Electrophysiological Mechanism of Enhanced Susceptibility of Hypertrophied Heart to Acquired Torsade de Pointes Arrhythmias

Abstract

Background-Cardiac hypertrophy is associated with increased incidence of sudden death and susceptibility to proarrhythmic effects of antiarrhythmic agents. However, the in vivo electrophysiologic mechanism of the arrhythmias has not been investigated in detail. Methods and Results-Dose-dependent susceptibility to Torsade de Pointes (TdP) by class III drug dofetilide, 3, 10, and 30 g/kg, was compared in 6 control dogs (C) and in 5 dogs 6 to 8 weeks after induction of complete atrioventricular block (AVB) that resulted in ventricular hypertrophy (H). Tridimensional ventricular activation and repolarization (R) patterns were simultaneously analyzed from unipolar extracellular electrograms, and local R was measured from activation recovery intervals. Both R and transmural dispersion of R (TDR) were significantly greater in dogs with H compared with C. Dofetilide resulted in cycle length-dependent and dose-dependent prolongation of R, which was more marked in left ventricular endocardium/midmyocardium compared with epicardium, resulting in significant increase of TDR. These changes were more accentuated in dogs with H compared with C. All 5 dogs with H developed TdP at a dose of 3 to 10 g/kg, whereas only 1 of 6 C dogs developed TdP at 30 g/kg. TdP was initiated by subendocardial focal activity that infringed on TDR, resulting in functional conduction block and reentrant excitation. Conclusions-Enhanced susceptibility of hypertrophied heart to class III drugs is attributable to baseline increased TDR and greater dose-related accentuation of TDR compared with nonhypertrophied heart. This provides the electrophysiologic substrate for drug-induced TdP.

Antiarrhythmic Drug Therapy for Atrial Fibrillation

“…Ventricular hypertrophy may predispose to the development of afterdepolarizations and thus may represent a substrate more prone to TDP in the presence of QT-prolonging medications (potassium channel blocking drugs). 49 …”

Temporal patterns of electrical remodeling in canine ventricular hypertrophy: Focus on IKs downregulation and blunted β-adrenergic activation

“…In the canine model of chronic complete atrioventricular block (AVB) and ventricular hypertrophy, increased spatial [1,4] and temporal dispersion of repolarization [5] predispose to acquired torsades de pointes and sudden cardiac death [6]. At the cellular level, K + currents I Ks and I Kr are reduced [1], whereas sarcoplasmic reticulum Ca 2+ release and I NaCaX are enhanced, especially at slow heart rates [7].…”

Ionic Mechanisms of Acquired QT Prolongation and Torsades de Pointes in Rabbits With Chronic Complete Atrioventricular Block

“…2 In the model, the bradycardia-induced volume overload causes biventricular hypertrophy and heterogeneous prolongation of the ventricular action potential. [3][4][5][6] Significant reduction of the slow component of the delayed rectifier K ϩ current (I Ks ) in both ventricles and that of the rapid component (I Kr ) in the RV were demonstrated. 5 TdP was easily induced in the canine model by class III antiarrhythmic drugs (eg, d-sotalol and almokalant) and programmed stimulation, 2,7 but documented spontaneous TdP episodes and the incidence of sudden cardiac death were relatively rare.…”