 ( ) Diabetes (examination 2) 17 (23) 114 (10) 2.64 ( ) 2.43 ( ) 1.77 ( ) Coronary artery disease (examination 2) 31 (38) 172 (14) 3.72 ( ) 2.33 ( ) 2.07 ( ) Incident MI between examinations 3 (4) 13 (1) 3.89 ( ) 1.91 ( ) Echocardiography (examination 2) LVEF, % Median (IQR) 75.4 ( ) 63.1 ( ) 0.88 ( ) c 0.83 ( ) e 50 4 (9) 16 (2) 5.03 ( ) 7.08 ( ) Diastolic dysfunction, any degree 49 (75) 478 (43) 3.93 ( ) 2.05 ( ) 1.81 ( ) LAVI, mean (IQR) 31.4 ( ) 25.4 ( ) 2.43 ( ) f 2.02 ( ) f E:e ratio, mean (IQR) 12.6 ( ) 10.4 ( ) 1.20 ( ) g 1.15 ( ) g Abbrevations: CI, confidence interval; E:e, ratio of mitral peak velocity of early filling to medial mitral annulus tissue velocity; HR, hazard ratio; IQR, interquartile range; LAVI, left atrial volume index; LVEF, left ventricular ejection fraction; MI, myocardial infarction. a Heart failure ascertained by International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic code 428. b Individuals with diagnostic code 428 heart failure at examination 2 excluded. c Multivariable model adjusted for age, hypertension, diabetes, and coronary artery disease. d Per 10 years of age. e Per 5% change in LVEF. f Per 10 cc/m2. g Per 5-unit change. 860 JAMA, August 24/31, 2011 Vol 306, No American Medical Association. All rights reserved.

6 None of the 12 participants with incident heart failure had LVEFs less than 50% at examination 1, and only 1 had an LVEF less than 50% at examination 2. Medical record abstraction revealed that 4 of the 12 participants experienced a transient decrease in LVEF to less than 50% when clinically symptomatic, only to recover normal LVEF by examination 2. Causes of these transient systolic heart failure events were uncontrolled hypertension (n=2), rapid atrial fibrillation (n=1), and apical ballooning syndrome (n=1). The 1 participant with incident heart failure whose LVEF was less than 50% at examination 2 had sustained a myocardial infarction. Figure 2. Cumulative Incidence of Heart Failure After Examination 2 New Heart Failure, % No. at risk Moderate or severe Mild Normal/normalized Heart Failure Surveillance After Examination 2 Surveillance after examination 2 identified both new inpatient and outpatient heart failure diagnoses. During 6.3 (SD, 2.3) years of additional followup, 81 participants developed heart failure. Age 65 years or older was the most potent predictor of heart failure (hazard ratio [HR], 8.38 [95% CI, ]) (TABLE 5). Multivariable analysis demonstrated the independent predictive power of diastolic dysfunction (HR, 1.81 [95% CI, ]), hypertension (HR, 2.21 [95% CI, ]), diabetes (HR, 1.77 [95% CI, ]), and coronary artery disease (HR, 2.07 [95% CI, ]). Persistent or worsening diastolic dysfunction was associated with heart failure (FIGURE 2). Cumulative heart failure incidence was 2.6% (95% CI, 1.4%-3.8%) in participants whose diastolic function remained normal or normalized between examinations; 7.8% (95% CI, 5.8%-13.0%) in those with persistent, or progression to, mild diastolic dysfunction; and 12.2% (95% CI, 8.5%-18.4%) in those with persistent, or progression to, moderate or severe diastolic dysfunction (P.001). Time-varying effects of covariates were examined using Cox models before and after the median event time of 3.5 years. In the initial 3.5 years after examination 2, age, hypertension, diabetes, coronary artery disease, diastolic dysfunction, left atrial volume index, and E:e ratio were associated with increased heart failure risk. In persons still at risk past 3.5 years, the effects of diabetes and E:e ratio disappeared. Potential for Participation Bias at Examination 2 Among 2042 examination 1 participants, 82 died before examination 2; of the 1960 surviving participants, 1402 (71.5%) returned for examination 2. Survivors who did not return were older (66.3 [SD, 12] vs 61.1 [SD, 10] years, P.001) and had a higher prevalence of comorbid conditions at examination 1 (hypertension, 33.4% vs 24.5% [P.001]; diabetes mellitus, 9.8% vs 6.3% [P=.004]; prior myocardial infarction, 7.8% vs 2.1% [P.001]; heart failure, 4.5% vs 1.1% [P.001]). Diastolic dysfunction was more prevalent among nonreturning than returning participants (41.1% vs 25.1%, P.001), as was LVEF of 50% or less (8.9% vs 2.4%, P.001). Mortality follow-up demonstrated better survival for returning than for nonreturning participants (98% vs 96%, respectively, at 1 year; 96% vs 91% at 3 years; and 90% Diastolic function Progression to or persistent moderate or severe dysfunction Progression to or persistent mild dysfunction Remained normal or normalized function Log-rank P< Years After Examination Groups represent 3 grades of severity and change in diastolic dysfunction from examination 1 and examination 2. Persons with heart failure at examination 2 and those in whom diastolic function could not be classified at both examinations 1 and 2 are excluded, leaving 1047 persons at risk after examination vs 86% at 5 years). Nonreturning participants experienced greater mortality risk (HR, 4.0 [95% CI, ]; P.001). COMMENT Our initial report from the OCHFS cohort provided cross-sectional estimates of left ventricular dysfunction prevalence in the community and characterized the relationship between ventricular dysfunction and clinical status. 11 This report adds a longitudinal change within individual dimension to left ventricular function measurements and clinical status. There was a marked progression of diastolic dysfunction: 23% of participants showed worse diastolic function, 68% were unchanged, and 9% improved. A similar pattern of worsening diastolic function also was observed in a subset of healthy participants. Incident heart failure during 6.3 (SD, 2.3) years of follow-up was associated with age, hypertension, diabetes, coronary artery disease, and diastolic dysfunction. Persistent or worsening diastolic dysfunction between examinations 1 and 2 was an independent risk factor for subsequent heart failure American Medical Association. All rights reserved. JAMA, August 24/31, 2011 Vol 306, No

7 Temporal Change in Left Ventricular Diastolic Function Community population studies report that approximately half of patients with heart failure have preserved LVEF. 11,15 Heart failure, with or without reduced LVEF, is marked by recurrent hospitalizations and 5-year mortality of 30% to 35%. 9,10 Echocardiographic measurements of diastolic function in populationbased cohorts show that approximately 7% of persons older than 45 years have moderate to severe diastolic dysfunction, most of whom report few, if any, symptoms. 11,13 The current longitudinal data confirm and extend the cross-sectional association reported between age and diastolic dysfunction: over a 4-year interval, middle-aged and elderly persons were 3 times more likely to manifest poorer diastolic function than better diastolic function That diastolic dysfunction worsened even in healthy persons supports the concept that aging may be accompanied by progressive deterioration in diastolic function. This age-related progression of diastolic dysfunction in the population contributes to the pathophysiologic substrate from which overt heart failure emerges. The biological pathways leading to heart failure with preserved LVEF are manifold, and understanding its pathophysiology remains a work in progress. Contributing factors include changes in myocardial relaxation and elastic recoil, changes in ventricular load and diastolic stiffness, external constraint, and abnormal systolic function Age-related loss of peripheral vascular elasticity, and its effect on left ventricular load and stiffness, may play an important role in this process. 20,37-42 Measurements of the interaction between left ventricular function and vascular load suggest that ventriculovascular coupling may play a role in the development of the diastolic dysfunction component of heart failure with preserved LVEF. 30,31,33-35,37 Indeed, previous cross-sectional analyses from this OCHFS cohort have shown significant correlations between age and vascular, ventricular endsystolic, and ventricular end-diastolic stiffness. 20 Incident Heart Failure Surveillance studies of the entire Olmsted County population from ( persons) have documented a constant incidence of heart failure with reduced LVEF but an increase in heart failure with preserved LVEF. 15 The current analysis identifies diastolic dysfunction as an independent predictor of these heart failure events. However, to put diastolic dysfunction in context, it should be noted that only about 1 in 4 persons with moderate or severe diastolic dysfunction at examination 2 developed incident heart failure during long-term follow-up. This suggests that superimposed clinical events play an important role in the transition from asymptomatic diastolic dysfunction to overt heart failure with preserved LVEF. Specifically, our findings are consistent with the hypothesis that a combination of cardiovascular aging and superimposed cardiovascular disease accelerates the deterioration in diastolic function, setting the stage for symptomatic heart failure with preserved LVEF in elderly persons. 20,35-37 The assessment of the few heart failure events between examinations 1 and 2 suggests some of these superimposed cardiovascular disease processes. An important clinical implication may be that prevention of risk factors for superimposed events, especially hypertension, might be fundamental to reducing heart failure with preserved LVEF. Study Strengths and Weaknesses Strengths of this study include its population-based randomly selected cohort, the ability to make protocolized serial observations for research purposes, the opportunity to examine interval clinical events in the cohort, and the ability to collect data on nonreturning participants. Study participants underwent a uniform evaluation at examinations 1 and 2 using the same measurement methods. An additional strength is the ability to ascertain both inpatient and outpatient heart failure diagnoses during long-term follow-up using a validated International Classification of Diseases, Ninth Revision, Clinical Modification code methodology. Several weaknesses warrant discussion. Comparison of participants who returned for examination 2 with those who did not return indicates that nonreturning participants had more baseline hypertension, diabetes, myocardial infarction, heart failure, and diastolic dysfunction as well as increased subsequent mortality. Therefore, the worsening diastolic dysfunction we report in returning participants may underestimate that finding in the whole cohort. Survival bias and participation bias may contribute to underestimation of the overall effect of diastolic dysfunction on heart failure in the cohort. The use of medical records for ascertainment of clinical outcomes has been used successfully in this population. However, some degree of misclassification could underestimate the strength of the observed associations. Last, our cohort was more than 95% white, so generalizability to other ethnic or racial populations may not be valid. CONCLUSION Longitudinal evaluation of participants in the population-based OCHFS cohort reveals that left ventricular diastolic dysfunction is highly prevalent, tends to worsen over time, and is associated with advancing age. Worsening diastolic function can be detected even in apparently healthy persons. Although confirmation in other studies would be helpful, our data suggest that persistence or progression of diastolic dysfunction is a risk factor for heart failure in elderly persons. Author Contributions: Drs Kane, Mahoney, and Rodeheffer had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kane, Mahoney, Redfield, Roger, Jacobsen, Rodeheffer. Acquisition of data: Karon, Mahoney, Roger, Jacobsen, Rodeheffer. 862 JAMA, August 24/31, 2011 Vol 306, No American Medical Association. All rights reserved.

8 Analysis and interpretation of data: Kane, Karon, Mahoney, Roger, Burnett, Jacobsen, Rodeheffer. Drafting of the manuscript: Kane, Mahoney, Roger, Rodeheffer. Critical revision of the manuscript for important intellectual content: Karon, Mahoney, Redfield, Burnett, Jacobsen, Rodeheffer. Statistical analysis: Kane, Mahoney, Rodeheffer. Obtained funding: Jacobsen, Rodeheffer. Administrative, technical, or material support: Burnett, Jacobsen, Rodeheffer. Study supervision: Rodeheffer. Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported. Funding/Support: This study was supported by National Heart, Lung, and Blood Institute grant R , grant 1UL1RR from the National Institutes of Health (NIH) National Center for Research Resources, and the Mayo Foundation. The research was supported by NIH HL-R (Dr Rodeheffer), NIH AR (Dr Jacobsen), and NIH HL (Redfield). The project was supported by NIH/ National Center for Research Resources (NCRR) Clinical and Translational Science Awards Grant UL RR and by the Rochester Epidemiology Project, grant R01- AG from the National Institute on Aging, and the Mayo Foundation. Role of the Sponsor: The study sponsors had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; or the preparation, review, or approval of the manuscript. Online-Only Material: The etable is available at http: // Additional Contributions: We thank Tammy Burns (Mayo Clinic) and Kasey Muetzel (Mayo Clinic) for invaluable assistance in manuscript preparation. Neither of these individuals received any compensation for their contributions apart from their employment. This article is dedicated to the memory of Kenneth L. Baughman, MD, physician and mentor. REFERENCES 1. Rodeheffer RJ, Jacobsen SJ, Gersh BJ, et al. The incidence and prevalence of congestive heart failure in Rochester, Minnesota. Mayo Clin Proc. 1993;68 (12): McKee PA, Castelli WP, McNamara PM, Kannel WB. The natural history of congestive heart failure: the Framingham study. N Engl J Med. 1971;285 (26): Levy D, Kenchaiah S, Larson MG, et al. Longterm trends in the incidence of and survival with heart failure. N Engl J Med. 2002;347(18): Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive heart failure in the community: trends in incidence and survival in a 10-year period. Arch Intern Med. 1999;159(1): Mosterd A, Hoes AW, de Bruyne MC, et al. Prevalence of heart failure and left ventricular dysfunction in the general population: the Rotterdam Study. Eur Heart J. 1999;20(6): Hunt SA, Abraham WT, Chin MH, et al; American College of Cardiology; American Heart Association Task Force on Practice Guidelines; American College of Chest Physicians; International Society for Heart and Lung Transplantation; Heart Rhythm Society. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005;112(12):e154-e Ammar KA, Jacobsen SJ, Mahoney DW, et al. Prevalence and prognostic significance of heart failure stages: application of the American College of Cardiology/ American Heart Association heart failure staging criteria in the community. Circulation. 2007;115 (12): Redfield MM. Heart failure an epidemic of uncertain proportions. N Engl J Med. 2002;347(18): Roger VL, Weston SA, Redfield MM, et al. Trends in heart failure incidence and survival in a communitybased population. JAMA. 2004;292(3): Bhatia RS, Tu JV, Lee DS, et al. Outcome of heart failure with preserved ejection fraction in a populationbased study. N Engl J Med. 2006;355(3): Redfield MM, Jacobsen SJ, Burnett JC Jr, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289(2): Davies M, Hobbs F, Davis R, et al. Prevalence of left-ventricular systolic dysfunction and heart failure in the Echocardiographic Heart of England Screening study: a population based study. Lancet. 2001; 358(9280): Abhayaratna WP, Marwick TH, Smith WT, Becker NG. Characteristics of left ventricular diastolic dysfunction in the community: an echocardiographic survey. Heart. 2006;92(9): Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol. 1999;33(7): Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med. 2006;355(3): Melton LJ III. History of the Rochester Epidemiology Project. Mayo Clin Proc. 1996;71(3): Jacobsen SJ, Mahoney DW, Redfield MM, Bailey KR, Burnett JC Jr, Rodeheffer RJ. Participation bias in a population-based echocardiography study. Ann Epidemiol. 2004;14(8): The Sixth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [published correction appears in Arch Intern Med. 1998;158(6):573]. Arch Intern Med. 1997;157(21): Pritchett AM, Mahoney DW, Jacobsen SJ, Rodeheffer RJ, Karon BL, Redfield MM. Diastolic dysfunction and left atrial volume: a population-based study. J Am Coll Cardiol. 2005;45(1): Redfield MM, Jacobsen SJ, Borlaug BA, Rodeheffer RJ, Kass DA. Age- and gender-related ventricularvascular stiffening: a community-based study. Circulation. 2005;112(15): Okura Y, Ohno Y, Ramadan MM, et al. Characterization of outpatients with isolated diastolic dysfunction and evaluation of the burden in a Japanese community: Sado Heart Failure Study. Circ J. 2007; 71(7): Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide to detect preclinical ventricular systolic or diastolic dysfunction: a community-based study. Circulation. 2004;109(25): Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002;40(5): McKie PM, Rodeheffer RJ, Cataliotti A, et al. Amino-terminal pro-b-type natriuretic peptide and B- type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure. Hypertension. 2006;47: Munagala VK, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Association of newer diastolic function parameters with age in healthy subjects: a population-based study. J Am Soc Echocardiogr. 2003;16(10): Ommen SR, Nishimura RA, Appleton CP, et al. Clinical utility of Doppler echocardiography and tissue Doppler imaging in the estimation of left ventricular filling pressures: a comparative simultaneous Doppler-catheterization study. Circulation. 2000; 102(15): Nishimura RA, Tajik AJ. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician s Rosetta Stone. JAm Coll Cardiol. 1997;30(1): Hurrell DG, Nishimura RA, Ilstrup DM, Appleton CP. Utility of preload alteration in assessment of left ventricular filling pressure by Doppler echocardiography: a simultaneous catheterization and Doppler echocardiographic study. J Am Coll Cardiol. 1997; 30(2): Redfield MM. Understanding diastolic heart failure. N Engl J Med. 2004;350(19): Borlaug BA, Lam CSP, Roger VL, Rodeheffer RJ, Redfield MM. Contractility and ventricular systolic stiffening in hypertensive heart disease insights into the pathogenesis of heart failure with preserved ejection fraction. J Am Coll Cardiol. 2009;54(5): Chantler PD, Lakatta EG, Najjar SS. Arterialventricular coupling: mechanistic insights into cardiovascular performance at rest and during exercise. J Appl Physiol. 2008;105(4): Zile MR, Baicu CF, Gaasch WH. Diastolic heart failure abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med. 2004; 350(19): Borlaug BA, Kass DA. Ventricular-vascular interaction in heart failure. Heart Fail Clin. 2008;4(1): Kass DA, Bronzwaer JGF, Paulus WJ. What mechanisms underlie diastolic dysfunction in heart failure? Circ Res. 2004;94(12): Kass DA. Ventricular arterial stiffening: integrating the pathophysiology. Hypertension. 2005; 46(1): Zile MR, Gaasch WH, Carroll JD, et al. Heart failure with a normal ejection fraction: is measurement of diastolic function necessary to make the diagnosis of diastolic heart failure? Circulation. 2001;104 (7): Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, II: the aging heart in health: links to heart disease. Circulation. 2003;107(2): Abhayaratna WP, Barnes ME, O Rourke MF, et al. Relation of arterial stiffness to left ventricular diastolic function and cardiovascular risk prediction in patients or =65 years of age. Am J Cardiol. 2006; 98(10): Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular disease enterprises, I: aging arteries: a set up for vascular disease. Circulation. 2003;107(1): Gerstenblith G, Frederiksen J, Yin FCP, Fortuin NJ, Lakatta EG, Weisfeldt ML. Echocardiographic assessment of a normal adult aging population. Circulation. 1977;56(2): Grewal J, McCully RB, Kane GC, Lam C, Pellikka PA. Left ventricular function and exercise capacity. JAMA. 2009;301(3): Cheng S, Fernandes VRS, Bluemke DA, McClelland RL, Kronmal RA, Lima JAC. Age-related left ventricular remodeling and associated risk for cardiovascular outcomes: the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Imaging. 2009;2(3): American Medical Association. All rights reserved. JAMA, August 24/31, 2011 Vol 306, No