Several key clinical questions, such as which patients with dilated cardiomyopathy (DC) will recover, how many will relapse, when will they relapse, and predictors of relapse, have sparse data. The present study examines the frequency and predictors of recovery and relapse in patients with DC. One hundred eighty-eight patients of a nonischemic DC cohort having baseline left ventricular ejection fraction (LVEF) ≤40% were divided into 3 groups: improved group with sustained recovery of LVEF to >40% with a net increase in LVEF of ≥10% from baseline, not-improved group without change or decrease in LVEF compared with that in baseline including patients with an increase in LVEF <10%, and relapsed group with decrease in LVEF ≥10% after initial improvement. Follow-up duration was 50 ± 31 months. One hundred ten patients (59%) did not improve. Of the 78 patients (41%) who improved, 50 (64%) had sustained improvement. Remaining 28 (36%) of the 78 improved patients relapsed on further follow-up of 36 ± 25 months. Baseline LVEF was similar in the 3 groups. Mean LVEF increased from 29 ± 8% to 50 ± 7% (p <0.001) in the improved group, changed from 27 ± 9% to 25 ± 9% (p = 0.95) in the not-improved group, and, after increasing from 30 ± 7% to 52 ± 6%, it decreased to 34 ± 9% (p <0.001) in the relapsed group. Multivariate analysis showed that the only variable associated with recovery of LVEF was shorter QRS duration (odds ratio 0.31, 95% confidence interval 0.15 to 0.67, p = 0.003). Recurrence of left ventricular systolic dysfunction was associated with long QRS duration (odds ratio 3.52, 95% confidence interval 1.27 to 9.76, p = 0.01). In conclusion, with currently recommended medical therapy, 1/4 of patients with nonischemic DC have sustained improvement, and >1/3 of those who improve relapse. QRS duration predicted both recovery and relapse. The survival rate of patients in the improved group was significantly better than that in the other 2 groups (p = 0.03, log-rank).
With the use of guideline-directed medical therapy and device implantation, a variable number of patients with the diagnosis of dilated cardiomyopathy (DC) show improvement in the left ventricular (LV) systolic function. However, most of these studies have included heterogeneous patient population, and only a few have studied the frequency and predictors of improvement in patients with nonischemic DC. Even lesser is known about the frequency and predictors of recurrence of LV systolic dysfunction in the patients who have recovered their LV ejection fraction (LVEF) and are continued on guideline-directed medical treatment. In the absence of guidelines and lack of reliable data, the decision to continue or stop anti–heart failure drugs after recovery of LVEF is left to the discretion of the treating physician. Because of infrequent use of devices, we have long-term follow-up of a cohort of patients with nonischemic DC who have largely been on optimal medical therapy, without using devices. The aim of the present study was to study the frequency and predictors of recovery of LVEF in this cohort of patients. We also aimed to study the relapse rate in the improved patients, duration at which relapse occurs, and factors that can predict relapse.
Methods
This is a retrospective, single-center, observational study of all patients in the nonischemic DC cohort, presenting to the Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, since June 2003 to May 2013. This study complies with the Declaration of Helsinki and is approved by the Institute’s Ethics Committee.
Patients aged >18 years of either gender who had an LVEF ≤40% at baseline and at least 1 echocardiographic evaluation on follow-up were selected and divided into 3 groups as follows: improved group, these patients had sustained recovery of LVEF to a level >40% with a net increase in LVEF of ≥10% from baseline till the end of follow-up; not-improved group, these patients had no change or decrease in LVEF compared with that in baseline, and patients with an increase in LVEF <10% compared with that in baseline were also included in this group; and relapsed group, these patients had a decrease in LVEF ≥10% at the end of follow-up after improving the LVEF to >40% with a net increase of ≥10% from baseline.
The information collected was clinical and physical examination findings, routine laboratory investigations, serial echocardiographic studies, electrocardiograms, and treatment at baseline and follow-up, and these were compared among the 3 groups. Daily doses of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and β blockers are reported as an equivalent of enalapril and carvedilol, respectively (enalapril equivalent doses: ramipril 0.3, losartan 3.3; carvedilol equivalent doses: sustained release metoprolol 2).
Patients with heart failure due to ischemic cadiomyopathy, myocarditis, valvular heart disease, stress-related cardiomyopathy, and cardiomyopathies associated with metabolic or endocrine diseases were excluded. Patients aged >35 years underwent routine coronary angiography. Coronary angiography was also done in younger patients clinically suspected to have a coronary artery disease. Patients were classified as having ischemic cardiomyopathy if they had any one of the following: (1) ≥50% obstructive lesion in any of the major epicardial coronary vessels or (2) a history of transmural myocardial infarction. We adopted stricter criteria for excluding coronary artery disease than usually followed in clinical trials.
Continuous data are expressed as mean ± SD. Categorical variables are expressed as percentage. Comparison among the 3 groups was done using 1-way analysis of variance for continuous variables. Differences within the group, from baseline to follow-up parameters, were compared using a t test for paired data. Categorical variables were compared by the chi-square or Fisher’s exact test. To study the role of various variables in predicting improvement in LVEF or recurrence of LV systolic dysfunction, a univariate logistic regression analysis was performed. A multivariate logistic regression analysis using the block method was performed on variables reaching a significance of p <0.10 on univariate analysis. A value of p <0.05 was considered significant. Statistical analysis was performed using SPSS, version 17 (SPSS Inc., Chicago, Illinois).
Results
From June 2003 to May 2013, a total of 199 consecutive patients included in the nonischemic DC cohort of the Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh, who had at least 1 follow-up echocardiographic examination were screened. Of these, 11 were excluded either because of the presence of significant coronary artery disease or because their baseline LVEF was >40%. The remaining 188 patients who fulfilled the inclusion criteria were selected for the study. Over the total follow-up duration of 50 ± 31 months (mean ± SD), 78 patients (41%) showed recovery of LVEF. However, sustained recovery of LVEF was observed in only 50 patients (27%) who were included in the improved group. Twenty-eight patients (15%) after having initial improvement had recurrence of LV systolic dysfunction and were placed in the relapsed group. One hundred ten patients (59%) who did not have recovery of LVEF were included in the not-improved group. The initial and final LVEF of individual patients are demonstrated in Figure 1 .
Table 1 lists the baseline, clinical, and laboratory parameters of the patients in the 3 groups. The baseline mean LVEF in the patients in the 3 groups was similar. After 21 ± 20 months of follow-up, patients in the improved group showed a significant increase in the LVEF from 29 ± 8% to 50 ± 7% (p <0.001), which was sustained till the end of follow-up. Patients in the not-improved group, with baseline LVEF of 27 ± 9%, at the end of 43 ± 32 months of follow-up, had no significant change in LVEF, with final LVEF of 25 ± 9% (p = 0.95). At 20 ± 18 months of follow-up, patients in the relapsed group had recovered their LVEF from 30 ± 7% to 52 ± 6% (p <0.001). However, 36 ± 25 months later, LV systolic dysfunction recurred in these patients with the mean LVEF falling to 34 ± 9%. As shown in Figure 2 , 78 of 188 patients (42%) showed recovery of LVEF over 10 years of follow-up. Forty eight of 78 patients (62%) had recovered their LVEF within 3 years of follow-up. However, as the follow-up duration increased, >1/3 of patients (28 of 78) had a relapse and developed LV systolic dysfunction. Of these, just 32% patients had relapsed till 5 years of follow-up and the majority (68%) relapsing after 5 years. The total duration of clinical follow-up was significantly more in patients in the relapsed group compared with both improved and not-improved groups.
| Variable | Recovered (n = 50) | Not Recovered (n = 110) | Relapsed Group (n = 28) | p Value |
|---|---|---|---|---|
| Age (years) | 39 ± 13 | 43 ± 14 | 44 ± 12 | 0.19 |
| Female | 22 (44%) | 51 (46%) | 14 (50%) | 0.88 |
| Symptom duration (months) | 23 ± 37 | 32 ± 32 | 29 ± 36 | 0.38 |
| NYHA class I/II | 44 (88%) | 74 (67%) | 22 (79%) | 0.02 |
| NYHA class III | 5 (10%) | 31 (28%) | 4 (14%) | 0.02 |
| NYHA class IV | 1 (2%) | 5 (5%) | 2 (7%) | 0.54 |
| Duration of follow up (months) | 51 ± 35 | 43 ± 32 | 75 ± 28 | <0.001 |
| Baseline heart rate (/minute) | 85 ± 18 | 90 ± 19 | 85 ± 18 | 0.17 |
| Final heart rate (/minute) | 71 ± 14 | 73 ± 15 | 73 ± 16 | 0.20 |
| Systolic blood pressure (mm Hg) | 121 ± 24 | 117 ± 23 | 121 ± 22 | 0.50 |
| Diastolic blood pressure (mm Hg) | 76 ± 17 | 76 ± 13 | 75 ± 13 | 0.88 |
| Hypertension | 16 (32%) | 27 (24%) | 13 (46%) | 0.07 |
| Diabetes mellitus | 4 (8%) | 14 (13%) | 6 (21%) | 0.23 |
| Creatinine (mg/dl) | 0.9 ± 0.4 | 0.9 ± 0.3 | 0.9 ± 0.3 | 0.79 |
| RVEF baseline (%) | 50 ± 14 (n = 34) | 45 ± 18 (n = 65) | 53 ± 12 (n = 25) | 0.09 |
| Etiology | ||||
| Idiopathic dilated cardiomyopathy | 41 (82%) | 96 (87%) | 27 (96%) | 0.19 |
| Peripartum | 6 (12%) | 8 (7%) | 0 | 0.15 |
| Familial | 3 (6%) | 6 (6%) | 1 (4%) | 0.89 |
| Echocardiography | ||||
| LVEF baseline (%) | 29 ± 8 | 27 ± 9 | 30 ± 7 | 0.14 |
| Final LVEF (%) | 51 ± 7 | 25 ± 9 | 34 ± 9 | <0.001 |
| LVID d (mm) | 59 ± 9 | 61 ± 10 | 55 ± 8 | 0.02 |
| Significant MR | 15 (30%) | 33 (30%) | 4 (14%) | 0.23 |
| PASP (mm Hg) | 25 ± 11 (n = 30) | 27 ± 11 (n = 65) | 36 ± 11 (n = 9) | 0.05 |
| Electrocardiogram | ||||
| Atrial fibrillation | 3 (6%) | 4 (4%) | 2 (7%) | 0.66 |
| Complete heart block | 0 | 4 (4%) | 0 | 0.23 |
| LBBB morphology | 6 (12%) | 35 (32%) | 7 (25%) | 0.03 |
| QRS duration (msec) | 99 ± 21 | 117 ± 28 | 114 ± 26 | <0.001 |
| Treatment | ||||
| Digoxin | 24 (48%) | 72 (65%) | 17 (61%) | 0.11 |
| Beta-blockers | 49 (98%) | 107 (97%) | 27 (96%) | 0.91 |
| ACE/ARB | 49 (98%) | 107 (97%) | 28 (100%) | 0.67 |
| Diuretics | 47 (94%) | 108 (98%) | 27 (96%) | 0.37 |
| Spironolactone/eplerenone | 46 (92%) | 108 (98%) | 28 (100%) | 0.07 |
Patients in the improved group had better functional capacity and lesser prevalence of left bundle branch block compared with patients in the not-improved group. The mean QRS duration in the improved group was 99 ± 21 ms and was significantly shorter than that in both the other groups ( Figure 3 ). Figure 4 describes the Kaplan-Meier survival curves of the 3 groups of patients. No patient died in the improved group compared with 10 deaths (9%) in the not-improved group and 2 deaths (7%) in the relapsed group. The survival rate of patients in the improved group was significantly better than that in the other 2 groups (p = 0.03, log-rank).
There was no difference between age, gender, symptom duration, baseline heart rate, final heart rate, systolic or diastolic blood pressure, cause of heart failure, and prevalence of hypertension and diabetes mellitus in the 3 groups. The echocardiographic parameter of LV internal diameter in diastole was much more in the relapsed group compared with the not-improved group. The treatment with digoxin, β blockers, ACE inhibitors or ARBs, diuretics, and spironolactone or eplerenone was also not significantly different among the 3 groups. Both the number of patients and dose of the drugs at the end of follow-up, for β blockers and ACE inhibitors or ARBs, was also not different between the improved and relapsed groups, with the dose of β blockers (expressed as equivalent of carvedilol) being 33 ± 15 and 34 ± 17 mg/day (p = 0.18), respectively, and that of ACE inhibitors or ARBs (expressed as equivalent of enalapril) being 29 ± 5 and 29 ± 4 mg/day (p = 0.23), respectively.
Table 2 lists that on univariate analysis of variables in the improved and not-improved groups, the recovery of LVEF was associated with lower New York Heart Association class, longer duration of follow-up, and shorter QRS duration. Baseline LVEF was not associated with recovery of LVEF. On multivariate analysis, the only factor that was associated with recovery of LVEF was shorter QRS duration ( Table 3 ). Similarly, binary logistic regression analysis showed that the odds of recurrence of LV systolic dysfunction in patients with longer QRS duration was 3.52 (95% confidence interval 1.27 to 9.76, p = 0.01). The percentage of patients with QRS duration of ≤110, 110 to ≤150, and >150 ms in the improved, not-improved, and relapsed groups were 84%, 54%, and 54%; 14%, 30%, and 36%; and 2%, 16%, and 10% (p = 0.0008, 0.05, and 0.03), respectively. Forty two of 116 patients (36%) with QRS duration ≤110 ms recovered LVEF compared with just 1 of 22 patients (4%) with QRS >150 ms (p = 0.003). Receiver operating characteristic curve analysis of QRS duration shows that for a cutoff of 98.5 ms, the sensitivity and specificity of QRS duration for prediction of sustained recovery of LVEF was 60% and 68%, respectively, with an area under the curve of 0.70 (95% confidence interval 0.61 to 0.78), and for a cutoff of 95 ms, the sensitivity and specificity of QRS duration for prediction of recurrence of LV systolic dysfunction was 75% and 54%, respectively, with area under the curve of 0.68 (95% confidence interval 0.55 to 0.80).
