Heart rate reduction with ivabradine improves left ventricular function and reverses multiple pathological maladaptations in dogs with chronic heart failure

Abstract

Purpose: We tested the hypothesis that heart rate (HR) reduction with ivabradine (IVA) leads to reversal of structural, biochemical, and molecular maladaptations characteristic of the heart failure (HF) state. HR reduction with IVA has been shown to improve left ventricular (LV) systolic function and clinical outcome in patients with HF. Methods: Studies were performed in 16 HF dogs produced by intracoronary microembolizations [LV ejection fraction (EF) ~35%]. Dogs were randomized to 3-month oral therapy with IVA (30 mg Bid, n = 8) or to no therapy (Control, n = 8). LV tissue was obtained from all dogs at the end of therapy and used for molecular, biochemical, and histological studies. Results: Average 24-h ambulatory Holter monitoring showed a significant decrease of HR in IVA-treated dogs compared with controls. Compared with pre-therapy, LV EF decreased at 3 months in controls (36 ± 1 vs. 32 ± 2%, P < 0.05) but increased significantly with IVA (40 ± 3 vs. 35 ± 3%, P < 0.05). Treatment with IVA was associated with (i) improved LV diastolic function; (ii) increased sarcoplasmic reticulum Ca2+ uptake and ATPase activity; (iii) decreased plasma levels of vasoactive neurohormones, natriuretic peptides, and pro-inflammatory cytokines; (iv) normalization of messenger RNA gene expression of multiple signalling pathways; and (v) reduced cardiomyocyte apoptosis and hypertrophy. Conclusion: In dogs with HF, HR reduction with IVA reversed many of the structural, biochemical, and molecular maladaptations characteristic of HF. The findings support the concept that HR reduction in HF can elicit benefits, albeit indirect, on a host of maladaptations implicated in the progressive worsening of the HF state.