Augmentation of myocardial I f dysregulates calcium homeostasis and causes adverse cardiac remodeling

HCN channels underlie the depolarizing funny current (I f ) that contributes importantly to cardiac pacemaking. I f is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice ( HCN4 tg/wt ) to assess functional consequences of HCN4 overexpression-mediated I f increase in cardiomyocytes to levels observed in human heart failure. HCN4 tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. I f augmentation induces a diastolic Na + influx shifting the Na + /Ca 2+ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca 2+ ] i . Changed Ca 2+ homeostasis results in significantly higher systolic [Ca 2+ ] i transients and stimulates apoptosis. Pharmacological inhibition of I f prevents the rise of [Ca 2+ ] i and protects from ventricular remodeling. Here we report that augmented myocardial I f alters intracellular Ca 2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial I f per se may constitute a therapeutic mechanism to prevent cardiomyopathy.