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.
abstract: In catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more susceptible to Ca(2+) dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (RyR2(R4496C+/Cx40eGFP)), we tested whether PC intracellular Ca(2+) ([Ca(2+)]i) dysregulation results from a constitutive [Na(+)]i surplus relative to VMs.
  
  
  
  Simultaneous optical mapping of voltage and [Ca(2+)]i in CPVT hearts showed that spontaneous Ca(2+) release preceded pacing-induced triggered activity at subendocardial PCs. On simultaneous current-clamp and Ca(2+) imaging, early and delayed afterdepolarizations trailed spontaneous Ca(2+) 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 Ca(2+) load, measured by caffeine-induced Ca(2+) 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. [Na(+)]i was higher in both control and CPVT PCs than VMs, whereas the density of the Na(+)/Ca(2+) exchanger current was not different between PCs and VMs. Computer simulations using a PC model predicted that the elevated [Na(+)]i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca(2+) release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na(+)]i monotonically increased delayed afterdepolarization frequency. Confocal imaging experiments showed that postpacing Ca(2+) spark frequency was highest in intact CPVT PCs, but such differences were reversed on saponin-induced membrane permeabilization, indicating that differences in [Na(+)]i played a central role.
  
  
  
  In CPVT mice, the constitutive [Na(+)]i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: B Cicero
authors.initials: BC
authors.lastname: Willis
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Sandeep V
authors.initials: SV
authors.lastname: Pandit
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Daniela
authors.initials: D
authors.lastname: Ponce-Balbuena
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Manuel
authors.initials: M
authors.lastname: Zarzoso
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Guadalupe
authors.initials: G
authors.lastname: Guerrero-Serna
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Bijay
authors.initials: B
authors.lastname: Limbu
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Makarand
authors.initials: M
authors.lastname: Deo
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Camors
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Rafael J
authors.initials: RJ
authors.lastname: Ramirez
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Sergey
authors.initials: S
authors.lastname: Mironov
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Todd J
authors.initials: TJ
authors.lastname: Herron
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.).
authors.forename: Héctor H
authors.initials: HH
authors.lastname: Valdivia
authors.affiliation: From University of Michigan, Ann Arbor (B.C.W., S.V.P., D.P.-B., M.Z., G.G.-S., R.J.R., S.M., T.J.H., H.H.V., J.J.); Norfolk State University, VA (B.L., M.D.); University of Tennessee Health Science Center, Memphis (E.C.); and Fundación Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.). jjalife@umich.edu.
authors.forename: José
authors.initials: J
authors.lastname: Jalife
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling; D006801:Humans; D051379:Mice; D032383:Myocytes, Cardiac / Q000502:physiology*; D011689:Purkinje Cells; D012964:Sodium / Q000378:metabolism*; D017180:Tachycardia, Ventricular / Q000378:metabolism*; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D012964:Sodium; D002118:Calcium
keywords: arrhythmias, cardiac; calcium; calcium signaling; sodium-calcium exchanger