2026-04-29T12:23:05Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/52192024-09-27T08:18:33Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19605

00925njm 22002777a 4500 dc Willis, B. Cicero author Pandit, Sandeep V. author Ponce-Balbuena, Daniela author Zarzoso, Manuel author Guerrero-Serna, Guadalupe author Limbu, Bijay author Deo, Makarand author Camors, Emmanuel author Ramirez, Rafael J. author Mironov, Sergey author Herron, Todd J. author Valdivia, Hector H. author Jalife, Jose author 2016 Background-In catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more susceptible to Ca2+ dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (Ry(R2R4496C+/Cx40eGFP)), we tested whether PC intracellular Ca2+ ([Ca2+](i)) dysregulation results from a constitutive [Na+](i) surplus relative to VMs. Methods and Results-Simultaneous optical mapping of voltage and [Ca2+](i) in CPVT hearts showed that spontaneous Ca2+ release preceded pacing-induced triggered activity at subendocardial PCs. On simultaneous current-clamp and Ca2+ imaging, early and delayed afterdepolarizations trailed spontaneous Ca2+ release and were more frequent in CPVT PCs than CPVT VMs. As a result of increased activity of mutant ryanodine receptor type 2 channels, sarcoplasmic reticulum Ca2+ load, measured by caffeine-induced Ca2+ transients, was lower in CPVT VMs and PCs than respective controls, and sarcoplasmic reticulum fractional release was greater in both CPVT PCs and VMs than respective controls. [Na2+](i) was higher in both control and CPVT PCs than VMs, whereas the density of the Na+/Ca2+ exchanger current was not different between PCs and VMs. Computer simulations using a PC model predicted that the elevated [Na2+](i) of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca2+ release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na2+](i) monotonically increased delayed afterdepolarization frequency. Confocal imaging experiments showed that postpacing Ca2+ spark frequency was highest in intact CPVT PCs, but such differences were reversed on saponin-induced membrane permeabilization, indicating that differences in [Na2+](i) played a central role. Conclusions-In CPVT mice, the constitutive [Na2+](i) excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs. 10.1161/CIRCULATIONAHA.116.021936 1524-4539 0009-7322 Circulation 27169737 http://hdl.handle.net/20.500.12105/5219 Arrhythmias, cardiac Calcium Calcium signaling Sodium-calcium exchanger BETA-ADRENERGIC STIMULATION CARDIAC RYANODINE RECEPTOR IN MOUSE MODEL SUDDEN-DEATH CELLULAR MECHANISM CA2+ ACTIVATION MURINE HEART FIBERS CONTRACTION MYOCARDIUM Constitutive Intracellular Na+ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia