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

Autores de IIS La Fe

• 

  Aitana Braza Boils

  Autor

• 

  Esther Zorio Grima

  Autor

Participantes ajenos a IIS La Fe

• Zissimopoulos, S
• Kirilenko, P
• Wang, YY
• Gomez, AM
• Cannell, MB
• Latinkic, B
• Fowler, ED

Grupos

• Cardiopatías familiares, muerte súbita y mecanismos de enfermedad (CAFAMUSME)

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 pacingpauses 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.

Copyright © 2025 The Authors. Published by Elsevier Ltd.. All rights reserved.

Keywords

• CPVT; Arrhythmias; Early afterdepolarizations; Calcium sparks; Repolarization reserve