Przemysław B Radwański1, Lucia Brunello2, Rengasayee Veeraraghavan3, Hsiang-Ting Ho2, Qing Lou2, Michael A Makara2, Andriy E Belevych2, Mircea Anghelescu4, Silvia G Priori5, Pompeo Volpe6, Thomas J Hund7, Paul M L Janssen2, Peter J Mohler8, John H B Bridge9, Steven Poelzing3, Sándor Györke10. 1. Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA Division of Pharmacy Practice and Administration, College of Pharmacy, The Ohio State University, Columbus, OH, USA sandor.gyorke@osumc.edu przemyslaw.radwanski@osumc.edu. 2. Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA. 3. VTC Research Institute, School of Biomedical Engineering and Sciences, Virginia Tech, Roanoke, VA, USA. 4. Department of Biological and Allied Health Sciences, Ohio Northern University, Ada, OH, USA. 5. Division of Cardiology and Molecular Cardiology, Maugeri Foundation-University of Pavia, Pavia, Italy. 6. Department of Biomedical Sciences, University of Padova, Padova, Italy. 7. Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA. 8. Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA Department of Internal Medicine, College of Medicine, The Ohio State University, Columbus, OH, USA. 9. Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT, USA. 10. Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, 473 West 12th Avenue, Room 507, Columbus, OH 43210, USA Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, OH, USA sandor.gyorke@osumc.edu przemyslaw.radwanski@osumc.edu.
Abstract
AIMS: Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study. METHODS AND RESULTS: We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice. CONCLUSIONS: Thus, our study offers the first evidence that nNav contribute to arrhythmogenic DCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: Sudden death resulting from cardiac arrhythmias is the most common consequence of cardiac disease. Certain arrhythmias caused by abnormal impulse formation including catecholaminergic polymorphic ventricular tachycardia (CPVT) are associated with delayed afterdepolarizations resulting from diastolic Ca2+ release (DCR) from the sarcoplasmic reticulum (SR). Despite high response of CPVT to agents directly affecting Ca2+ cycling, the incidence of refractory cases is still significant. Surprisingly, these patients often respond to treatment with Na+ channel blockers. However, the relationship between Na+ influx and disturbances in Ca2+ handling immediately preceding arrhythmias in CPVT remains poorly understood and is the object of this study. METHODS AND RESULTS: We performed optical Ca2+ and membrane potential imaging in ventricular myocytes and intact cardiac muscles as well as surface ECGs on a CPVT mouse model with a mutation in cardiac calsequestrin. We demonstrate that a subpopulation of Na+ channels (neuronal Na+ channels; nNav) colocalize with ryanodine receptor Ca2+ release channels (RyR2). Disruption of the crosstalk between nNav and RyR2 by nNav blockade with riluzole reduced and also desynchronized DCR in isolated cardiomyocytes and in intact cardiac tissue. Such desynchronization of DCR on cellular and tissue level translated into decreased arrhythmias in CPVT mice. CONCLUSIONS: Thus, our study offers the first evidence that nNav contribute to arrhythmogenicDCR, thereby providing a conceptual basis for mechanism-based antiarrhythmic therapy. Published on behalf of the European Society of Cardiology. All rights reserved.
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