Cellular Mechanisms Underlying the Development of Catecholaminergic Ventricular Tachycardia

Abstract

Background-Mutations in the ryanodine 2 receptor (RyR2) gene have been identified in patients with catecholaminergic polymorphic ventricular tachycardia. We examined the cellular basis for the ECG features and arrhythmia mechanisms using low-dose caffeine to mimic the defective calcium homeostasis encountered under these conditions. Methods and Results-A transmural ECG and action potentials were recorded simultaneously from epicardial, M, and endocardial cells in arterially perfused canine ventricular wedge preparations. Caffeine alone produced no change (10 to 100 mol/L) or a slight abbreviation (300 mol/L) of the QT interval and no change in transmural dispersion of repolarization. Isoproterenol (100 nmol/L) alone induced sustained monomorphic ventricular tachycardia (VT) that originated in the epicardium in 3 of 14 wedge preparations. Isoproterenol in the presence of caffeine (100 to 300 mol/L) induced epicardial VT in 9 of 16 wedge preparations. Delayed afterdepolarization-induced triggered beats that originated in the epicardium were associated with an increased T peak -T end interval and transmural dispersion of repolarization. Bidirectional VT developed in 11 of 16 wedge preparations as a consequence of alternation in the origin of ectopic activity between endocardial, M, and epicardial regions. Single extrastimuli delivered during sustained epicardial VT induced a rapid polymorphic VT/ventricular fibrillation (VF) in 3 of 9 wedges. Spontaneous polymorphic VT was observed in 3 of 16 preparations. Propranolol (1.0 mol/L) or verapamil (1.0 mol/L) completely suppressed ectopic activity that arose from the epicardium and prevented induction of polymorphic VT. Conclusions-Our data suggest delayed afterdepolarization-induced extrasystolic activity serves to trigger catecholamineinduced VT/VF under conditions of defective calcium handling. Epicardial origin of the ectopic beats increases transmural dispersion of repolarization, thus providing the substrate for the development of reentrant tachyarrhythmias that underlie rapid polymorphic VT/VF.

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

“…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…”

Cellular basis for arrhythmogenesis in an experimental model of the SQT1 form of the short QT syndrome

“…A similar protocol was repeated after switching the basic stimulus (S 1 ) to epicardium as reversal of direction of activation of the left ventricle has been shown to amplify TDR and facilitate induction of pVT. 15 The effective refractory period (ERP) was defined as the longest S 1 -S 2 interval at which S 2 failed to capture. Ventricular tachycardia (VT) inducibility was examined under each condition (control, PD-118057, + Quinidine).…”

Increasing Ryanodine Receptor Open Probability Alone Does Not Produce Arrhythmogenic Calcium Waves

“…Work on ventricular wedge preparations found that increasing RyR probability (with caffeine) did not produce arrhythmias unless catecholaminergic stimulation was also present. 17 This study, however, did not investigate cellular Ca 2ϩ handling.…”