{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T18:15:18Z","timestamp":1790014518482,"version":"4.0.1"},"reference-count":45,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"24","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2016,6,14]]},"abstract":"<jats:sec>\n                    <jats:title>Background\u2014<\/jats:title>\n                    <jats:p>\n                      In catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac Purkinje cells (PCs) appear more susceptible to Ca\n                      <jats:sup>2+<\/jats:sup>\n                      dysfunction than ventricular myocytes (VMs). The underlying mechanisms remain unknown. Using a CPVT mouse (RyR2\n                      <jats:sup>R4496C+\/Cx40eGFP<\/jats:sup>\n                      ), we tested whether PC intracellular Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ([Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      ) dysregulation results from a constitutive [Na\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      surplus relative to VMs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and Results\u2014<\/jats:title>\n                    <jats:p>\n                      Simultaneous optical mapping of voltage and [Ca\n                      <jats:sup>2+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      in CPVT hearts showed that spontaneous Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release preceded pacing-induced triggered activity at subendocardial PCs. On simultaneous current-clamp and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      imaging, early and delayed afterdepolarizations trailed spontaneous Ca\n                      <jats:sup>2+<\/jats:sup>\n                      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\n                      <jats:sup>2+<\/jats:sup>\n                      load, measured by caffeine-induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      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\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      was higher in both control and CPVT PCs than VMs, whereas the density of the Na\n                      <jats:sup>+<\/jats:sup>\n                      \/Ca\n                      <jats:sup>2+<\/jats:sup>\n                      exchanger current was not different between PCs and VMs. Computer simulations using a PC model predicted that the elevated [Na\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca\n                      <jats:sup>2+<\/jats:sup>\n                      release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      monotonically increased delayed afterdepolarization frequency. Confocal imaging experiments showed that postpacing Ca\n                      <jats:sup>2+<\/jats:sup>\n                      spark frequency was highest in intact CPVT PCs, but such differences were reversed on saponin-induced membrane permeabilization, indicating that differences in [Na\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      played a central role.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\u2014<\/jats:title>\n                    <jats:p>\n                      In CPVT mice, the constitutive [Na\n                      <jats:sup>+<\/jats:sup>\n                      ]\n                      <jats:sub>i<\/jats:sub>\n                      excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circulationaha.116.021936","type":"journal-article","created":{"date-parts":[[2016,5,12]],"date-time":"2016-05-12T00:19:05Z","timestamp":1463012345000},"page":"2348-2359","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":26,"title":["Constitutive Intracellular Na\n                    <sup>+<\/sup>\n                    Excess in Purkinje Cells Promotes Arrhythmogenesis at Lower Levels of Stress Than Ventricular Myocytes From Mice With Catecholaminergic Polymorphic Ventricular Tachycardia"],"prefix":"10.1161","volume":"133","author":[{"given":"B. Cicero","family":"Willis","sequence":"first","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandeep V.","family":"Pandit","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Ponce-Balbuena","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuel","family":"Zarzoso","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guadalupe","family":"Guerrero-Serna","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bijay","family":"Limbu","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Makarand","family":"Deo","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel","family":"Camors","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael J.","family":"Ramirez","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Mironov","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd J.","family":"Herron","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e9ctor H.","family":"Valdivia","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Jalife","sequence":"additional","affiliation":[{"name":"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 Fundaci\u00f3n Centro Nacional de Investigaciones Cardiovasculares, Madrid, Spain (J.J.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.91.5.1512"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrcardio.2012.93"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.103.2.196"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1086\/324565"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds104"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1111\/febs.13184"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000235869.50747.e1"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00779.2011"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.107.148064"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.110.221481"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2010.06.010"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1540-8167.2012.02406.x"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2009.09.017"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.126714"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.262535"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2006.121475"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1161\/hh1601.095894"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2012.10.002"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.0000016701.85760.97"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000173375.26489.fe"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(03)74758-4"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000192146.85173.4b"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.109.202267"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01138.2000"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cardiores.2007.04.010"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10974-007-9109-6"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.107.754051"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1986.sp016040"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.0000169067.51055.72"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-3495(82)84474-3"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA.111.246512"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCEP.109.928820"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1159\/000079666"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.36.3.497"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.hrthm.2011.01.013"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/415198a"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.RES.86.4.448"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.105.557561"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199702203360805"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.99.9.1265"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.1989.256.4.C813"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.2014.281204"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1113\/jphysiol.1988.sp017046"},{"key":"e_1_3_4_45_2","first-page":"H996","article-title":"Acidosis depresses delayed afterdepolarization in guinea pig myocardium.","volume":"257","author":"Yano T","year":"1989","unstructured":"Yano T, Hotokebuchi N, Morioka T, Nishi K. 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