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

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Rotors anchored by refractory islands drive torsades de pointes in an experimental model of electrical storm
Heart Rhythm ( IF 5.5 ) Pub Date : 2021-10-20 , DOI: 10.1016/j.hrthm.2021.10.012
Masatoshi Yamazaki ₁ , Naoki Tomii ₂ , Koichi Tsuneyama ₃ , Hiroki Takanari ₃ , Ryoko Niwa ₄ , Haruo Honjo ₄ , Itsuo Kodama ₄ , Tatsuhiko Arafune ₅ , Naomasa Makita ₆ , Ichiro Sakuma ₂ , Dobromir Dobrev ₇ , Stanley Nattel ₈ , Yukiomi Tsuji ₉

Affiliation

Department of Cardiology, Nagano Hospital, Soja, Japan; Medical Device Development and Regulation Research Center, The University of Tokyo, Tokyo, Japan.
Medical Device Development and Regulation Research Center, The University of Tokyo, Tokyo, Japan; Department of Precision Engineering, The University of Tokyo, Tokyo, Japan.
Department of Pathology and Laboratory Medicine, Institute of Post-LED Photonics, Tokushima University Faculty of Medicine, Tokushima, Japan.
Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
School of Science and Engineering, Tokyo Denki University, Saitama, Japan.
Omics Research Center, National Cerebral and Cardiovascular Center, Osaka, Japan.
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.
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.
Department of Physiology of Visceral Function, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

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.

中文翻译：

由耐火岛锚定的转子驱动电风暴实验模型中的尖端扭转型室速

背景

电风暴 (ES) 是室性心动过速/心室颤动 (VF) 高危患者的危及生命的紧急情况，但其病理生理学和分子基础知之甚少。

客观的

本研究的目的是探索实验 ES 的电生理底物。

方法

通过在植入除颤器的兔子中诱导慢性完全房室传导阻滞创建了一个模型，该模型概括了 QT 延长、尖端扭转型室性心动过速 (TdP) 和 VF 发作。

结果

光学映射显示左心室的岛状区域具有动作电位持续时间 (APD) 延长，导致 ES 兔的空间 APD 分散增加（定义为 ≥ 3 次 VF 发作/24 小时）。最大 APD 及其离散度与体内 VF 发作的总数相关。TdP 由未能进入该岛的异位搏动引发并形成折返波，并由其中心在该岛外围旋转的转子持续存在。^{肾上腺素通过延长 APD 和增强 APD 弥散性来加重岛，这在晚期 Na +}后不太明显用 10 μM 雷诺嗪阻断电流。非 ES 兔心脏中的非持续性室性心动过速与均匀 APD 延长是由多个病灶引起的，其心电图形态不同于 ES 兔心脏中的漂移转子驱动的 TdP。神经元 Na ⁺ -通道亚基 Na _V 1.8 在 ES 兔左心室组织中上调，并在对应于光学映射 ES 兔心脏中岛位置的心肌内表达。Na _V 1.8 阻滞剂 A-803467（10 mg/kg，静脉注射）减弱 QT 间期延长并抑制肾上腺素诱发的 TdP。