Constitutive intracellular Na+excess in purkinje cells promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia

B. Cicero Willis, Sandeep V. Pandit, Daniela Ponce-Balbuena, Manuel Zarzoso, Guadalupe Guerrero-Serna, Bijay Limbu, Makarand Deo, Emmanuel Camors, Rafael J. Ramirez, Sergey Mironov, Todd J. Herron, Héctor H. Valdivia, José Jalife

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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 (RyR2 R4496C+/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. [Na+] 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 [Na+] i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca2+ release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na+] 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 [Na+] i played a central role. Conclusions - In CPVT mice, the constitutive [Na+] i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.

Original languageEnglish (US)
Pages (from-to)2348-2359
Number of pages12
JournalCirculation
Volume133
Issue number24
DOIs
StatePublished - Jun 14 2016

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Purkinje Cells
Muscle Cells
Ryanodine Receptor Calcium Release Channel
Sarcoplasmic Reticulum
Polymorphic catecholergic ventricular tachycardia
Ventricular Dysfunction
Saponins
Caffeine
Computer Simulation

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Constitutive intracellular Na+excess in purkinje cells promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia. / Willis, B. Cicero; Pandit, Sandeep V.; Ponce-Balbuena, Daniela; Zarzoso, Manuel; Guerrero-Serna, Guadalupe; Limbu, Bijay; Deo, Makarand; Camors, Emmanuel; Ramirez, Rafael J.; Mironov, Sergey; Herron, Todd J.; Valdivia, Héctor H.; Jalife, José.

In: Circulation, Vol. 133, No. 24, 14.06.2016, p. 2348-2359.

Research output: Contribution to journalArticle

Willis, BC, Pandit, SV, Ponce-Balbuena, D, Zarzoso, M, Guerrero-Serna, G, Limbu, B, Deo, M, Camors, E, Ramirez, RJ, Mironov, S, Herron, TJ, Valdivia, HH & Jalife, J 2016, 'Constitutive intracellular Na+excess in purkinje cells promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia', Circulation, vol. 133, no. 24, pp. 2348-2359. https://doi.org/10.1161/CIRCULATIONAHA.116.021936
Willis, B. Cicero ; Pandit, Sandeep V. ; Ponce-Balbuena, Daniela ; Zarzoso, Manuel ; Guerrero-Serna, Guadalupe ; Limbu, Bijay ; Deo, Makarand ; Camors, Emmanuel ; Ramirez, Rafael J. ; Mironov, Sergey ; Herron, Todd J. ; Valdivia, Héctor H. ; Jalife, José. / Constitutive intracellular Na+excess in purkinje cells promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia. In: Circulation. 2016 ; Vol. 133, No. 24. pp. 2348-2359.
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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 (RyR2 R4496C+/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. [Na+] 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 [Na+] i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca2+ release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na+] 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 [Na+] i played a central role. Conclusions - In CPVT mice, the constitutive [Na+] i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.",
author = "Willis, {B. Cicero} and Pandit, {Sandeep V.} and Daniela Ponce-Balbuena and Manuel Zarzoso and Guadalupe Guerrero-Serna and Bijay Limbu and Makarand Deo and Emmanuel Camors and Ramirez, {Rafael J.} and Sergey Mironov and Herron, {Todd J.} and Valdivia, {H{\'e}ctor H.} and Jos{\'e} Jalife",
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T1 - Constitutive intracellular Na+excess in purkinje cells promotes arrhythmogenesis at lower levels of stress than ventricular myocytes from mice with catecholaminergic polymorphic ventricular tachycardia

AU - Willis, B. Cicero

AU - Pandit, Sandeep V.

AU - Ponce-Balbuena, Daniela

AU - Zarzoso, Manuel

AU - Guerrero-Serna, Guadalupe

AU - Limbu, Bijay

AU - Deo, Makarand

AU - Camors, Emmanuel

AU - Ramirez, Rafael J.

AU - Mironov, Sergey

AU - Herron, Todd J.

AU - Valdivia, Héctor H.

AU - Jalife, José

PY - 2016/6/14

Y1 - 2016/6/14

N2 - 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 (RyR2 R4496C+/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. [Na+] 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 [Na+] i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca2+ release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na+] 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 [Na+] i played a central role. Conclusions - In CPVT mice, the constitutive [Na+] i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.

AB - 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 (RyR2 R4496C+/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. [Na+] 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 [Na+] i of PCs promoted delayed afterdepolarizations, which were always preceded by spontaneous Ca2+ release events from hyperactive ryanodine receptor type 2 channels. Increasing [Na+] 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 [Na+] i played a central role. Conclusions - In CPVT mice, the constitutive [Na+] i excess of PCs promotes triggered activity and arrhythmogenesis at lower levels of stress than VMs.

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