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

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.