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

Published:October 19, 2021DOI:


      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.


      The purpose of this study was to explore the electrophysiological substrate for experimental ES.


      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.


      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.


      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.

      Graphical abstract


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        • Tsuji Y.
        • Hojo M.
        • Voigt N.
        • et al.
        Ca2+-related signaling and protein phosphorylation abnormalities play central roles in a new experimental model of electrical storm.
        Circulation. 2011; 123: 2192-2203
        • Rokita A.G.
        • Anderson M.E.
        New therapeutic targets in cardiology: arrhythmias and Ca2+/calmodulin-dependent kinase II (CaMKII).
        Circulation. 2012; 126: 2125-2139
        • Yamazaki M.
        • Honjo H.
        • Ashihara T.
        • et al.
        Regional cooling facilitates termination of spiral-wave reentry through unpinning of rotors in rabbit hearts.
        Heart Rhythm. 2012; 9: 107-114
        • Tomii N.
        • Yamazaki M.
        • Arafune T.
        • et al.
        Detection algorithm of phase singularity using phase variance analysis for epicardial optical mapping data.
        IEEE Trans Biomed Eng. 2016; 63: 1795-1803
        • Belardinelli L.
        • Liu G.
        • Smith-Maxwell C.
        • et al.
        A novel, potent, and selective inhibitor of cardiac late sodium current suppresses experimental arrhythmias.
        J Pharmacol Exp Ther. 2013; 344: 23-32
        • Parikh A.
        • Mantravadi R.
        • Kozhevnikov D.
        • et al.
        Ranolazine stabilizes cardiac ryanodine receptors: a novel mechanism for the suppression of early afterdepolarization and torsades de pointes in long QT type 2.
        Heart Rhythm. 2012; 9: 953-960
        • Yang T.
        • Atack T.C.
        • Stroud D.M.
        • et al.
        Blocking Scn10a channels in heart reduces late sodium current and is antiarrhythmic.
        Circ Res. 2012; 111: 322-332
        • Yang T.
        • Chun Y.W.
        • Stroud D.M.
        • et al.
        Screening for acute IKr block is insufficient to detect torsades de pointes liability: role of late sodium current.
        Circulation. 2014; 130: 224-234
        • Glynn P.
        • Musa H.
        • Wu X.Q.
        • et al.
        Voltage-gated sodium channel phosphorylation at Ser571 regulates late current, arrhythmia, and cardiac function in vivo.
        Circulation. 2015; 132: 567-577
        • Ahmad S.
        • Tirilomis P.
        • Pabel S.
        • et al.
        The functional consequences of sodium channel NaV1.8 in human left ventricular hypertrophy.
        ESC Heart Fail. 2019; 6: 154-163
        • Dybkova N.
        • Ahmad S.
        • Pabel S.
        • et al.
        Differential regulation of sodium channels as a novel proarrhythmic mechanism in the human failing heart.
        Cardiovasc Res. 2018; 114: 1728-1737
        • Tsuji Y.
        • Opthof T.
        • Yasui K.
        • et al.
        Ionic mechanisms of acquired QT prolongation and torsades de pointes in rabbits with chronic complete atrioventricular block.
        Circulation. 2002; 106: 2012-2018
        • Tsuji Y.
        • Zicha S.
        • Qi X.Y.
        • Kodama I.
        • Nattel S.
        Potassium channel subunit remodeling in rabbits exposed to long-term bradycardia or tachycardia: discrete arrhythmogenic consequences related to differential delayed-rectifier changes.
        Circulation. 2006; 113: 345-355
        • Qi X.
        • Yeh Y.H.
        • Chartier D.
        • et al.
        The calcium/calmodulin/kinase system and arrhythmogenic afterdepolarizations in bradycardia-related acquired long-QT syndrome.
        Circ Arrhythm Electrophysiol. 2009; 2: 295-304
        • Samie F.H.
        • Jalife J.
        Mechanisms underlying ventricular tachycardia and its transition to ventricular fibrillation in the structurally normal heart.
        Cardiovasc Res. 2001; 50: 242-250
        • Stroud D.M.
        • Yang T.
        • Bersell K.
        • et al.
        Contrasting Nav1.8 activity in Scn10a−/− ventricular myocytes and the intact heart.
        J Am Heart Assoc. 2016; 5e002946
        • Asano Y.
        • Davidenko J.M.
        • Baxter W.T.
        • Gray R.A.
        • Jalife J.
        Optical mapping of drug-induced polymorphic arrhythmias and torsade de pointes in the isolated rabbit heart.
        J Am Coll Cardiol. 1997; 29: 831-842
        • Maruyama M.
        • Lin S.F.
        • Xie Y.
        • et al.
        Genesis of phase 3 early afterdepolarizations and triggered activity in acquired long-QT syndrome.
        Circ Arrhythm Electrophysiol. 2011; 4: 103-111
        • Brunner M.
        • Peng X.
        • Liu G.X.
        • et al.
        Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome.
        J Clin Invest. 2008; 118: 2246-2259