2026-04-29T12:23:10Zhttps://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
Repisalud author 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 funder NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos) funder American Heart Association 2017-10-30T13:15:44Z 2017-10-30T13:15:44Z 2016 10.1161/CIRCULATIONAHA.116.021936 1524-4539 0009-7322 Circulation 27169737 http://hdl.handle.net/20.500.12105/5219 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. eng 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 journal article URL https://repisalud.isciii.es/bitstreams/494e7bff-ef8c-4697-9ac7-b3c95751cf97/download File MD5 7ef174ee0919a0605dd87e78a84bb90b 3633579 application/pdf ConstitutiveIntracellularNaExcess_2016 URL https://repisalud.isciii.es/bitstreams/79437b45-7bde-467d-96ed-c11df7311bf9/download File MD5 4cbe7b759afc5002cdf81b82d5664d87 89056 text/plain ConstitutiveIntracellularNaExcess_2016.txt