Purkinje cell calcium dysregulation is the cellular mechanism that underlies catecholaminergic polymorphic ventricular tachycardia

Todd J. Herron, Michelle L. Milstein, Justus Anumonwo, Silvia G. Priori, José Jalife

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Inherited arrhythmias can be caused by mutations in the cardiac ryanodine receptor (RyR2). The cellular source of these arrhythmias is unknown. Isolated RyR2R4496C mouse ventricular myocytes display arrhythmogenic activity related to spontaneous Ca2+ release during diastole. On the other hand, recent whole-heart epicardial and endocardial optical mapping data demonstrate that ventricular arrhythmias in the RyR2 R4496C mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT) originate in the His-Purkinje system, suggesting that Purkinje cells, and not ventricular myocytes, may be the cellular source of arrhythmogenic activity. The relative effect of the RyR2R4496C mutation on calcium homeostasis in ventricular myocytes versus Purkinje cells is unknown. Objective: This study sought to determine which cardiac cell type is more severely affected, in terms of calcium handling, by expression of the RyR2R4496C mutant channel: the ventricular myocytes or the Purkinje cells. Methods and Results: To discriminate Purkinje cells from ventricular myocytes, we crossed the RyR2R4496C mouse model of CPVT with the Cx40EGFP/+ transgenic mouse. This genetic cross yields Purkinje cells that express eGFP, and therefore fluoresce green when excited by the appropriate wavelength; ventricular myocytes, which do not express connexin 40, are not green. Intracellular calcium was measured in each cell type using calcium-sensitive probes. Purkinje cells of the RyR2R4496C mouse model of CPVT show an approximately 2× greater rate (P <.05) and approximately 2× to 3× greater amplitude (P <.000001) of spontaneous calcium release events than ventricular myocytes isolated from the same heart. Conclusion: These results demonstrate that focally activated arrhythmias originate in the specialized electrical conducting cells of the His-Purkinje system in the RyR2R4496C mouse model of CPVT.

Original languageEnglish
Pages (from-to)1122-1128
Number of pages7
JournalHeart Rhythm
Volume7
Issue number8
DOIs
Publication statusPublished - 2010

Keywords

  • Calcium
  • Cardiac Purkinje cells
  • Inherited arrhythmias
  • Molecular mechanisms of arrhythmia
  • Ryanodine receptor
  • Ventricular cardiac myocytes

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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