Augmentation of myocardial If dysregulates calcium homeostasis and causes adverse cardiac remodeling

Pessah Yampolsky, Michael Koenen, Matias Mosqueira, Pascal Geschwill, Sebastian Nauck, Monika Witzenberger, Claudia Seyler, Thomas Fink, Mathieu Kruska, Claus Bruehl, Alexander P. Schwoerer, Heimo Ehmke, Rainer H. A. Fink, Andreas Draguhn, Dierk Thomas, Hugo A. Katus and Patrick A. Schweizer ()
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Pessah Yampolsky: Medical University Hospital Heidelberg
Michael Koenen: Medical University Hospital Heidelberg
Matias Mosqueira: Heidelberg University
Pascal Geschwill: Heidelberg University
Sebastian Nauck: Medical University Hospital Heidelberg
Monika Witzenberger: Heidelberg University
Claudia Seyler: Medical University Hospital Heidelberg
Thomas Fink: Medical University Hospital Heidelberg
Mathieu Kruska: Medical University Hospital Heidelberg
Claus Bruehl: Heidelberg University
Alexander P. Schwoerer: University Medical Centre Hamburg-Eppendorf
Heimo Ehmke: University Medical Centre Hamburg-Eppendorf
Rainer H. A. Fink: Heidelberg University
Andreas Draguhn: Heidelberg University
Dierk Thomas: Medical University Hospital Heidelberg
Hugo A. Katus: Medical University Hospital Heidelberg
Patrick A. Schweizer: Medical University Hospital Heidelberg

Nature Communications, 2019, vol. 10, issue 1, 1-16

Abstract: Abstract HCN channels underlie the depolarizing funny current (If) that contributes importantly to cardiac pacemaking. If is upregulated in failing and infarcted hearts, but its implication in disease mechanisms remained unresolved. We generated transgenic mice (HCN4tg/wt) to assess functional consequences of HCN4 overexpression-mediated If increase in cardiomyocytes to levels observed in human heart failure. HCN4tg/wt animals exhibit a dilated cardiomyopathy phenotype with increased cellular arrhythmogenicity but unchanged heart rate and conduction parameters. If 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 If prevents the rise of [Ca2+]i and protects from ventricular remodeling. Here we report that augmented myocardial If alters intracellular Ca2+ homeostasis leading to structural cardiac changes and increased arrhythmogenicity. Inhibition of myocardial If per se may constitute a therapeutic mechanism to prevent cardiomyopathy.

Date: 2019
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DOI: 10.1038/s41467-019-11261-2

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