Familial inappropriate sinus tachycardia: a new chapter in the story of HCN4 channelopathies.

The sinoatrial node (SAN) contains a small number of pacemaker cells (PCs), specialized cardiomyocytes whose automatic firing triggers each heart beat. Autonomic and endocrine modulation of PC automaticity enables precise neurohormonal regulation of heart rate (HR) in accordance with physiological demand. While the cellular mechanisms that underlie HR regulation are complex and still actively debated, several critical molecular players have been identified and cloned over the past few decades. Among the most important are the hyperpolarization-activated, cyclic nucleotide-gated (Hcn) ion channels, which conduct an inward cation current that is activated by hyperpolarization and modulated by cAMP binding. Hcn current, also known as funny current, contributes to early diastolic depolarization in PCs, and hence to firing rate. Of the Hcn channel isoforms, Hcn4 is the most important for regulation of mammalian heart rhythm. Hcn4 is expressed in a steep gradient that parallels the gradient of automaticity among different types of cardiomyocyte: SAN PCs exhibit high level Hcn4 expression, atrioventricular nodal myocytes exhibit moderate expression, the His–Purkinje system exhibits lower expression, and there is minimal expression in working atrial and ventricular cardiomyocytes. Heart-specific Hcn4 deletion in adult mice causes severe bradycardia and death, and loss-of-function mutations in human Hcn4 cause familial sinus bradycardia, a rare genetic arrhythmia syndrome marked by early-onset sinus node dysfunction and bradycardia. Since the original description of familial sinus bradycardia, several other Hcn4-associated cardiac syndromes have emerged, including atrioventricular block, early-onset atrial fibrillation, Brugada syndrome, prolonged QT, and left ventricular noncompaction. Of note, each of these syndromes is associated with Hcn4 loss of function. The study by Baruscotti et al. in this issue of the journal adds a new piece to this puzzle by identifying the first gain-of-function mutation in Hcn4 associated with a clinical syndrome, inappropriate sinus tachycardia (IST). In doing so, the authors also make a contribution to the ongoing debate about the roles of Hcn4 in setting basal HR and in regulating chronotropic response, and provide a plausible mechanistic explanation for a unique form of IST that may also be relevant to patients with non-familial IST.