Paradoxical Effect of Increased Diastolic Ca2+ Release and Decreased Sinoatrial Node Activity in a Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia

Article

关键词: CARDIAC RYANODINE RECEPTOR;    PACEMAKER ACTIVITY;    ATRIAL-FIBRILLATION;    FUNNY CURRENT;    SUDDEN-DEATH;    FOLLOW-UP;    CELLS;    HEART;    CALCIUM;    AUTOMATICITY;   

DOI  :  10.1161/CIRCULATIONAHA.111.075382

来源: SCIE

【 摘 要 】

Background-Catecholaminergic polymorphic ventricular tachycardia is characterized by stress-triggered syncope and sudden death. Patients with catecholaminergic polymorphic ventricular tachycardia manifest sinoatrial node (SAN) dysfunction, the mechanisms of which remain unexplored. Methods and Results-We investigated SAN [Ca2+](i) handling in mice carrying the catecholaminergic polymorphic ventricular tachycardia-linked mutation of ryanodine receptor (RyR2(R4496C)) and their wild-type (WT) littermates. In vivo telemetric recordings showed impaired SAN automaticity in RyR2(R4496C) mice after isoproterenol injection, analogous to what was observed in catecholaminergic polymorphic ventricular tachycardia patients after exercise. Pacemaker activity was explored by measuring spontaneous [Ca2+](i) transients in SAN cells within the intact SAN by confocal microscopy. RyR2(R4496C) SAN presented significantly slower pacemaker activity and impaired chronotropic response under beta-adrenergic stimulation, accompanied by the appearance of pauses (in spontaneous [Ca2+](i) transients and action potentials) in 75% of the cases. Ca2+ spark frequency was increased by 2-fold in RyR2R4496C SAN. Whole-cell patch-clamp experiments performed on isolated RyR2R4496C SAN cells showed that L-type Ca2+ current (I-Ca,I-L) density was reduced by approximate to 50%, an effect blunted by internal Ca2+ buffering. Isoproterenol dramatically increased the frequency of Ca2+ sparks and waves by approximate to 5 and approximate to 10-fold, respectively. Interestingly, the sarcoplasmic reticulum Ca2+ content was significantly reduced in RyR2(R4496C) SAN cells in the presence of isoproterenol, which may contribute to stopping the Ca2+ clock rhythm generation, originating SAN pauses. Conclusion-The increased activity of RyR2(R4496C) in SAN leads to an unanticipated decrease in SAN automaticity by a Ca2+-dependent decrease of I-Ca,I-L and sarcoplasmic reticulum Ca2+ depletion during diastole, identifying subcellular pathophysiological alterations contributing to the SAN dysfunction in catecholaminergic polymorphic ventricular tachycardia patients. (Circulation. 2012;126:392-401.)

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