Review: HCN Channels in the Heart

Pacemaker cells are the basis of rhythm in the heart. Cardiovascular diseases, and in particular, arrhythmias are a leading cause of hospital admissions and have been implicated as a cause of sudden death. The prevalence of people with arrhythmias will increase in the next years due to an increase in the ageing population and risk factors. The current therapies are limited, have a lot of side effects, and thus, are not ideal. Pacemaker channels, also called hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, are the molecular correlate of the hyperpolarization-activated current, called I(h) (from hyperpolarization) or I(f) (from funny), that contribute crucially to the pacemaker activity in cardiac nodal cells and impulse generation and transmission in neurons. HCN channels have emerged as interesting targets for the development of drugs, in particular, to lower the heart rate. Nonetheless, their pharmacology is still rather poorly explored in comparison to many other voltage-gated ion channels or ligand-gated ion channels. Ivabradine is the first and currently the only clinically approved compound that specifically targets HCN channels. The therapeutic indication of ivabradine is the symptomatic treatment of chronic stable angina pectoris in patients with coronary artery disease with a normal sinus rhythm. Several other pharmacological agents have been shown to exert an effect on heart rate, although this effect is not always desired. This review is focused on the pacemaking process taking place in the heart and summarizes the current knowledge on HCN channels.