HCN4 gain-of-function mutation increases intrinsic heart rate and limits maladaptive remodeling under pressure overload.

Introduction: Gain-of-function (GOF) mutations in the cardiac pacemaker channel HCN4 have been associated with inappropriate sinus tachycardia in human patients. Chronic tachycardia is generally associated with adverse cardiac remodeling and cardiomyopathy, but whether enhanced HCN4 activity can induce or modulate such remodeling remains unknown. We aimed to investigate the influence of an HCN4 gain-of-function mutation on cardiac function and structure under baseline and pressure overload conditions. Methods and Results: We generated HCN4(Y527F) knock-in mice (HCN4F) carrying a GOF mutation in the C-linker of HCN4 channels, which shifts their activation curves to more positive potentials. Electrophysiological recordings confirmed increased channel availability at physiological membrane potentials. Telemetric ECGs and Discussion: The HCN4(Y527F) gain-of-function mutation increases intrinsic heart rate without inducing structural or functional deterioration. Under pressure overload, it even confers considerable protection against maladaptive dilatation and contractile dysfunction. These findings challenge the concept that persistent inappropriately elevated heart rate is necessarily detrimental and suggest that enhanced HCN4 activity may facilitate adaptive cardiac responses to stress.