Abstract 17715: Heart Rate Reduction Alone Produces Reverse Remodeling in Heart Failure Patients Refractory to Beta-Blockers: The PROBE-IT Trial

Abstract

In a 2-center trial ( P ulse R eduction o n Be ta-Blocker and I vabradine T herapy (PROBE-IT)) we tested the hypothesis that failure to adequately reduce heart rate (HR) contributes to non-response to beta-blockers. Twenty-two dilated cardiomyopathy patients (DCM) with a sinus rhythm (SR) heart rate (HR) ≥70 bpm without reverse remodeling after target doses of beta-blockers were randomized 2:1 to 5±2.5 mg b.i.d of ivabradine (IVB) or matching placebo, and treated for 24 weeks with continuation of beta-blockers. Echocardiograms for LVEF measurements and endomyocardial biopsies for measurement of global gene expression by RNA-Sequencing were performed at baseline and end of study. The protocol design aimed for approximately equal numbers of patients with a HR reduction (HRι) and a control group with no change in HR (HRν), with the predefined statistical analysis plan comparing subjects above and below the median HR change. Characteristics and changes from baseline in the 17 patients who completed the trial were (*P <0.05, † P <0.01 vs. HRν):HRν patients had a longer duration of HF,, 112 months vs. 35 months in HRι (P = 0.005). In HRι vs. HRν, gene expression findings included 18 mRNAs at a P <0.0005 and 39 at a P of <0.001 with higher abundance, and 34 (P <0.0005) and 94 (P <0.001) lower abundance. The classification of these genes was distinct from molecular changes described for reverse remodeling from beta-blockers alone, with only a 2.1% overlap. Gene expression changes that could have contributed to reverse remodeling in HRι included: increases in NRG1 (neuregulin 1), PP1R3C (protein phosphatase 1), and multiple mitochondrial electron transport genes; and lower expression of genes encoding cardiotrophin-1 cytokines (CTF1 and CLCF1). Conclusions: In NDC patients meeting the PROBE-IT entry criteria, HR lowering produces a substantial increase in LVEF accompanied by gene expression changes that differ from those associated with beta-blocker therapy.