Usefulness of Left Ventricular End-Systolic Dimension by Echocardiography to Predict Reverse Remodeling in Patients With Newly Diagnosed Severe Left Ventricular Systolic Dysfunction

Usefulness of Left Ventricular End-Systolic Dimension by Echocardiography to Predict Reverse Remodeling in Patients With Newly Diagnosed Severe Left Ventricular Systolic Dysfunction Pradeep K. Bhat, MD, Mahi L. Ashwath, MD, David S. Rosenbaum, MD, and Ottorino Costantini, MD* In many patients with left ventricular (LV) systolic dysfunction, the LV ejection fraction (LVEF)—a surrogate for reverse remodeling—fails to improve despite optimal medical therapy. The early identification of such patients would allow instituting aggressive treatment, including early therapy with implantable cardioverter defibrillators. We sought to establish the predictors of reverse remodeling in patients with LV systolic dysfunction receiving optimal medical therapy. Patients (n ⴝ 568) with newly documented LVEF of <0.35, who had >1 follow-up echocardiogram after >3 months, were evaluated. Reverse remodeling was defined as improvement in LVEF to >0.35. The clinical, laboratory, and echocardiographic data were compared between patients with (n ⴝ 263) and without (n ⴝ 305) reverse remodeling. The mean follow-up was 27 ⴞ 16 months. Patients who demonstrated reverse remodeling had a significantly greater mean follow-up LVEF (0.51 ⴞ 0.09 vs 0.25 ⴞ 0.08; p <0.001). On multivariate analysis, the baseline LV end-systolic diameter index was the strongest predictor of reverse remodeling (odds ratio 5.79; 95% confidence interval 1.82 to 18.46; p <0.001). Other independent predictors of reverse remodeling were female gender (odds ratio 1.88; 95% confidence interval 1.19 to 2.98; p ⴝ 0.007), and nonischemic cardiomyopathy (odds ratio 1.65; 95% confidence interval 1.05 to 2.58; p ⴝ 0.03). Baseline LVEF was not an independent predictor of reverse remodeling. In conclusion, among patients with newly diagnosed LV systolic dysfunction, the LV end-systolic diameter index, but not the LVEF, at diagnosis, was a strong predictor of reverse remodeling. Patients with a low likelihood of reverse remodeling might benefit from more aggressive heart failure therapy, including the possible early use of implantable cardioverter defibrillators. © 2012 Published by Elsevier Inc. (Am J Cardiol 2012;110:83– 87)

Predicting whether a patient with left ventricular (LV) systolic dysfunction is likely to undergo reverse remodeling is challenging. Small studies evaluating the baseline LV size as a predictor, not only yielded conflicting results, but were also performed in the era when the combined use of angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blockers (ARBs) and ␤ blockers was not widespread.1,2 Although ␤ blockers and/or ACE inhibitors have been demonstrated to result in reverse remodeling,3–7 despite their combined use, reverse remodeling does not occur in a number of patients with systolic heart failure. Although a number of studies have evaluated reverse remodeling after cardiac resynchronization therapy, a paucity of data is available in patients with LV systolic dysfunction who are only receiving optimal medical therapy with both ACE inhibitors/ARBs and ␤ blockers. The early identification of patients whose LV systolic function will not improve might allow for more aggressive therapy, such as the use of implantable cardioverter defibrillators (ICDs) earlier in the

Heart and Vascular Center, MetroHealth Campus, Case Western Reserve University, Cleveland, Ohio. Manuscript received December 17, 2011; revised manuscript received and accepted February 21, 2012. *Corresponding author: Tel: (216) 778-8765; fax: 216-778-3927. E-mail address: [email protected] (O. Costantini). 0002-9149/12/$ – see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.amjcard.2012.02.054

disease course. Therefore, the aims of our study were to evaluate the incidence of LV reverse remodeling in patients with LV systolic dysfunction optimally treated with ACE inhibitors/ARBs and ␤ blockers and to determine the predictors of LV reverse remodeling. Methods This was a retrospective study conducted at the MetroHealth Campus of Case Western Reserve University in Cleveland, Ohio. The local institutional review board approved the study. The echocardiographic hospital database was used to identify all patients who underwent echocardiography for the evaluation of clinical signs and symptoms of heart failure and had a newly documented left ventricular ejection fraction (LVEF) of ⱕ0.35. From this group, all patients who had ⱖ1 follow-up echocardiogram done ⱖ3 months after the index echocardiogram were included in the present study. The echocardiograms were read by the staff cardiologists not directly involved in the care of the study patients, and the LVEF was measured using the biplane area-length method.8 In our study, reverse remodeling was defined as an improvement in LVEF to ⬎0.35 at last follow-up echocardiogram. The patients were categorized into 2 groups: those who demonstrated reverse remodeling (reverse remodeling www.ajconline.org

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Table 1 Clinical characteristics Variable

Age (years) Women Race White Black Diabetes mellitus Hypertension Cardiomyopathy Ischemic Nonischemic History of myocardial infarction Duration of heart failure (months) Atrial fibrillation/flutter Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) New York Heart Association functional class B-type natriuretic peptide (pg/ml) Medications ␤ Blocker Angiotensin-converting enzyme inhibitor/ angiotensin receptor blocker Digoxin Diuretics Nitrates Hydralazine Baseline QRS (ms)

Table 2 Echocardiographic characteristics Reverse Remodeling

p Value

Yes (n ⫽ 263)

No (n ⫽ 305)

57 ⫾ 14 119 (45%)

58 ⫾ 14 110 (36%)

125 (47%) 108 (41%) 98 (37%) 210 (80%)

132 (43%) 148 (48%) 106 (35%) 219 (72%)

98 (37%) 165 (63%) 35 (13%)

142 (47%) 163 (53%) 49 (16%)

0.16

5 ⫾ 10

0.17

3⫾7

0.57 0.02 0.16

0.08 0.02 0.01

44 (17%) 86 ⫾ 19 133 ⫾ 23

48 (16%) 83 ⫾ 18 128 ⫾ 25

0.45 0.23 0.007

72 ⫾ 17

69 ⫾ 18

0.06

3.05 ⫾ 0.97

3.02 ⫾ 0.96

0.73

1,126 ⫾ 658

1,001 ⫾ 631

0.85

251 (95%) 249 (95%)

291 (95%) 285 (93%)

0.57 0.33

78 (30%) 195 (74%) 102 (39%) 75 (28%) 109 ⫾ 30

158 (52%) 255 (84%) 134 (44%) 87 (28%) 113 ⫾ 30

⬍0.001 0.004 0.12 0.49 0.04

[⫹RR] group) and those who did not (no reverse remodeling [⫺RR] group). The clinical, electrocardiographic, and laboratory variables were recorded at both the baseline and the follow-up echocardiographic visit and were compared between the 2 groups. The variables included age, gender, race, history of hypertension, etiology of cardiomyopathy (ischemic or nonischemic), and QRS duration. The use of ACE inhibitors/ARBs and ␤ blockers, including their doses, were recorded for each visit. The echocardiographic chamber dimensions obtained from 2-dimensional recordings (parasternal long-axis view) were normalized for body surface area to obtain the LV end-diastolic diameter index (LVEDDI) and LV end-systolic diameter index (LVESDI). The percentage of change in the LVEDDI and LVESDI between the initial and final echocardiogram was recorded. Mitral regurgitation was assessed semiquantitatively by color Doppler echocardiography and graded as mild, moderate, or severe.9 It was considered significant if it was moderate or greater. Patients were excluded if the LV dimensions could not be measured accurately or if they had

Variable

Reverse remodeling Yes

Follow-up (months) Total number of follow-up echocardiograms Left ventricular ejection fraction (%) Baseline Final Left ventricular end-diastolic diameter index Baseline (cm/m2) Percentage of change between baseline and final Left ventricular end-systolic diameter index Baseline (cm/m2) Percentage of change between baseline and final Left ventricular mass index (g/m2) Significant mitral regurgitation

p value

No

25 ⫾ 14 2.5 ⫾ 0.6

28 ⫾ 17 2.5 ⫾ 0.7

0.06 0.84

27 ⫾ 7 51 ⫾ 9

25 ⫾ 7 25 ⫾ 8

0.001 ⬍0.001

2.73 ⫾ 0.46 ⫺6.3 ⫾ 15.9

3.02 ⫾ 0.53 0.68 ⫾ 12.0

⬍0.001 ⬍0.001

2.28 ⫾ 0.47 ⫺15.1 ⫾ 21.1

2.58 ⫾ 0.52 1.69 ⫾ 16.4

⬍0.001 ⬍0.001

138 ⫾ 47

149 ⫾ 43

0.001

38 (14%)

63 (21%)

0.03

Figure 1. Improvement in LVEF in patients with reverse remodeling. Of 263 patients who demonstrated reverse remodeling, most (n ⫽ 245; 93%) had a clinically important increase in LVEF of ⱖ10 percentage points.

received cardiac resynchronization therapy during the study period. Ischemic cardiomyopathy was defined as either the presence of an obstructive coronary lesion (ⱖ70% diameter narrowing) or a history of revascularization (percutaneous coronary intervention or coronary artery bypass grafting) in ⱖ1 of the 3 major coronary arteries. Nonischemic cardiomyopathy was defined as the absence of ischemic cardiomyopathy according to the above criteria. The target doses of ␤ blockers and ACE inhibitors/ARBs were defined in accordance with the current best evidence (i.e., metoprolol ⱖ200 mg/day; carvedilol ⱖ50 mg/day; lisinopril 40 mg/ day; valsartan 320 mg/day; and losartan 100 mg/day). The categorical variables are reported as counts and percentages and were compared using chi-square statistics. Continuous variables are presented as the mean ⫾ SD and

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Figure 2. Reverse remodeling occurred across a number of baseline LVEF values. The patients whose LVEF improved to ⬎0.35% were distributed across a number of baseline LVEF values. The distribution was as follows: baseline LVEF ⱕ0.15%, 39 (37%) of 105; LVEF 0.20%, 45 (38%) of 117; LVEF 0.25%, 41 (45%) of 91; LVEF 0.30%, 65 (56%) of 115; and LVEF 0.35%, 73 (52%) of 140.

were compared using Student’s t test or the Wilcoxon nonparametric statistic. A p value of ⬍0.05 was considered statistically significant. The clinical, laboratory, and echocardiographic variables were initially evaluated individually and, if found significant, were analyzed using a multivariate logistic regression model. Odds ratios were calculated to determine the independent predictors of reverse remodeling. The data were analyzed using PASW Statistics, version 18 (SPSS, Chicago, Illinois). Results A total of 700 patients were identified with a documented LVEF of ⱕ0.35 and a follow-up echocardiogram performed ⱖ3 months later. A total of 32 patients who received cardiac resynchronization therapy were excluded and another 100 were excluded for the lack of data on LV dimensions. The remaining 568 patients were included in the present study. The duration of heart failure symptoms before the first echocardiogram was 4 ⫾ 9 months, and the duration of follow-up was 27 ⫾ 16 months. The cause of cardiomyopathy was ischemic in 230 patients (40%) and nonischemic in 338 (60%). A total of 256 patients (45%) in our study were black. Most patients (n ⫽ 542; 95%) were taking both an ACE inhibitor/ARB and a ␤ blocker at baseline. A total of 263 patients (46%) exhibited reverse remodeling, and the remaining 305 (54%) did not. The clinical and electrocardiographic characteristics of the 2 groups are listed in Table 1. A history of hypertension was more common in the ⫹RR group, and the use of digoxin and diuretics was more common in the ⫺RR group. The use of ACE inhibitors/ARBs and ␤ blockers, including their target doses, was similar in both groups. In the ⫹RR group, 131 patients (50%) were receiving the target dose of ACE inhibitors/ARBs and 123 (47%) the target ␤-blocker dose. The corresponding data for the ⫺RR group were 143 (47%) for ACE inhibitors/ARBs and 132 (43%) for ␤ blockers. The mean baseline LVEF was 0.27% in the ⫹RR group and 0.25 in the ⫺RR group (Table 2). Patients in the ⫹RR group had a lower baseline LVEDDI and LVESDI. The 2 groups were similar with respect to the follow-up duration and the number of follow-up echocardiograms. At followup, 263 patients (46%) achieved an LVEF ⬎0.35 and 143 of

Table 3 Multivariate predictors of reverse remodeling Variable

Odds Ratio

95% Confidence Interval

p Value

Women Nonischemic cardiomyopathy Baseline left ventricular endsystolic diameter index (cm/m2)

1.88 1.65 5.79

1.19–2.98 1.05–2.58 1.82–18.46

0.007 0.03 0.003

them (25% of all patients) achieved an LVEF of ⱖ0.50. The patients in the ⫹RR group had a significantly greater follow-up LVEF and a significant reduction in both LVEDDI and LVESDI (Table 2). Of the 263 patients who demonstrated reverse remodeling, 245 patients (93%) demonstrated a clinically meaningful increase in LVEF of ⱖ10% (Figure 1). Also, patients in the ⫹RR group were distributed across a number of baseline LVEFs and not limited to those with the greatest baseline LVEF (Figure 2). When we evaluated the study population for events that could potentially influence reverse remodeling during the follow-up period, we found no difference in the 2 groups with respect to the rates of acute myocardial infarction occurring at enrollment (⫹RR, 18 [7%] vs ⫺RR, 20 (6%); p ⫽ NS), the rates of acute myocardial infarction during the follow-up period (⫹RR 10 [4%] vs ⫺RR 16 [5%]; p ⫽ NS); or the rates of revascularization procedures during the study period (⫹RR, 40 [15%] vs ⫺RR, 39 [13%]; p ⫽ NS). The univariate predictors of reverse remodeling were female gender, history of hypertension, presence of nonischemic cardiomyopathy, digoxin use, diuretic use, baseline QRS duration, baseline systolic blood pressure, and baseline echocardiographic variables (i.e., LVEF, rates of significant mitral regurgitation, LV mass index, LVEDDI, and LVESDI). In a multivariate model that included these variables, the strongest predictor of reverse remodeling was the baseline LVESDI (Table 3). Other independent predictors of reverse remodeling were female gender and the presence of nonischemic cardiomyopathy. Although the QRS duration was increased in patients in the ⫺RR group, it was not a strong predictor of reverse remodeling (109 ⫾ 30 ms vs 113 ⫾ 30 ms; odds ratio 1.01; 95% confidence

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interval 1.00 to 1.02; p ⫽ 0.003). Similarly, the baseline systolic blood pressure was not a strong predictor of reverse remodeling (odds ratio 0.99; 95% confidence interval 0.98 to 1.00; p ⫽ 0.03). Although the initial LVEF was slightly greater in patients in the ⫹RR group, it was not an independent predictor of reverse remodeling. Discussion Our study demonstrates that in a contemporary population of patients with LV systolic dysfunction receiving optimal medical therapy, the incidence of reverse remodeling (measured by an improvement in LVEF to ⬎0.35) was 46%. The baseline LVESDI was the best independent predictor of LV reverse remodeling. Other independent predictors were female gender and nonischemic cardiomyopathy. Importantly, the likelihood of reverse remodeling was not influenced by the initial LVEF and occurred across a range of baseline LVEF values. In patients with LV systolic dysfunction, identifying those at risk of sudden cardiac death is critical. A depressed LVEF, despite its limitations, is currently the best risk stratification tool to identify patients at high risk of sudden cardiac death. Although patients whose LVEF does not improve with time are at a greater risk of sudden death, a number of patients will have favorable remodeling over time, such that their LVEF is significantly greater after the initial diagnosis. Therefore, a “waiting period” of 3 to 9 months, as recommended by the current guidelines,10 –12 might allow time for optimization of medical therapy and, possibly, for reverse remodeling. Our study was designed to evaluate the predictors of reverse remodeling and thereby possibly identify those likely to remain at high risk of sudden death at an early stage. Previous studies of LV size as a predictor of reverse remodeling have yielded conflicting results and were limited by either a small sample size and suboptimal use of ␤ blockers1 or a lack of the use of ACE inhibitors/ARBs.2 Therefore, these studies do not reflect contemporary therapy of patients with heart failure that almost always have included ␤ blockers and ACE inhibitors/ARBs. In our study, the LVESDI at diagnosis was the strongest independent predictor of reverse remodeling. Additionally, in patients who demonstrated reverse remodeling, the LVEDDI and LVESDI were not only lower at baseline but had also decreased significantly during the follow-up period. Studies evaluating the underlying molecular basis of reverse remodeling might offer some clues in understanding why the LV size might be closely associated with reverse remodeling.13–15 It is possible that left ventricular dilation could either by itself be detrimental to reverse remodeling (partly because of unfavorable wall stress) or be the end result of the cascade of molecular events involved in remodeling. In our study, the presence of nonischemic cardiomyopathy was an independent predictor of reverse remodeling. Several trials of patients with nonischemic cardiomyopathy have demonstrated lower than expected mortality and equivocal mortality benefit from ICDs.16,17 Some of these observed differences could be related to the greater likelihood of reverse remodeling in nonischemic cardiomyopathy.18 In patients with ischemic cardiomyopathy, reverse

remodeling might be adversely influenced by a number of factors, including incomplete or delayed revascularization, and the presence of a large scar burden. In contrast, patients with nonischemic cardiomyopathy might have a greater proportion of reversible causes of cardiomyopathy such as hypertension and tachycardia-induced cardiomyopathy. Our study has demonstrated that women were more likely to undergo reverse remodeling compared with men. Although men were more likely to have ischemic cardiomyopathy, gender was an independent predictor of reverse remodeling. The gender differences in myocyte death, apoptosis, and reverse remodeling have been previously reported.19 –21 Although the exact reasons for these differences are unclear, our study has confirmed the findings of these interesting observations and points to the need for more research in this area. The prospective validation of our results could assist in the development of a noninvasive risk assessment tool that could allow physicians to predict the likelihood of reverse remodeling early in the disease course and offer therapy tailored to the individual patient with LV systolic dysfunction. Our study has some limitations. The definition of reverse remodeling used in our study was an improvement in LVEF to ⬎0.35. Because considerable variation exists in published studies regarding what constitutes reverse remodeling,22 our definition was chosen because of the clinical relevance for planning implantation of primary prevention ICDs. This definition was inclusive of the 1 used in several studies (i.e., an improvement in LVEF of ⱖ0.05).23–25 Also, measuring the LV dimensions and function using echocardiography has its own limitations. Although we do not have data on the intra- and interobserver variability, comparisons of the LVEF obtained echocardiographically by our group with those obtained by cardiac magnetic resonance imaging indicated an excellent correlation (r ⫽ 0.92), similar to the correlations reported in previous studies.26 In addition, echocardiography is the accepted method of directing therapeutic interventions, including patient selection for ICD therapy. Hence, we believe that our findings would be relevant in the clinical arena. 1. Levine TB, Levine AB, Bolenbaugh J, Stomel RJ. Impact of left ventricular size on pharmacologic reverse remodeling in heart failure. Clin Cardiol 2000;23:355–358. 2. Kotlyar E, Hayward CS, Keogh AM, Feneley M, MacDonald PS. The impact of baseline left ventricular size and mitral regurgitation on reverse left ventricular remodelling in response to carvedilol: size doesn’t matter. Heart 2004;90:800 – 801. 3. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in Dilated Cardiomyopathy (MDC) Trial Study Group. Lancet 1993;342:1441–1446. 4. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind randomized study. J Am Coll Cardiol 1995;25:1225–1231. 5. Reiken S, Wehrens XH, Vest JA, Barbone A, Klotz S, Mancini D, Burkhoff D, Marks AR. Beta-blockers restore calcium release channel function and improve cardiac muscle performance in human heart failure. Circulation 2003;107:2459 –2466. 6. Pfeffer MA, Braunwald E, MoyeMoyé LA, Basta L, Brown EJ Jr, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau J, Rutherfor J, Wertheimer JH, Hawkins CM. Effect of captopril on mortality and morbidity in

Heart Failure/Predictors of LV Reverse Remodeling

7.

8.

9.

10.

11.

12.

13. 14.

15.

patients with left ventricular dysfunction after myocardial infarction: Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992;327:669 – 677. Peng H, Carretero OA, Vuljaj N, Liao TD, Motivala A, Peterson EL, Rhaleb NE. Angiotensin-converting enzyme inhibitors: a new mechanism of action. Circulation 2005;112:2436 –2445. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ; Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005; 18:1440 –1463. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, Nihoyannopoulos P, Otto CM, Quinones MA, Rakowski H, Stewart WJ, Waggoner A, Weissman NJ; American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777– 802. Decision memo for implantable defibrillators (CAG-00157R3). Available from: http://www.cms.gov/medicare-coverage-database/details/ nca-decision-memo.aspx?NCAId⫽148%26ver⫽16%26NcaName⫽ Implantable⫹Defibrillators⫹%26x28;3rd⫹Recon%26x29;%26bc⫽ BEAAAAAAEAAA%26. Accessed November 27, 2011. Kadish A, Dyer A, Daubert JP, Quigg R, Estes NA, Anderson KP, Calkins H, Hoch D, Goldberger J, Shalaby A, Sanders WE, Schaechter A, Levine JH; Defibrillators in Non-Ischemic Cardiomyopathy Treatment Evaluation (DEFINITE) Investigators. Prophylactic defibrillator implantation in patients with nonischemic dilated cardiomyopathy. N Engl J Med 2004;350:2151–2158. Bänsch D, Antz M, Boczor S, Volkmer M, Tebbenjohanns J, Seidl K, Block M, Gietzen F, Berger J, Kuck KH. Primary prevention of sudden cardiac death in idiopathic dilated cardiomyopathy: the Cardiomyopathy Trial (CAT). Circulation 2002;105:1453–1458. Hein S, Kostin S, Heling A, Maeno Y, Schaper J. The role of the cytoskeleton in heart failure. Cardiovasc Res 2000;45:273–278. Kostin S, Hein S, Arnon E, Scholz D, Schaper J. The cytoskeleton and related proteins in the human failing heart. Heart Fail Rev 2000;5: 271–280. Narula J, Haider N, Arbustini E, Chandrashekhar Y. Mechanisms of disease: apoptosis in heart failure—seeing hope in death. Nat Clin Pract Cardiovasc Med 2006;3:681– 688.

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16. Strickberger SA, Hummel JD, Bartlett TG, Frumin HI, Schuger CD, Beau SL, Bitar C, Morady F; AMIOVIRT Investigators. Amiodarone versus implantable cardioverter-defibrillator: randomized trial in patients with nonischemic dilated cardiomyopathy and asymptomatic nonsustained ventricular tachycardia—AMIOVIRT. J Am Coll Cardiol 2003;41:1707–1712. 17. Desai AS, Fang JC, Maisel WH, Baughman KL. Implantable defibrillators for the prevention of mortality in patients with nonischemic cardiomyopathy: a meta-analysis of randomized controlled trials. JAMA 2004;292:2874 –2879. 18. Woo GW, Petersen-Stejskal S, Johnson JW, Conti JB, Aranda JA Jr, Curtis AB. Ventricular reverse remodeling and 6-month outcomes in patients receiving cardiac resynchronization therapy: analysis of the MIRACLE study. J Interv Card Electrophysiol 2005;12:107–113. 19. Lilli A, Ricciardi G, Porciani MC, Perini AP, Pieragnoli P, Musilli N, Colella A, Del Pace S, Michelucci A, Turreni F, Sassara M, Achilli A, Barold SS, Padeletti LL. Cardiac resynchronization therapy: gender related differences in left ventricular reverse remodeling. Pacing Clin Electrophysiol 2007;30:1349 –1355. 20. Guerra S, Leri A, Wang X, Finato N, Di Loreto C, Beltrami CA, Kajstura J, Anversa P. Myocyte death in the failing human heart is gender dependent. Circ Res 1999;85:856 – 866. 21. Olivetti G, Giordano G, Corradi D, Melissari M, Lagrasta C, Gambert SR, Anversa P. Gender differences and aging: effects on the human heart. J Am Coll Cardiol 1995;26:1068 –1079. 22. Fornwalt BK, Sprague WW, BeDdell P, Suever JD, Gerritse B, Merlino JD, Fyfe DA, León AR, Oshinski JN.. Agreement is poor among current criteria used to define response to cardiac resynchronization therapy. Circulation 2010;121:1985–1991. 23. Bax JJ, Marwick TH, Molhoek SG, Bleeker GB, van Erven L, Boersma E, Steendijk P, van der Wall EE, Schalij MJ. Left ventricular dyssynchrony predicts benefit of cardiac resynchronization therapy in patients with end-stage heart failure before pacemaker implantation. Am J Cardiol 2003;92:1238 –1240. 24. Bleeker GB, Bax JJ, Fung JWH, van der Wall EE, Zhang Q, Schalij MJ, Chan JYS, Yu CM. Clinical versus echocardiographic parameters to assess response to cardiac resynchronization therapy. Am J Cardiol 2006;97:260 –263. 25. White JA, Yee R, Yuan XP, Krahn A, Skanes A, Parker M, Klein G,, Drangova M. Delayed enhancement magnetic resonance imaging predicts response to cardiac resynchronization therapy in patients with intraventricular dyssynchrony. J Am Coll Cardiol 2006;48:1953–1960. 26. Caiani EG, Corsi C, Zamorano J, Sugeng L, MacEneaney P, Weinert L, Battani R, Gutiérrez-Chico JL, Koch R, Perez de Isla L, Mor-Avi V, Lang RM, Lang RM. Improved semiautomated quantification of left ventricular volumes and ejection fraction using 3-dimensional echocardiography with a full matrix-array transducer: comparison with magnetic resonance imaging. J Am Soc Echocardiogr 2005;18:779 – 788.