Conduction Slowing Contributes to Spontaneous Ventricular Arrhythmias in Intrinsically Active Murine RyR2‐P2328S Hearts |
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Authors: | YANMIN ZHANG MD PhD JINGJING WU MD PhD KAMALAN JEEVARATNAM DVM PhD JAMES H KING MD LAILA GUZADHUR
PhD XIAOLEI REN BS ANDREW A GRACE MD PhD MING LEI MD PhD CHRISTOPHER L‐H HUANG MD PhD ScD JAMES A FRASER BM BCh PhD |
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Institution: | 1. Physiological Laboratory, University of Cambridge, Cambridge, UK;2. Department of Paediatrics, First Affiliated Hospital, Xi’an Jiaotong University, Xi’an, China;3. Union Hospital, Huazhong University of Sciences and Technology, Wuhan, China;4. Perdana University‐Royal College of Surgeons in Ireland, Serdang, Selangor, Malaysia;5. School of Physiology and Pharmacology, University of Bristol, Bristol, UK;6. Cardiovascular Biology Group, Department of Biochemistry, University of Cambridge, Cambridge, UK;7. Institute of Cardiovascular Science, University of Manchester, Manchester, UK |
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Abstract: | Conduction Changes in RyR2‐P2328S Hearts . Introduction: The familial condition catecholaminergic polymorphic ventricular tachycardia (CPVT) is characterized by episodic bidirectional ventricular tachycardia (BVT), polymorphic ventricular tachycardia (PVT), and ventricular fibrillation following adrenergic challenge. It is associated with mutations involving the cardiac ryanodine receptor (RyR2). Methods and Results: We explored for a slowing of myocardial conduction that could potentially result in a substrate for the spontaneous arrhythmogenesis that was observed following introduction of isoproterenol and caffeine in intrinsically beating murine RyR2‐P2328S hearts. Such pharmacological challenge increased the number of arrhythmic episodes in electrocardiographic recordings from intact anesthetized mice, with the greatest effects in the homozygote RyR2S/S. Arrhythmias took the form of bigeminy, BVT, monomorphic ventricular tachycardia, and PVT, as found in human CPVT. Ventricular epicardial conduction velocities (CVs) measured using multielectrode array recordings and maximum action potential upstroke rates, (dV/dt)max, measured using intracellular microelectrodes were indistinguishable in untreated wild‐type (WT) and RyR2S/S. Pharmacological challenge of RyR2S/S, but not WT hearts, then reduced CV and (dV/dt)max and also revealed a strongly arrhythmic phenotype. There was no evidence of gross structural or fibrotic changes in either RyR2+/S or RyR2S/S hearts on light microscopy. Conclusions: We associate altered ventricular myocardial CV potentially resulting in arrhythmogenic substrate with arrhythmic properties associated with genetic RyR2 alterations for the first time. (J Cardiovasc Electrophysiol, Vol. 24, pp. 210‐218, February 2013) |
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Keywords: | action potential arrhythmia conduction velocity CPVT ryanodine receptors |
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