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

• Published in: Nature communications Vol. 10; no. 1; p. 3295
• Main Authors: Yampolsky, Pessah, Koenen, Michael, Mosqueira, Matias, Geschwill, Pascal, Nauck, Sebastian, Witzenberger, Monika, Seyler, Claudia, Fink, Thomas, Kruska, Mathieu, Bruehl, Claus, Schwoerer, Alexander P, Ehmke, Heimo, Fink, Rainer H A, Draguhn, Andreas, Thomas, Dierk, Katus, Hugo A, Schweizer, Patrick A
• Format: Journal Article
• Language: English
• Published: England 23-07-2019
• Subjects: Animals; Apoptosis; Calcium - metabolism; Cardiac Electrophysiology; Gene Expression Profiling; Heart - physiology; Homeostasis; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - genetics; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - metabolism; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels - physiology; Mice, Transgenic; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle Proteins - physiology; Myocardium - metabolism; Myocardium - pathology; Myocytes, Cardiac - metabolism; Potassium Channels - genetics; Potassium Channels - metabolism; Potassium Channels - physiology; Troponin I - genetics; Troponin I - metabolism; Troponin I - physiology
• ISSN: 2041-1723
• DOI: 10.1038/s41467-019-11261-2

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.