Masatoshi Yamazaki1, Naoki Tomii2, Koichi Tsuneyama3, Hiroki Takanari3, Ryoko Niwa4, Haruo Honjo4, Itsuo Kodama4, Tatsuhiko Arafune5, Naomasa Makita6, Ichiro Sakuma2, Dobromir Dobrev7, Stanley Nattel8, Yukiomi Tsuji9. 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 NaV1.8 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 NaV1.8 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. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES.
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 NaV1.8 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 NaV1.8 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. NaV1.8-mediated late Na+ current merits further investigation as a contributor to the substrate for ES.
Authors: Ashish Parikh; Rajkumar Mantravadi; Dmitry Kozhevnikov; Michael A Roche; Yanping Ye; Laura J Owen; Jose Luis Puglisi; Jonathan J Abramson; Guy Salama Journal: Heart Rhythm Date: 2012-01-11 Impact factor: 6.343
Authors: Nataliya Dybkova; Shakil Ahmad; Steffen Pabel; Petros Tirilomis; Nico Hartmann; Thomas H Fischer; Philipp Bengel; Theodoros Tirilomis; Senka Ljubojevic; André Renner; Jan Gummert; David Ellenberger; Stefan Wagner; Norbert Frey; Lars S Maier; Katrin Streckfuss-Bömeke; Gerd Hasenfuss; Samuel Sossalla Journal: Cardiovasc Res Date: 2018-11-01 Impact factor: 10.787
Authors: Dina Myers Stroud; Tao Yang; Kevin Bersell; Dymtro O Kryshtal; Satomi Nagao; Christian Shaffer; Laura Short; Lynn Hall; Thomas C Atack; Wei Zhang; Bjorn C Knollmann; Franz Baudenbacher; Dan M Roden Journal: J Am Heart Assoc Date: 2016-11-02 Impact factor: 5.501
Authors: Tao Yang; Young Wook Chun; Dina M Stroud; Jonathan D Mosley; Bjorn C Knollmann; Charles Hong; Dan M Roden Journal: Circulation Date: 2014-06-03 Impact factor: 29.690