New therapeutic targets in cardiology: heart failure and arrhythmia: HCN channels.

H eart failure (HF) affects ≈2% to 3% of the population in many industrialized countries 1 and is a major cause of mortality. Although widely used treatments such as β-blockers and renin-angiotensin system antagonists have largely improved outcomes in the past 2 decades, prognosis remains poor. Accumulating data collected in >200 000 individuals in various epidemiological studies support that an elevated heart rate (HR) is a risk marker for future cardiovascular outcomes (including sudden cardiac death) in the general population, in patients with risk factors for coronary artery disease (CAD), and in those with established CAD (both stable and unstable), as well as an established risk factor in those with HF, as discussed below. 2,3 HR reduction is particularly beneficial in chronic HF, and novel therapeutic approaches that selectively target HR have been recently proposed and raise new hopes for the treatment of HF. HR generation relies on different molecular mechanisms, including the hyperpolarization-activated cyclic nucleotide-gated (HCN) channels 4,5 (Figure 1). The HCN family of channels is involved in numerous physiological functions in the central nervous system and heart where they are responsible for the I f current in the sinoatrial node (SAN). HCN channels have been shown to be involved in the pathophysiology of neu-rological disorders, including epilepsy (reviewed by Lewis and Chetkovich 7) and chronic pain, 8 as well as in retinal physiology 9 (see Table 1 for a summary of HCN functions in extracar-diac pathophysiology). HCN channels have also emerged as interesting targets for the development of drugs that lower HR. 3 In this review, we first briefly highlight the current knowledge of the biophysical properties of HCN channels. We then discuss the molecular mechanisms underlying the regulation and function of HCN channels as revealed through studies in different animal models. Finally, we present their role in human diseases by focusing on HF and arrhythmias through data from recent clinical studies with the HCN channel inhibitor ivabradine. HCN channels belong to the superfamily of voltage-gated pore-loop cation channels. Four isoforms (HCN1–HCN4) with a high homology have been cloned 16 and share common biophysical properties. They have a reverse voltage dependence leading to activation on hyperpolarization, a unique mechanism among vertebrate voltage-gated ion channels. 17 HCN channels are constituted of 4 subunits, forming a tetramer. Each monomer is composed of 6 transmembrane α-helical segments, named S1 to S6, with S4 being the putative voltage sensor (Figure 2). In …