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dc.contributor.author | Willis, B. Cicero | |
dc.contributor.author | Pandit, Sandeep V. | |
dc.contributor.author | Ponce-Balbuena, Daniela | |
dc.contributor.author | Zarzoso, Manuel | |
dc.contributor.author | Guerrero-Serna, Guadalupe | |
dc.contributor.author | Limbu, Bijay | |
dc.contributor.author | Deo, Makarand | |
dc.contributor.author | Camors, Emmanuel | |
dc.contributor.author | Ramirez, Rafael J. | |
dc.contributor.author | Mironov, Sergey | |
dc.contributor.author | Herron, Todd J. | |
dc.contributor.author | Valdivia, Hector H. | |
dc.contributor.author | Jalife, Jose | |
dc.date.accessioned | 2017-10-30T13:15:44Z | |
dc.date.available | 2017-10-30T13:15:44Z | |
dc.date.issued | 2016 | |
dc.identifier | ISI:000378045100008 | |
dc.identifier.issn | 0009-7322 | |
dc.identifier.uri | http://hdl.handle.net/20.500.12105/5219 | |
dc.description.abstract | 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. | |
dc.description.sponsorship | This work was supported by National Heart, Lung, and Blood Institute grants P01-HL039707, P01-HL087226, and R01-HL122352; the Leducq Foundation: Transatlantic Network of Excellence Program on ``Structural Alterations in the Myocardium and the Substrate for Cardiac Fibrillation´´ (Dr Jalife); grants HL055438 and HL120108 (to Dr Valdivia); and American Heart Association grant 12SDG11480010 (Dr Deo). | |
dc.language.iso | eng | |
dc.publisher | Lippincott Williams & Wilkins (LWW) | |
dc.type.hasVersion | VoR | |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | * |
dc.subject | Arrhythmias, cardiac | |
dc.subject | Calcium | |
dc.subject | Calcium signaling | |
dc.subject | Sodium-calcium exchanger | |
dc.subject | BETA-ADRENERGIC STIMULATION | |
dc.subject | CARDIAC RYANODINE RECEPTOR | |
dc.subject | IN MOUSE MODEL | |
dc.subject | SUDDEN-DEATH | |
dc.subject | CELLULAR MECHANISM | |
dc.subject | CA2+ ACTIVATION | |
dc.subject | MURINE HEART | |
dc.subject | FIBERS | |
dc.subject | CONTRACTION | |
dc.subject | MYOCARDIUM | |
dc.title | Constitutive Intracellular Na+ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia | |
dc.type | journal article | |
dc.rights.license | Attribution-NonCommercial-NoDerivatives 4.0 Internacional | * |
dc.identifier.pubmedID | 27169737 | |
dc.format.volume | 133 | |
dc.format.page | 2348+ | |
dc.identifier.doi | 10.1161/CIRCULATIONAHA.116.021936 | |
dc.contributor.funder | NIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos) | |
dc.contributor.funder | American Heart Association | |
dc.description.peerreviewed | Sí | |
dc.identifier.e-issn | 1524-4539 | |
dc.relation.publisherversion | https://doi.org/10.1161/CIRCULATIONAHA.116.021936 | |
dc.identifier.journal | Circulation | |
dc.repisalud.orgCNIC | CNIC::Grupos de investigación::Arritmias Cardíacas | |
dc.repisalud.institucion | CNIC | |
dc.rights.accessRights | open access | es_ES |