Predictive Value of Normal Left Atrial Volume in Stress Echocardiography

Transcription

1 Journal of the American College of Cardiology Vol. 47, No. 5, by the American College of Cardiology Foundation ISSN /06/$32.00 Published by Elsevier Inc. doi: /j.jacc Predictive Value of Normal Left Atrial Volume in Stress Echocardiography Ahmed A. Alsaileek, MD, Martin Osranek, MD, Kaniz Fatema, PHD, Robert B. McCully, MD, Teresa S. Tsang, MD, James B. Seward, MD Rochester, Minnesota OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS Our objective was to evaluate whether normal left atrial volume index (LAVI) is a predictor of a normal stress echocardiogram and thus a predictor of low ischemic risk. Left atrial enlargement is closely related to the chronicity and intensity of the burden of increased ventricular filling pressure. Typically ischemic heart disease (IHD) has a long period of subclinical dysfunction. Increased filling pressure, reflected by enlarged LAVI, is hypothesized to mirror the burden of subclinical and overt IHD. We hypothesized that a normal LAVI might also be useful in predicting low IHD risk. One hundred eighty randomly selected patients (mean age, years; 53% men) underwent outpatient exercise or dobutamine stress echocardiography for known or suspected coronary artery disease. Left atrial volume index was measured retrospectively with the biplane area-length method. The stress echocardiogram was interpreted as abnormal if wall motion abnormalities (WMAs) were noted at rest and/or with stress. Left atrial volume index was categorized as 28 ml/m 2 (normal), 28.1 to 32 ml/m 2, 32.1 to 36 ml/m 2, and 36 ml/m 2. Abnormal stress echocardiography was identified in 57 patients (31.7%). The percentage of abnormal stress echocardiograms in each LAVI category was 5.7%, 21.9%, 38.7%, and 54.7%, respectively. The negative predictive value for LAVI 28 ml/m 2 was 94.3%. Normal resting LAVI ( 28 ml/m 2 ) was strongly predictive of a normal stress echocardiogram. Left atrial volume index might be a simple means of identifying patients with low ischemic risk and should be further evaluated as a complement to the assessment of ischemic risk. (J Am Coll Cardiol 2006;47:1024 8) 2006 by the American College of Cardiology Foundation Left atrial volume index (LAVI) is a preferred method for determining LA size and provides incremental prognostic information beyond that afforded by clinical risk factors (1,2). Left atrial volume index reflects the chronicity and magnitude of the increased left ventricular (LV) filling pressure and is closely related to general cardiovascular risk burden (3 5). Ischemic heart disease (IHD) has been demonstrated to cause subclinical diastolic dysfunction before systolic dysfunction becomes evident (6 8). Multiple studies have shown the value of normal LAVI for the prediction of general cardiovascular risk (9 14) and a normal stress test for the prediction of low ischemic risk (15 18). Our study specifically addressed the hypothesis that a normal resting LAVI is also predictive of a normal stress echocardiogram and a low risk of IHD. In many clinical settings, stress testing might not be available, whereas it is often possible to obtain a focused echocardiographic examination, which could include measurement of LAVI. METHODS Study population. Approval was obtained from the institutional review board of the Mayo Foundation. We used the From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minnesota. Dr. Osranek was supported by post-doctoral fellowships from the Austrian Science Fund (Schrödinger Stipend) and the American Heart Association. Manuscript received May 23, 2005; revised manuscript received August 16, 2005, accepted September 19, stress echocardiography database to identify patients who had undergone clinically indicated outpatient exercise or dobutamine stress echocardiography between February 1, 2004, and March 31, The entry criterion was resting two-dimensional images appropriate for blinded retrospective off-line measurement of LAVI. Exclusion criteria were images inadequate for measuring LAVI, an indeterminate stress result, and denial of research authorization. Of 1,000 patients, we randomly selected a sample of 200 subject studies with a computer algorithm. Data acquisition. Atrial volume, with the biplane arealength method, was indexed to body surface area. With off-line rest images obtained before the stress test, LAVI was measured at the end of ventricular systole just before opening of the mitral valve (1). Left atrial volume (LAV) was calculated as follows: Area 4-chamber Area 2-chamber 0.85 Shortest length Normal and abnormal LAVIs have been previously published (5,19,20). For this study, we used LAVI 28 ml/m 2 as normal. As published previously (21,22), the stress echocardiograms were interpreted as normal if wall motion was normal both at rest and with stress. Wall motion abnormalities (WMAs) were divided into three groups: 1) fixed WMA at rest, which remained unchanged with stress; 2) mixed

2 JACC Vol. 47, No. 5, 2006 March 7, 2006: Alsaileek et al. Predictive Value of Normal Left Atrial Volume 1025 WMA at rest and additional WMA with stress; and 3) new WMA no WMA at rest and new WMA with stress. Statistical analysis. Results are presented as mean values SD for continuous variables and as frequency percentages for categorical variables. Group comparisons were performed with a standard t test or chi-square test, as appropriate. Univariate associations of stress echocardiographic (normal/abnormal test), LAVI, and clinical variables were assessed with logistic models. The effect of LAVI on stress echocardiographic variables was also estimated with a logistic model after adjusting for age, gender, low ejection fraction ( 0.50), LV end-diastolic diameter, and LV hypertrophy. Left atrial volume index was used as a dichotomous variable (LAVI 28 ml/m 2 ) in all the models. Significance was defined as p 0.05 for all analyses. Some clinically significant variables were forced into the model with an insignificant p value. The interobserver variability for LAV measurements was determined for 20 randomly selected studies. The LAV measurement was obtained by two independent observers, and the interclass correlation was estimated to be 0.91 (95% confidence interval, 0.82 to 0.96). RESULTS Abbreviations and Acronyms CAD coronary artery disease IHD ischemic heart disease LAV left atrial volume LAVI left atrial volume index LV left ventricle/ventricular WMA wall motion abnormality Of the 200 randomly selected patients, 20 (10%) were excluded because echocardiographic images suitable for LAVI measurement had not been obtained. Of the 180 remaining patients, 96 (53%) were men (mean age, years; range, 27 to 89 years) and 47.8% underwent dobutamine stress echocardiography. The patients baseline characteristics are presented in Table 1. Normal LAVI. Normal LAVI (LAVI 28 ml/m 2 ) was found in 53 patients (29.4%) (mean age, years; range, 27 to 85 years); 45% were men and 36% underwent dobutamine stress echocardiography (Table 2). The indications for stress testing in patients with normal LAVI were chest pain and shortness of breath in 52.8%, preoperative assessment in 20.8%, known coronary artery disease (CAD) in 11.3%, and other in 15%. Of 53 patients with normal LAVI, 50 (94.3%) had completely normal stress echocardiograms and 3 (5.7%) had fixed WMA of a small localized area in the inferior wall (Fig. 1). No patient with LAVI 28 ml/m 2 had stress echocardiography with ischemic or mixed WMA (positive for ischemia). Normal LAVI had 94.7% sensitivity, 41% specificity, 94.3% negative predictive value, and 42.9% positive predictive value for abnormal stress echocardiography. LAVI and stress echocardiography results. Wall motion was interpreted as being entirely normal (no WMA) in 123 patients (68.3%) and abnormal (any WMA) in 57 (31.7%). The indications for stress echocardiography in normal and abnormal studies were chest pain and shortness of breath in 43.1% versus 28.1%, preoperative assessment in 28.4% versus 33.3%, known CAD in 10% versus 29.8%, and other in 18.5% versus 8.8%, respectively. For patients with normal wall motion, LAVI was ml/m 2 (range, 16.9 to 68.8 ml/m 2 ), and for those with abnormal wall motion, LAVI was ml/m 2 (range, 23.3 to 79.9 ml/m 2 ) (p ) (Fig. 2). Left atrial volume index was largest for older patients with mixed WMA, ml/m 2. Table 1. Clinical and Echocardiographic Features of the Study Group, Categorized by Stress Echocardiography Results Myocardial Wall Motion Abnormal (n 57) Feature Normal (n 123) Ischemic (n 12) Fixed (n 19) Mixed (n 26) Age, yrs, mean SD (range) (27 89) (36 86) (51 88) 72 9* (50 89) Men, % * WMSI, mean SD Resting * * At peak * * * LAVI, ml/m 2, mean SD (range) ( ) * ( ) * ( ) * ( ) Dobutamine echo, % LV wall thickness, mm Septal Posterior wall LV dimensions, cm LVDD * * LVSD * * LVEF, % Resting * * At peak * * *p 0.05 compared with the normal. EF ejection fraction; LAVI left atrial volume index; LV left ventricular; LVDD left ventricular end-diastolic; LVSD left ventricular end-systolic; WMSI wall motion score index.

3 1026 Alsaileek et al. JACC Vol. 47, No. 5, 2006 Predictive Value of Normal Left Atrial Volume March 7, 2006: Table 2. Clinical and Echocardiographic Features of the Study Group, Categorized by LAVI Results Feature <28 (n 53) (n 32) (n 31) >36 (n 64) Age, yrs, mean SD (range) (27 85) (32 80) (35 86) 71 13* (44 89) Men, % BMI, kg/m 2, mean SD WMSI, mean SD Resting * At peak * Dobutamine echo, % LV wall thickness, mm Septal Posterior wall LV dimensions, cm LVDD * LVSD * * LVEF, % Resting * At peak * *p 0.05 compared with LAVI 28 ml/m 2. BMI body mass index; other abbreviations as in Table 1. LAVI Categories, ml/m 2 Any WMA also increased in frequency relative to an increase in LAVI (Fig. 1). With logistic regression (Table 3), LAVI was an independent predictor of normal stress echocardiography even after adjusting for age, gender, resting ejection fraction, LV hypertrophy, and LV dimensions (p ). DISCUSSION This study demonstrates that LAVI is strongly predictive of stress echocardiographic results. Two observations deserve emphasis. First, a normal LAVI is strongly associated with a normal stress echocardiogram. Of the patients with LAVI 28 ml/m 2, only three (5.7% of abnormal exams) had a resting WMA and 100% had no stress-induced WMA. In three patients a fixed WMA was small and localized to the basal inferior wall. Second, the more abnormal the LAVI, the more likely the presence of abnormal wall motion (new, fixed, or mixed), which is consistent with data suggesting the greatest risk for IHD is in the mixed WMA subgroup (21 23). This study was designed to address the value of normal LAVI as an indicator of low general cardiovascular and ischemic risk. Left atrial volume index has been shown to be highly predictive of general cardiovascular risk, including hypertension, atrial fibrillation, heart failure, stroke, death associated with dilated cardiomyopathy, and death after acute myocardial infarction (5,9 14,24). Forty-seven patients (50%) with LAVI 32 ml/m 2 had a normal stress echocardiogram. As we previously reported (5,25), increased LAVI is consistent with chronic elevation of filling pressure and increased general cardiovascular risk. A normal stress echocardiogram is highly associated with a low risk of developing IHD within two to three years (15 18,21,23). The current study shows a strong relation Figure 1. The percentage of patients with a normal and abnormal stress echocardiogram with normal or abnormal (ischemic, fixed, or mixed) wall motion for each category of left atrial volume index (LAVI). None of the patients with LAVI 28 ml/m 2 had a positive stress echocardiogram (i.e., new wall motion abnormality), but three had a fixed wall motion abnormality localized to the inferior wall. Figure 2. Mean SD left atrial volume index (LAVI) according to different wall motion abnormality (WMA) results. Left atrial volume index is significantly different between normal and any WMA (new, fixed, or mixed). An atrial volume 28 ml/m 2 is associated with escalating cardiovascular risk, including risk of ischemic heart disease.

4 JACC Vol. 47, No. 5, 2006 March 7, 2006: Alsaileek et al. Predictive Value of Normal Left Atrial Volume 1027 Table 3. Logistic Regression Showing the Effect of Normal LAVI ( 28 ml/m 2 ) on Normal Stress Echocardiography After Adjusting for Age, Gender, Low Resting EF ( 0.50), LVH, and LVDD Variable Odds Ratio 95% CI p Value Age Gender, male LVDD, mm Low resting EF ( 0.50) LVH LAVI 28 ml/m CI confidence interval; LVH left ventricular hypertrophy; other abbreviations as in Table 1. between a normal LAVI and a normal stress echocardiogram. Thus, if validated, a normal resting LAVI could be used as a predictor of low ischemic risk as well as general cardiovascular risk. The chronicity and burden of decreased myocardial compliance and increased filling pressure are thus reflected in the magnitude of increased LAVI (5,26). Elevated filling pressures cause increased atrial wall tension and myocyte stretch, which induces atrial enlargement, myolysis, apoptosis, and fibrosis (27 30). The normal LAVI is 22 6 ml/m 2 (upper normal, approximately 28 ml/m 2 )(5,19,20,26). With normal hemodynamics, a normal LAVI remains relatively unchanged throughout life (31,32). End-systolic LAV does not change significantly with acute alterations in loading (33). In contrast to other measures of loading pressure, LAVI best represents the average burden of elevated filling pressure (25). Cardiovascular risk, including acute and chronic IHD, is preceded by a long period of asymptomatic change in cardiovascular pathophysiology. A normal stress echocardiogram is a strong predictor of a low IHD risk (15 18,21,23). Echocardiographic combined with clinical findings have been shown to provide a risk model for assessing death after an exercise stress test (34). Left atrial volume index was not included in that particular study. The current study suggests that LAVI in conjunction with stress testing should be examined further. Study limitations. The study population was small and selected randomly from an outpatient referral cardiology practice. Left atrial volume index was measured retrospectively but in a blinded manner. Although a normal stress echocardiogram indicates a favorable outcome, it does not necessarily exclude general cardiovascular risk. At best, current stress testing, including nuclear, has a sensitivity and specificity of approximately 85% (35 37); however, a normal stress test is consistently associated with a low risk for subsequent cardiovascular events. We found that a normal LAVI was highly predictive of a normal stress test. In certain clinical settings, LAVI might be useful in determining low IHD risk. Left atrial volume index following acute coronary syndrome is highly predictive of death (13), but LAVI during an acute event has not been prospectively performed, although LAVI is relatively insensitive to acute changes in loading, which would accompany an acute ischemic event (33). Conclusions. Patients with a normal stress echocardiogram are at low risk for the development of a coronary event within two years. A normal LAVI ( 28 ml/m 2 ) strongly predicted a normal stress echocardiogram. The magnitude of increased LAVI is closely related to the magnitude of IHD detected. Left atrial volume index is also known to predict low general cardiovascular risk. Left atrial volume index should be assessed further for its complementary role in stress testing as a means of enhancing prediction of cardiovascular risk. Reprint requests and correspondence: Dr. James B. Seward, Division of Cardiovascular Diseases, Mayo Clinic, 200 First Street SW, Rochester, Minnesota REFERENCES 1. Lester SJ, Ryan EW, Schiller NB, Foster E. Best method in clinical practice and in research studies to determine left atrial size. Am J Cardiol 1999;84: Pritchett AM, Jacobsen SJ, Mahoney DW, Rodeheffer RJ, Bailey KR, Redfield MM. Left atrial volume as an index of left atrial size: a population-based study. J Am Coll Cardiol 2003;41: Simek CL, Feldman MD, Haber HL, Wu CC, Jayaweera AR, Kaul S. Relationship between left ventricular wall thickness and left atrial size: comparison with other measures of diastolic function. J Am Soc Echocardiogr 1995;8: Appleton CP, Galloway JM, Gonzalez MS, Gaballa M, Basnight MA. Estimation of left ventricular filling pressures using twodimensional and Doppler echocardiography in adult patients with cardiac disease: additional value of analyzing left atrial size, left atrial ejection fraction and the difference in duration of pulmonary venous and mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22: Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90: Apstein CS, Grossman W. Opposite initial effects of supply and demand ischemia on left ventricular diastolic compliance: the ischemiadiastolic paradox. J Mol Cell Cardiol 1987;19: Hirota Y. A clinical study of left ventricular relaxation. Circulation 1980;62: Bonow RO, Kent KM, Rosing DR, et al. Improved left ventricular diastolic filling in patients with coronary artery disease after percutaneous transluminal coronary angioplasty. Circulation 1982; 66: Møller JE, Hillis GS, Oh JK, et al. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation 2003;107: Beinart R, Boyko V, Schwammenthal E, et al. Long-term prognostic significance of left atrial volume in acute myocardial infarction. J Am Coll Cardiol 2004;44: Di Tullio MR, Sacco RL, Sciacca RR, Homma S. Left atrial size and the risk of ischemic stroke in an ethnically mixed population. Stroke 1999;30: Barnes ME, Miyasaka Y, Seward JB, et al. Left atrial volume in the prediction of first ischemic stroke in an elderly cohort without atrial fibrillation. Mayo Clin Proc 2004;79: Tsang TS, Barnes ME, Bailey KR, et al. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76: Tsang TS, Barnes ME, Gersh BJ, et al. Prediction of risk for first age-related cardiovascular events in an elderly population: the incremental value of echocardiography. J Am Coll Cardiol 2003;42:

5 1028 Alsaileek et al. JACC Vol. 47, No. 5, 2006 Predictive Value of Normal Left Atrial Volume March 7, 2006: Elhendy A, Modesto KM, Mahoney DW, Khandheria BK, Seward JB, Pellikka PA. Prediction of mortality in patients with left ventricular hypertrophy by clinical, exercise stress, and echocardiographic data. J Am Coll Cardiol 2003;41: McCully RB, Roger VL, Ommen SR, et al. Outcomes of patients with reduced exercise capacity at time of exercise echocardiography. Mayo Clin Proc 2004;79: McCully RB, Roger VL, Mahoney DW, et al. Outcome after normal exercise echocardiography and predictors of subsequent cardiac events: follow-up of 1,325 patients. J Am Coll Cardiol 1998;31: Sawada SG, Ryan T, Conley MJ, Corya BC, Feigenbaum H, Armstrong WF. Prognostic value of a normal exercise echocardiogram. Am Heart J 1990;120: Wang Y, Gutman JM, Heilbron D, Wahr D, Schiller NB. Atrial volume in a normal adult population by two-dimensional echocardiography. Chest 1984;86: Gutman J, Wang YS, Wahr D, Schiller NB. Normal left atrial function determined by 2-dimensional echocardiography. Am J Cardiol 1983;51: Krivokapich J, Child JS, Walter DO, Garfinkel A. Prognostic value of dobutamine stress echocardiography in predicting cardiac events in patients with known or suspected coronary artery disease. J Am Coll Cardiol 1999;33: Chuah SC, Pellikka PA, Roger VL, McCully RB, Seward JB. Role of dobutamine stress echocardiography in predicting outcome in 860 patients with known or suspected coronary artery disease. Circulation 1998;97: Marcovitz PA, Shayna V, Horn RA, Hepner A, Armstrong WF. Value of dobutamine stress echocardiography in determining the prognosis of patients with known or suspected coronary artery disease. Am J Cardiol 1996;78: Sabharwal N, Cemin R, Rajan K, Hickman M, Lahiri A, Senior R. Usefulness of left atrial volume as a predictor of mortality in patients with ischemic cardiomyopathy. Am J Cardiol 2004;94: 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: Douglas PS. The left atrium: a biomarker of chronic diastolic dysfunction and cardiovascular disease risk. J Am Coll Cardiol 2003;42: Boixel C, Fontaine V, Rucker-Martin C, et al. Fibrosis of the left atria during progression of heart failure is associated with increased matrix metalloproteinases in the rat. J Am Coll Cardiol 2003;42: Li D, Fareh S, Leung TK, Nattel S. Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort. Circulation 1999;100: Boyden PA, Tilley LP, Pham TD, Liu SK, Fenoglic JJ Jr., Wit AL. Effects of left atrial enlargement on atrial transmembrane potentials and structure in dogs with mitral valve fibrosis. Am J Cardiol 1982;49: Rücker-Martin C, Pecker F, Godreau D, Hatem SN. Dedifferentiation of atrial myocytes during atrial fibrillation: role of fibroblast proliferation in vitro. Cardiovasc Res 2002;55: Thomas L, Levett K, Boyd A, Leung DY, Schiller NB, Ross DL. Compensatory changes in atrial volumes with normal aging: is atrial enlargement inevitable? J Am Coll Cardiol 2002;40: 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: Barberato SH, Mantilla DE, Misocami MA, et al. Effect of preload reduction by hemodialysis on left atrial volume and echocardiographic Doppler parameters in patients with end-stage renal disease. Am J Cardiol 2004;94: Elhendy A, Mahoney DW, McCully RB, Seward JB, Burger KN, Pellikka PA. Use of a scoring model combining clinical, exercise test, and echocardiographic data to predict mortality in patients with known or suspected coronary artery disease. Am J Cardiol 2004;93: Geleijnse ML, Fioretti PM, Roelandt JR. Methodology, feasibility, safety and diagnostic accuracy of dobutamine stress echocardiography. J Am Coll Cardiol 1997;30: Taillefer R, DePuey EG, Udelson JE, Beller GA, Latour Y, Reeves F. Comparative diagnostic accuracy of Tl-201 and Tc-99m sestamibi SPECT imaging (perfusion and ECG-gated SPECT) in detecting coronary artery disease in women. J Am Coll Cardiol 1997;29: Geleijnse ML, Elhendy A, Fioretti PM, Roelandt JR. Dobutamine stress myocardial perfusion imaging. J Am Coll Cardiol 2000;36: