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dc.contributor.authorWillis, B. Cicero
dc.contributor.authorPandit, Sandeep V.
dc.contributor.authorPonce-Balbuena, Daniela
dc.contributor.authorZarzoso, Manuel
dc.contributor.authorGuerrero-Serna, Guadalupe
dc.contributor.authorLimbu, Bijay
dc.contributor.authorDeo, Makarand
dc.contributor.authorCamors, Emmanuel
dc.contributor.authorRamirez, Rafael J.
dc.contributor.authorMironov, Sergey
dc.contributor.authorHerron, Todd J.
dc.contributor.authorValdivia, Hector H.
dc.contributor.authorJalife, Jose 
dc.date.accessioned2017-10-30T13:15:44Z
dc.date.available2017-10-30T13:15:44Z
dc.date.issued2016
dc.identifierISI:000378045100008
dc.identifier.issn0009-7322
dc.identifier.urihttp://hdl.handle.net/20.500.12105/5219
dc.description.abstractBackground-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.sponsorshipThis 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.isoeng
dc.publisherLippincott Williams & Wilkins (LWW) 
dc.type.hasVersionVoR
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/*
dc.subjectArrhythmias, cardiac
dc.subjectCalcium
dc.subjectCalcium signaling
dc.subjectSodium-calcium exchanger
dc.subjectBETA-ADRENERGIC STIMULATION
dc.subjectCARDIAC RYANODINE RECEPTOR
dc.subjectIN MOUSE MODEL
dc.subjectSUDDEN-DEATH
dc.subjectCELLULAR MECHANISM
dc.subjectCA2+ ACTIVATION
dc.subjectMURINE HEART
dc.subjectFIBERS
dc.subjectCONTRACTION
dc.subjectMYOCARDIUM
dc.titleConstitutive Intracellular Na+ Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia
dc.typejournal article
dc.rights.licenseAttribution-NonCommercial-NoDerivatives 4.0 Internacional*
dc.identifier.pubmedID27169737
dc.format.volume133
dc.format.page2348+
dc.identifier.doi10.1161/CIRCULATIONAHA.116.021936
dc.contributor.funderNIH - National Heart, Lung, and Blood Institute (NHLBI) (Estados Unidos) 
dc.contributor.funderAmerican Heart Association 
dc.description.peerreviewed
dc.identifier.e-issn1524-4539
dc.relation.publisherversionhttps://doi.org/10.1161/CIRCULATIONAHA.116.021936
dc.identifier.journalCirculation
dc.repisalud.orgCNICCNIC::Grupos de investigación::Arritmias Cardíacas
dc.repisalud.institucionCNIC
dc.rights.accessRightsopen accesses_ES


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Attribution-NonCommercial-NoDerivatives 4.0 Internacional
Este Item está sujeto a una licencia Creative Commons: Attribution-NonCommercial-NoDerivatives 4.0 Internacional