Does nitric oxide mediate the effects of ivabradine in patients with heart failure?

vabradine is a pure heart rate-lowering agent and was recently approved for the treatment of heart failure (1). Ivabradine was approved for use in Europe by the European Medicines Agency for treating patients with heart failure with reduced ejection fraction of ≤35% and those with sinus rhythm with a resting heart rate (HR) ≥75 bpm because it was shown to confer a survival benefit in a subgroup analysis of this patient population (2). In the United States, there is a lower HR limit (≥70 bpm) for ivabradine initiation (3). Despite its clinical use, the precise mechanism of its beneficial action in patients with heart failure remains poorly understood. Animal studies have suggested that improved cardiomyocyte calcium handling (4, 5), reduced wall stress after myocardial infarction (MI) (5), improved coronary reserve due to reduced accumulation of perivascular collagen (6), improved diastolic compliance due to reduced fibrosis (7), and antiarrhythmic effects due to reduced pathological HCN4 expression in ventricular cardiomyocytes (8) play a role in the mechanism of action of ivabradine.