Updates on HCN Channels in the Heart: Function, Dysfunction and Pharmacology

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play an important role in the generation of pacemaker activity of cardiac sinoatrial node cells and immature cardiomyocytes. HCN channels are also present in adult atrial and ventricular cardiomyocytes, where the physiological role is currently under investigation. In different cardiac pathologies, dysfunctional HCN channels have been suggested to be a direct cause of rhythm disorders. While loss-of-function mutations of HCN channels are associated with sinus bradycardia, HCN channel gain-of-function in atrial fibrillation, ventricular hypertrophy and failure might help enhance ectopic electrical activity and promote arrhythmogenesis. Blockade of HCN channels with ivabradine, a selective bradycardic agent currently available for clinical use, improves cardiac performance and counteracts functional remodeling in experimental hypertrophy. Accordingly, ivabradine ameliorates clinical outcome in patients with chronic heart failure. Novel compounds with enhanced selectivity for cardiac HCN channel isoforms are being studied as potential candidates for new drug development.