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.