Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm

Masatoshi Yamazaki; Naoki Tomii; Koichi Tsuneyama; Hiroki Takanari; Ryoko Niwa; Haruo Honjo; Itsuo Kodama; Tatsuhiko Arafune; Naomasa Makita; Ichiro Sakuma; Dobromir Dobrev; Stanley Nattel; Yukiomi Tsuji

doi:10.1016/j.hrthm.2021.10.012

Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm

Heart Rhythm. 2022 Feb;19(2):318-329. doi: 10.1016/j.hrthm.2021.10.012. Epub 2021 Oct 20.

Authors

Affiliations

¹ Department of Cardiology, Nagano Hospital, Soja, Japan; Medical Device Development and Regulation Research Center, The University of Tokyo, Tokyo, Japan.
² Medical Device Development and Regulation Research Center, The University of Tokyo, Tokyo, Japan; Department of Precision Engineering, The University of Tokyo, Tokyo, Japan.
³ Department of Pathology and Laboratory Medicine, Institute of Post-LED Photonics, Tokushima University Faculty of Medicine, Tokushima, Japan.
⁴ Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
⁵ School of Science and Engineering, Tokyo Denki University, Saitama, Japan.
⁶ Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan.
⁷ Institute of Pharmacology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas; Departments of Medicine and Research Center, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.
⁸ Institute of Pharmacology, West German Heart and Vascular Center, University of Duisburg-Essen, Essen, Germany; Departments of Medicine and Research Center, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada; Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada; IHU LIYRC Institute, Bordeaux, France.
⁹ Department of Physiology of Visceral Function, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. Electronic address: yukiomitsuji@nagasaki-u.ac.jp.

Abstract

Background: Electrical storm (ES) is a life-threatening emergency in patients at high risk of ventricular tachycardia/ventricular fibrillation (VF), but the pathophysiology and molecular basis are poorly understood.

Objective: The purpose of this study was 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, 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 blockade with 10 μM ranolazine. Nonsustained ventricular tachycardia 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 Na_V1.8 was upregulated in ES rabbit left ventricular tissues and expressed within the myocardium corresponding to the island location in optically mapped ES rabbit hearts. The Na_V1.8 blocker A-803467 (10 mg/kg, intravenously) 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. Na_V1.8-mediated late Na⁺ current merits further investigation as a contributor to the substrate for ES.

Keywords: Electrical storm; Late sodium current; Neuronal sodium channel; Rotors; Torsades de pointes.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Action Potentials
Animals
Atrioventricular Block / drug therapy
Atrioventricular Block / physiopathology*
Defibrillators, Implantable
Disease Models, Animal
Long QT Syndrome / physiopathology
Rabbits
Ranolazine / pharmacology
Tachycardia, Ventricular / physiopathology*
Torsades de Pointes / physiopathology*

Substances

Ranolazine

Abstract

Publication types

MeSH terms

Substances

Grants and funding