Ventricular conduction abnormality in patients with mild to moderate cardiomyopathy

Abstract Background In mild‐to‐moderate cardiomyopathy, cardiac resynchronization therapy (CRT) is indicated in patients with high burden of right ventricular pacing but not in those with intrinsic ventricular conduction abnormalities. Hypothesis We hypothesized that CRT positively impacts outcomes of patients with intrinsic ventricular conduction delay and left ventricular ejection fraction (LVEF) of 36%‐50%. Methods Of 18 003 patients with LVEF ≤ 50%, 5966 (33%) patients had mild‐to‐moderate cardiomyopathy, of whom 1741 (29%) have a QRS duration ≥120 ms. Patients were followed to the endpoints of death and heart failure (HF) hospitalization. Outcomes were compared between patients with narrow versus wide QRS. Results Of the 1741 patients with mild‐to‐moderate cardiomyopathy and wide QRS duration, only 68 (4%) were implanted with a CRT device. Over a median follow‐up of 3.35 years, 849 (51%) died and 1004 (58%) had a HF hospitalization. The adjusted risk of death (hazard ratio (HR) = 1.11, p = 0.046) and of death or HF hospitalization (HR = 1.10, p = 0.037) were significantly higher in patients with wide versus narrow QRS duration. In patients with wide QRS complex, CRT was associated with reduction in the adjusted risk of death (HR = 0.47, p = 0.020) and of death or HF hospitalization (HR = 0.58, p = 0.008). Conclusions Patients with mild‐to‐moderate cardiomyopathy and wide QRS duration are rarely implanted with CRT devices and have worse outcomes compared to those with narrow QRS. Randomized trials are needed to examine if CRT has salutary effects in this population.


| INTRODUCTION
Cardiac resynchronization therapy (CRT) is an established treatment for heart failure (HF) patients with severe cardiomyopathy and evidence of ventricular conduction abnormalities on surface electrocardiogram. [1][2][3][4][5][6] In this context, CRT provides incremental survival benefit and improvement in the symptoms of HF over established guideline directed medical therapy. [1][2][3] For patients with mild-to-moderate cardiomyopathy whose left ventricular ejection fraction (LVEF) is between 36% and 50%, CRT is indicated only when patients are expected to have a high burden of right ventricular pacing 5,7,8 but not when they exhibit evidence of intrinsic wide QRS complex on the surface electrocardiogram. 5 It is plausible that the same mechanisms that afford benefit of CRT in severe cardiomyopathy or in the context of right ventricular pacing would also apply to patients with mild-to-moderate cardiomyopathy with intrinsic ventricular conduction abnormalities. To date, however, there are no clinical trials that have studies this important clinical question.
To address this gap in knowledge, we designed this clinical study using real-world data from a large, multi-hospital academic institution. The present analysis focuses on the impact of QRS width on mortality and HF hospitalizations in patients with mild-to-moderate cardiomyopathy and explores the potential role of CRT in this context.

| Patient population and endpoints
The present study was approved by the institutional review board of the University of Pittsburgh who waived the requirement to obtain a consent from patients, due to the retrospective, observational nature of this analysis. We performed a cohort analysis of 18 003 consecutive patients with cardiomyopathy (LVEF ≤ 50%) who were seen at the hospitals and clinics of the University of Pittsburgh Medical Center from January 1, 2011 through December 31, 2017.
Of this group, 5966 (33%) had a LVEF between 36% and 50% inclusively, with 1741 patients in this group having evidence of prolonged QRS duration (≥120 ms) on surface electrocardiogram. In that latter group, only 68 patients received a CRT device. The composition of the overall data set by severity of cardiomyopathy, QRS width and CRT status is shown in Figure 1.
Baseline demographic, clinical, and medications data were obtained from the institutional electronic health and administrative records from the hospitals and outpatient clinics of the UPMC healthcare system and were compiled by the analytic warehouse for analysis. Patients were followed from the time of first documented LVEF in the 36%-50% range to the endpoints of all-cause mortality or the composite endpoint of death or HF hospitalization, through March of 2019.

| Statistical analysis
Baseline characteristics are presented as mean ± standard deviation for continuous variables and numbers (%) for discrete variables and compared in the cohort of patients with mild-to moderate cardiomyopathy between those with narrow versus wide QRS duration, and in that latter group between patients with versus without CRT device, using Student t-test and χ 2 test, as appropriate. Kaplan-Meier survival curves were constructed to compare the overall survival as well as the survival free from HF hospitalization between mild-to-moderate cardiomyopathy patients with narrow versus wide QRS and in the latter group between CRT recipients versus those who did not receive resynchronization therapy. Cox multivariable models adjusting for the age of patients at initial contact within our institution, sex, race, their type of cardiomyopathy (ischemic vs. nonischemic), and the presence of a history of hypertension, diabetes mellitus, congestive heart failure, atrial fibrillation, or liver cirrhosis in addition to the baseline serum hemoglobin level and glomerular filtration rate, were developed to examine the independent impact of QRS duration on the study endpoints as well as the impact of CRT device implantation on these same endpoints. Given the small number of CRT recipients (n = 68), we limited the follow-up duration for the CRT analysis to 2 years and imputed the missing values for the serum hemoglobin and glomerular filtration rate to the mean value for these covariates.
A two-sided p value <0.05 was considered statistically significant.
Statistical analyses were performed on SPSS software (version 27, IBM).
F I G U R E 1 Overview of the cohort of patients with cardiomyopathy with focus on patients with mild to moderate ventricular dysfunction (LVEF 36%-50%). The cohort was stratified by QRS duration and the presence or absence of cardiac resynchronization therapy device. CMP, cardiomyopathy; CRT, cardiac resynchronization therapy; LVEF, left ventricular ejection fraction. Table 1 details the baseline characteristics of the overall cohort of patients with mild-to-moderate cardiomyopathy, stratified by QRS width. It also details the baseline characteristics of patients with mild-to-moderate cardiomyopathy and prolonged QRS duration by their CRT status. As depicted in Tables 1, 1741 (33%) patients with mild-to-moderate cardiomyopathy had a prolonged ventricular activation time on the surface electrocardiogram and of those, only 68 patients were implanted with a CRT device. Compared to patients with a narrow QRS complex, those with prolonged QRS duration were significantly older, more likely to be white men, more likely to have coronary artery disease, heart failure, atrial fibrillation, and had more comorbidities, including hypertension, diabetes mellitus and chronic kidney disease. Within the cohort of patients with ventricular conduction delay, CRT recipients had more heart failure and atrial fibrillation but were otherwise comparable to patients who did not receive a CRT device despite having a wide QRS duration.
In patients with wide QRS, CRT was associated with a significant reduction in the risk of death (HR = 0.44, 95% CI 0.24-0.83, Figure 3) and in the risk of death or HF hospitalization (HR = 0.64, 95% CI 0.43-0.96, p = 0.030, Figure 3). As shown in Importantly, despite small numbers, our data suggest that CRT may be associated with significant improvement in these end- CRT has been shown to improve all-cause mortality and the combined endpoint of death or HF events. [1][2][3] The underlying mechanism of these benefits is thought to be through an increase in myocardial contractility and efficiency without a concomitant increase in oxygen consumption. 11,12 The clinical benefits of CRT have been demonstrated in the context of severe cardiomyopathy with either intrinsic ventricular conduction delay 1,2 or high burden of right ventricular pacing. 7  and afford changes in practice patterns.