Compromised repolarization reserve in a murine model of catecholaminergic polymorphic ventricular tachycardia caused by RyR2-R420Q mutation

J Mol Cell Cardiol. 2025 Sep:206:127-140. doi: 10.1016/j.yjmcc.2025.07.014. Epub 2025 Jul 24.

Abstract

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a malignant inherited heart disease characterised by stress-induced arrhythmias that are thought to be caused by delayed afterdepolarizations resulting from abnormal Ca2+ cycling. Some patients exhibit unusually large ECG U-waves that could be associated with altered ventricular repolarization, but the possible link with dysfunctional RyR2 is unclear. We investigated whether increased Ca2+ leak during systole disrupts repolarization in a transgenic mouse model of CPVT.

Methods: Electrocardiograms were recorded in patients with RyR2-R420Q CPVT mutation (R420Q). Experiments were performed on control and R420Q knock-in mouse hearts and ventricular myocytes.

Results: R420Q patients had larger resting U-waves than family member controls. R420Q mouse hearts exhibited greater prolongation of monophasic APs following pauses in pacing and during beta-adrenergic stimulation. Ventricular ectopic beats during repolarization were more prevalent in R420Q mouse hearts following pacing-pauses and during premature electrical stimulation. Early afterdepolarizations (EADs) occurred in isolated R420Q myocytes during beta-adrenergic stimulation and coincided with increased Ca2+ leak during the Ca2+ transient decay, in the form of late Ca2+ sparks (LCS). AP voltage clamp electrophysiology experiments, analysis of LCS recovery, and computer simulations of hyperactive RyR2 supported a mechanism involving increased RyR2 sensitivity and/or reduced refractoriness that increased LCS frequency and inward sodium/calcium exchange current, resulting in AP prolongation and EADs.

Conclusions: Ca2+-mediated AP lengthening and EADs may contribute to proarrhythmic behaviour in CPVT caused by gain-of-function R420Q mutation. Loss of repolarization reserve is not specifically targeted by CPVT therapies but could be an opportunity for therapeutic intervention.

Keywords: Arrhythmias; CPVT; Calcium sparks; Early afterdepolarizations; Repolarization reserve.

MeSH terms

  • Action Potentials
  • Animals
  • Calcium / metabolism
  • Disease Models, Animal
  • Electrocardiography
  • Female
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Mutation*
  • Myocytes, Cardiac / metabolism
  • Polymorphic Catecholaminergic Ventricular Tachycardia
  • Ryanodine Receptor Calcium Release Channel* / genetics
  • Ryanodine Receptor Calcium Release Channel* / metabolism
  • Tachycardia, Ventricular* / genetics
  • Tachycardia, Ventricular* / metabolism
  • Tachycardia, Ventricular* / physiopathology

Substances

  • Ryanodine Receptor Calcium Release Channel
  • Calcium
  • ryanodine receptor 2. mouse