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⁺/Ca²⁺ exchanger equilibrium towards ‘reverse mode’ leading to increased [Ca²⁺]_i. Changed Ca²⁺ homeostasis results in significantly higher systolic [Ca²⁺]_i transients and stimulates apoptosis. Pharmacological inhibition of I_f prevents the rise of [Ca²⁺]_i and protects from ventricular remodeling. Here we report that augmented myocardial I_f alters intracellular Ca²⁺ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial I_fper se may constitute a therapeutic mechanism to prevent cardiomyopathy.