New Therapeutic Targets in Cardiology

Heart failure (HF) affects ≈2% to 3% of the population in many industrialized countries1 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 >2 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) channels4,5 (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 neurological disorders, including epilepsy (reviewed by Lewis and Chetkovich7) and chronic pain,8 as well as in retinal physiology9 (see Table 1 for a summary of HCN functions in extracardiac pathophysiology). HCN channels have also emerged as interesting targets for the development of drugs that lower HR.3View this table:Table 1. HCN Channels in Noncardiac Physiology or Pathophysiology: Central Nervous System and RetinaFigure 1. Main currents in the sinus node and their involvement in depolarization and repolarization activity. Computer simulation of ion currents involved in the spontaneous activity of sinoatrial node cells. The I f …