Arrhythmogenic Mechanisms in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Abstract

Abstract-Catecholaminergic polymorphic ventricular tachycardia (VT) is a lethal familial disease characterized by bidirectional VT, polymorphic VT, and ventricular fibrillation. Catecholaminergic polymorphic VT is caused by enhanced Ca 2ϩ release through defective ryanodine receptor (RyR2) channels. We used epicardial and endocardial optical mapping, chemical subendocardial ablation with Lugol's solution, and patch clamping in a knockin (RyR2/RyR2 R4496C ) mouse model to investigate the arrhythmogenic mechanisms in catecholaminergic polymorphic VT. In isolated hearts, spontaneous ventricular arrhythmias occurred in 54% of 13 RyR2/RyR2 R4496C and in 9% of 11 wild-type (Pϭ0.03) littermates perfused with Ca 2ϩ and isoproterenol; 66% of 12 RyR2/RyR2 R4496C and 20% of 10 wild-type hearts perfused with caffeine and epinephrine showed arrhythmias (Pϭ0.04). Epicardial mapping showed that monomorphic VT, bidirectional VT, and polymorphic VT manifested as concentric epicardial breakthrough patterns, suggesting a focal origin in the His-Purkinje networks of either or both ventricles. Monomorphic VT was clearly unifocal, whereas bidirectional VT was bifocal. Polymorphic VT was initially multifocal but eventually became reentrant and degenerated into ventricular fibrillation. Endocardial mapping confirmed the Purkinje fiber origin of the focal arrhythmias. Chemical ablation of the right ventricular endocardial cavity with Lugol's solution induced complete right bundle branch block and converted the bidirectional VT into monomorphic VT in 4 anesthetized RyR2/RyR2 R4496C mice. Under current clamp, single Purkinje cells from RyR2/RyR2 R4496C mouse hearts generated delayed afterdepolarization-induced triggered activity at lower frequencies and level of adrenergic stimulation than wild-type. Overall, the data demonstrate that the His-Purkinje system is an important source of focal arrhythmias in catecholaminergic polymorphic VT. 604772) is an inherited disease leading to arrhythmias and sudden cardiac death. 1 The autosomal dominant form has been linked to ryanodine receptor gene (RyR2) mutations, leading to increased spontaneous Ca 2ϩ release from the sarcoplasmic reticulum. 2 Typical arrhythmias are bidirectional ventricular tachycardia (BVT) and polymorphic ventricular tachycardia (PVT) that can degenerate into ventricular fibrillation (VF) and thus sudden cardiac death. 3 BVT is infrequent, characterized by beat-to-beat 180°alternation of the QRS of the ECG and occurs in CPVT, as well as in digitalis toxicity; thus, it has been inferred that arrhythmogenesis in CPVT is mediated by delayed afterdepolarization (DAD)-induced triggered activity (TA).Mice heterozygous for the R4496C mutation (RyR2/ RyR2 R4496C ) recapitulate the human phenotype of CPVT by developing BVT, PVT, and/or VF under adrenergic stimulation. 4 Recently, Liu et al 5 have demonstrated DADs in RyR2/RyR2 R4496C mouse ventricular myocytes both in control and in the presence of isoproterenol. However, it remains to be demonstrated whether the arrhythmia origin...

Reduction in Kv Current Enhances the Temporal Dispersion of the Action Potential in Diabetic Myocytes: Insights From a Novel Repolarization Algorithm

“…This intervention induced ventricular tachycardia (VT) in 1 of the 7 Ctrl mice, whereas in the majority of diabetic animals (6 of 7), it elicited a bidirectional pattern of ventricular activation (Figure 4A through 4C), previously identified as bidirectional VT (BVT) 28, 29, 42. BVT was associated with a reduction in RR interval (Figure 4D) coupled with enhanced sinus discharge.…”

“…The altered regional properties of cardiac tissue may have affected locally the refractoriness of the myocardium, negatively interfering with electrical conduction and pattern of impulse propagation. Although further experiments are warranted, these initial findings suggests that altered spatial heterogeneity of the myocardium with diabetes represents the basis for the alternation in the polarity of the QRS axis observed during episodes of BVT 29, 58…”

Mechanisms of Ca2+-Triggered Arrhythmias

“…When EAD and DAD reach thresholds of depolarizing currents, new triggering action potentials are generated that may elicit self-sustaining trains of triggered activity (Figure 1). Of the different cell types in the heart, Purkinje cells are particularly prone to initiating afterdepolarizations, suggesting that Ca 2+ -dependent arrhythmic triggers may arise from the Purkinje fiber network (Boyden et al, 2000;Cerrone et al, 2007). This pro-arrhythmic behaviour is enhanced by disease-causing mutations in the RyR2 and greatly exacerbated by cathecholaminergic stimulation (Kang et al, 2010).…”

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“…This process is enhanced especially under conditions of β-adrenergic stimulation. 17,18 It has been proposed that this mechanism underlying CPVT principally originates in the HisPurkinje system. 19,20 Mutations in RyR2 alter the channel regulation mechanism, particularly its sensitivity to calcium activation.…”