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

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