Abstract
Catecholaminergic polymorphic ventricular tachycardia (CPVT) predisposes to ventricular arrhythmia due to altered Ca2+ homeostasis and can arise from ryanodine receptor (RyR2) mutations including RyR2-P2328S. Previous reports established that homozygotic murine RyR2-P2328S (RyR2S/S) hearts show an atrial arrhythmic phenotype associated with reduced action potential (AP) conduction velocity and sodium channel (Nav1.5) expression. We now relate ventricular arrhythmogenicity and slowed AP conduction in RyR2S/S hearts to connexin-43 (Cx43) and Nav1.5 expression and Na+ current (INa). Stimulation protocols applying extrasystolic S2 stimulation following 8 Hz S1 pacing at progressively decremented S1S2 intervals confirmed an arrhythmic tendency despite unchanged ventricular effective refractory periods (VERPs) in Langendorff-perfused RyR2S/S hearts. Dynamic pacing imposing S1 stimuli then demonstrated that progressive reductions of basic cycle lengths (BCLs) produced greater reductions in conduction velocity at equivalent BCLs and diastolic intervals in RyR2S/S than WT, but comparable changes in AP durations (APD90) and their alternans. Western blot analyses demonstrated that Cx43 protein expression in whole ventricles was similar, but Nav1.5 expression in both whole tissue and membrane fractions were significantly reduced in RyR2S/S compared to wild-type (WT). Loose patch-clamp studies similarly demonstrated reduced INa in RyR2S/S ventricles. We thus attribute arrhythmogenesis in RyR2S/S ventricles resulting from arrhythmic substrate produced by reduced conduction velocity to downregulated Nav1.5 reducing INa, despite normal determinants of repolarization and passive conduction. The measured changes were quantitatively compatible with earlier predictions of linear relationships between conduction velocity and the peak INa of the AP but nonlinear relationships between peak INa and maximum Na+ permeability.
Highlights
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic syndrome characterized by episodic syncope and/or sudden cardiac arrest, typically triggered by adrenergic stimulation as occurs during strenuous exercise or emotional stress [1, 34, 46]
CPVT has been associated with mutations in various Ca2+ handling proteins, which lead to abnormalities in Ca2+ homeostasis; most notably, these mutations are found in the cardiac ryanodine receptor-Ca2+ release channel (RyR2) [25, 35] and the sarcoplasmic reticulum (SR) Ca2+-binding protein calsequestrin 2 (CASQ2) [13, 19]
The present experiments demonstrate that reduced Nav1.5 expression and Na current is associated with the reduced conduction velocity and consequent arrhythmic substrate and ventricular arrhythmogenesis in homozygotic murine RyR2P2328S (RyR2S/S) hearts
Summary
Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmic syndrome characterized by episodic syncope and/or sudden cardiac arrest, typically triggered by adrenergic stimulation as occurs during strenuous exercise or emotional stress [1, 34, 46]. Some RyR2 mutations predispose to atrial arrhythmias [4, 34, 39]. The RyR2-P2328S mutation is associated with high incidences of both CPVT and atrial tachycardia (AT) [25, 37, 40]. This RyR2 variant has been associated with a normal luminal SR Ca2+ release sensitivity but an increased sensitivity to cytosolic Ca2+ [31], giving rise to lower cytosolic Ca2+ thresholds leading to Ca2+ release. If reached during increased heart rates, these could be sufficient to elicit a ‘leak’ of SR Ca2+ triggering arrhythmia
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