Abstract
BACKGROUND: Heart rate (HR) affects heart failure outcomes, via uncertain mechanisms that may include left ventricular remodeling. However, in human ventricular myocardium, HR change has not been associated with a particular remodeling molecular phenotype. METHODS: Patients with nonischemic dilated cardiomyopathy (N=22) in sinus rhythm and refractory to β-blockade for both HR lowering and reverse remodeling were randomized 2:1 double-blind to the HCN4 (hyperpolarization-activated cyclic nucleotide-gated potassium channel 4) channel inhibitor ivabradine or placebo for 24 weeks treatment while maintaining target doses of β-blockers. Reverse remodeling was measured by left ventricular ejection fraction (LVEF), and myocardial gene expression by sequencing RNA extracted from endomyocardial biopsies. The primary statistical analysis was between HR change categories divided at the median, which resulted in Decreased HR (N=90) and Unchanged HR (N=8) groups. RESULTS: Respective HRs at baseline and 24 weeks were as follows: Decreased HR, 82.9±6.8 and 69.7±8.0 beats per minute (P=0.0005) and Unchanged HR, 80.8±5.7 and 79.2±11.6 beats per minute (P=0.58). All completing Decreased HR subjects were treated with ivabradine, whereas in the Unchanged HR group, 3 received ivabradine and 5 placebo. In Decreased HR, LVEF increased from 29.4±8.8% at baseline to 44.2±9.4% at 24 weeks (P=0.0003), compared with respective values of 26.6±11.4% and 29.2±12.0% (P=0.28) in Unchanged HR. HR and LVEF changes were not different from a previously conducted β-blocker nonischemic dilated cardiomyopathy study subdivided into LVEF responders and nonresponders. However, differentially expressed genes (N=151) in the Decreased versus Unchanged HR groups were >99% nonconcordant and therefore individually unique compared with β-blocker HR/LVEF responders versus nonresponders (2 shared differentially expressed genes). Multiple unique differentially expressed genes in Decreased HR including NRG1 upregulation are considered cardioprotective or involved in cardiac development. CONCLUSIONS: In patients with nonischemic dilated cardiomyopathy in sinus rhythm, HR lowering per se (1) is associated with substantial left ventricular reverse remodeling; (2) its absence can cause β-blocker reverse remodeling nonresponse; and (3) when from HCN4 channel inhibition, results in a unique molecular phenotype. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02973594.