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

ABSTRACT: 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 [Ca

SUBMITTER: Yampolsky P 

PROVIDER: S-EPMC6650438 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature