Pacemaker activity of the human sinoatrial node: role of the hyperpolarization-activated current, I(f)

The mechanism of primary, spontaneous cardiac pacemaker activity of the sinoatrial node (SAN) has extensively been studied in several animal species, but is virtually unexplored in man. Understanding the mechanisms of human SAN pacemaker activity is important for developing new therapeutic approaches for controlling the heart rate in the sick sinus syndrome and in diseased myocardium. Here we review the functional role of the hyperpolarization-activated 'funny' current, I(f), in human SAN pacemaker activity. Despite the many animal studies performed over the years, the contribution of I(f) to pacemaker activity is still controversial and not fully established. However, recent clinical data on mutations in the I(f) encoding HCN4 gene, which is thought to be the most abundant isoform of the HCN gene family in SAN, suggest a functional role of I(f) in human pacemaker activity. These clinical findings are supported by recent experimental data from single isolated human SAN cells that provide direct evidence that I(f) contributes to human SAN pacemaker activity. Therefore, controlling heart rate in clinical practice via I(f) blockers offers a valuable approach to lowering heart rate and provides an attractive alternative to conventional treatment for a wide range of patients with confirmed stable angina, while upregulation or artificial expression of I(f) may relieve disease-causing bradycardias.