Rotors anchored by refractory islands drive Torsades de Pointes in an experimental model of electrical storm

Abstract Background Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/fibrillation (VT/VF), but the pathophysiology and molecular basis are poorly understood. Objective To explore the electrophysiological substrate for experimental ES. Methods A model was created by inducing chronic complete atrioventricular-block in defibrillator-implanted rabbits, which recapitulates QT-prolongation, Torsades-des-Pointes (TdP) and VF-episodes. Results Optical mapping revealed island-like regions with action potential duration (APD) prolongation in the left ventricle (LV), leading to increased spatial APD-dispersion, in rabbits with ES (defined as ≥3 VF-episodes/24-h). The maximum APD and its dispersion correlated with the total number of VF-episodes in-vivo. TdP was initiated by an ectopic beat that failed to enter the island and formed a reentrant wave, and perpetuated by rotors whose centers swirled in the periphery of the island. Epinephrine exacerbated the island by prolonging APD and enhancing APD-dispersion, which was less evident after late Na+-current (INa-L) blockade with 10 μM ranolazine. Non-sustained VT in a non-ES rabbit heart with homogeneous APD prolongation resulted from multiple foci with an electrocardiographic morphology different from TdP driven by drifting rotors in ES-rabbit hearts. The neuronal Na+-channel subunit NaV1.8 was upregulated in ES-rabbit LV-tissues and expressed within myocardium corresponding to the island location in optically mapped ES-rabbit hearts. The NaV1.8-blocker A-803467 (10 mg/kg, i.v.) attenuated QT-prolongation and suppressed epinephrine-evoked TdP. Conclusion A tissue-island with enhanced refractoriness contributes to the generation of drifting rotors that underlies ES in this model. NaV1.8-mediated INa-L merits further investigation as a contributor to the substrate for ES.