Therapy with Ivabradine Improves Sarcoplasmic Reticulum Calcium Uptake in Dogs with Chronic Heart Failure

Background: Ivabradine (IVA), a heart rate (HR) lowering drug, acts by selective inhibition of the cardiac pacemaker current If and has no direct effects on myocardial contractility or relaxation. In heart failure (HF), sarcoplasmic reticulum (SR) Ca2+ uptake is reduced leading to Ca2+ overload, arrhythmias and cell death and contributes to progressive left ventricular (LV) dysfunction. Objective: We tested the hypothesis that therapy with IVA in dogs with HF improves SR Ca2+ uptake by lowering HR and prolonging diastole; the latter is the period during which Ca2+ uptake into the SR takes place. Methods: Studies were performed in 24 dogs with coronary microembolizations-induced HF (LV ejection fraction, EF~35%). Dogs were randomized to 3 months therapy with low dose IVA (15 mg bid, n=8); high dose IVA (30 mg bid, n=8) or placebo control (CON, n=8). LV EF and average HR from ambulatory ECG Holters, were obtained before (PRE) and 3 months after initiating therapy (POST). Treatment effect Δ was calculated as the difference between PRE and POST. LV tissue from all HF dogs and 6 normal (NL) dogs was used to prepare SR fractions to measure oxylate-dependent SR Ca2+ uptake (Vmax). Results: In CON dogs, LV EF decreased whereas low and high doses of IVA increased EF in a dose-dependent manner. HR decreased by 4, 8 and 12 beats/min in CON, low dose and High dose IVA respectively. In CON dogs, Vmax was lower than in NL dogs but increased in a dose-dependent manner after therapy with IVA (Table). Conclusion: In HF dogs, prolonging diastole by HR reduction with IVA improves SR Ca2+ uptake thus limiting Ca2+ overload. The findings provide a mechanism for the observed improvement of LV function following therapy with IVA