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

Pessah Yampolsky1,2, Michael Koenen1,2, Matias Mosqueira3

  • 1Department of Cardiology, Medical University Hospital Heidelberg, Im Neuenheimer Feld 410, 69120, Heidelberg, Germany.

Nature Communications
|July 25, 2019
PubMed

Insights

Increased funny current (If) in heart cells causes calcium imbalances, leading to dilated cardiomyopathy and arrhythmias. Inhibiting this current may prevent heart damage.

Area of Science:

  • Cardiovascular Physiology
  • Molecular Cardiology
  • Cardiac Electrophysiology

Background:

  • The funny current (If), mediated by HCN channels, is crucial for cardiac pacemaking.
  • If is elevated in heart failure, but its role in disease pathogenesis is unclear.

Purpose of the Study:

  • To investigate the functional consequences of increased HCN4-mediated If in cardiomyocytes.
  • To determine the impact of If upregulation on cardiac structure, function, and arrhythmogenicity.

Main Methods:

  • Generation of transgenic mice (HCN4tg/wt) overexpressing HCN4.
  • Assessment of cardiac phenotype, electrophysiology, and intracellular calcium handling.
  • Pharmacological inhibition of If.

Main Results:

  • HCN4tg/wt mice developed dilated cardiomyopathy with increased cellular arrhythmogenicity.
  • Elevated If caused diastolic Na+ influx, promoting reverse mode Na+/Ca2+ exchange and increased intracellular calcium ([Ca2+]i).
  • Augmented [Ca2+]i led to higher systolic calcium transients, stimulated apoptosis, and ventricular remodeling.

Conclusions:

  • Augmented myocardial If disrupts intracellular calcium homeostasis, causing structural cardiac changes and arrhythmogenicity.
  • Inhibition of myocardial If can prevent calcium dysregulation and protect against cardiomyopathy development.

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