Bradycardic effects of mutations in the HCN4 gene at different levels of autonomic tone in humans

HCN4 channels are expressed in the human sinoatrial node (SAN) and conduct the hyperpolarization-activated 'funny current', I_f, also known as 'pacemaker current'. Several loss-of-function mutations in the HCN4 gene have been associated with human sinus bradycardia. Clinical observations suggest that bradycardic effects are present at all levels of autonomic tone. We assessed the effects of three different mutations in HCN4 on human SAN pacemaker activity at different levels of autonomic tone by incorporating experimentally identified mutation-induced changes in I_f into the recently developed Fabbri et al. model of a single human SAN cell. Different levels of autonomic tone were obtained through simulated administration of specific levels of acetylcholine (ACh) or isoprenaline (Iso). The G480R, A485V, and 695X mutations in HCN4 lowered the control beating rate from 74 to 62, 59, and 65 bpm, the ACh beating rate from 49 to 40, 37, and 45 bpm, and the Iso beating rate from 140 to 115, 100, and 109 bpm, respectively, all in accordance with the clinical observations. We conclude that experimentally observed changes in the expression and kinetics of I_f channels can explain the clinically observed bradycardic effects of loss-of-function mutations in HCN4 at different levels of autonomic tone.