HCN4 in the atrioventricular node

Abstract

Hyperpolarization-activated cyclic nucleotide-gated channel 4 (HCN4) drives the funny current in cardiac pacemaker regions. Its involvement in sinoatrial node pacemaker generation is well known, but its function in the atrioventricular (AV) node (AVN) has not intensively been studied. HCN4 is expressed in the AVN, and its expression within the AVN seems similar across mammalian species with HCN4 presence in the inferior nodal extensions, compact node, and AV bundle. The main direct regulators of HCN4 are cAMP and protein kinase A. In addition, indirect regulators may affect HCN4 via trafficking and localization. However, these effects are underexplored in the AVN. AVN-specific effects in knockout and knockin mice include reduced funny current density and increased AV block. HCN4 expression in the AVN could be affected by aging, exercise, heart failure, and diabetes. This could underlie changes in PR interval, atria-His interval, Wenckebach cycle length, and AVN effective refractory period. Clinical reports link the HCN4 variant G1097W to AV block. Other clinical data come from studies assessing ivabradine, an HCN4 inhibitor. In animals, ivabradine resulted in prolonged PR and atrial-his intervals. To date, uncertainty regarding the role of HCN4 in the AVN remains. However, AVN-focused studies suggest HCN4’s importance for AVN function. This review summarizes recent findings and highlights the involvement of HCN4 in normal and pathological AVN function.