Abstract 9342: Ivabradine Reduces Interstitial Fibrosis and Enhances the Recovery of Cardiomyocyte Excitation-Contraction Coupling Produced by Mechanical Unloading

Abstract

Improved Ca2+ handling in patients with end stage heart failure (HF) is associated with myocardial recovery during left ventricular assist device (LVAD) therapy. LVAD-induced myocardial atrophy and fibrosis are postulated to oppose recovery. Ivabradine (IVA) displays positive structural and excitation-contraction (EC) coupling effects in animal models of HF, and has been used effectively in human HF therapy. However, the effects of IVA during mechanical unloading (MU) are unknown. We studied the chronic effects (4 weeks) of oral IVA (10mg/kg/day), alone and in combination with MU (heterotopic abdominal transplantation), on whole heart/cardiomyocyte structure and function in rat cardiomyopathy (12 weeks) induced by left coronary artery ligation. IVA improved ejection fraction (p<0.01) compared with untreated HF group. IVA caused regression of HF-induced myocyte hypertrophy but did not affect MU-induced myocyte atrophy (cell volume measured by di-8-ANNEPS staining and confocal microscopy (µm3)): IVA 52070 ± 15850 (n =50) p<0.001 vs HF 59710 ± 13610 (n=52), MU+IVA 25569 ± 6171 (n= 40) p >0.05 vs MU 27052 ± 8422 (n=45). IVA reduced HF-induced myocardial fibrosis, an effect that was maintained during MU (interstitial fibrosis measured histologically using picrosirius red staining (% area)): IVA 3.1 ± 0.3 p<0.001 vs HF 7.6 ± 0.3, MU+IVA 2.4 ± 0.2 p< 0.001 vs MU 7.9 ± 0.4 (n=70 for all groups). IVA when used alone or in combination with MU had positive effects on EC coupling of isolated ventricular myocytes. Time to peak (TTP (s)) for sarcomere shortening and for Ca2+ transient (CaT) were reduced by IVA therapy alone: IVA: 0.12 ± 0.05 p< 0.001 vs HF 0.16 ± 0.01 and IVA: 0.07 ± 0.05 p< 0.001 vs HF 0.12 ± 0.02, respectively (n=40 for all groups). IVA enhanced the recovery of both sarcoplasmic reticulum (SR) Ca2+ content and CaT amplitude achieved by MU (SR Ca2+ content (ratio units): MU+IVA 0.27 ± 0.07 (n=45) p< 0.05 vs MU 0.24 ± 0.50 (n=40), and CaT amplitude (ratio units): MU+IVA 0.25 ± 0.06 (n=45) p<0.001 vs MU 0.18 ± 0.05 (n=40). We conclude that IVA reduces interstitial fibrosis and enhances MU-induced recovery of CaT amplitude and SR Ca2+ content in rodent HF. Such effects may be exploited to enhance myocardial recovery in HF patients treated with LVADs and requires further studies.