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

Todd J Herron1, Michelle L Milstein, Justus Anumonwo

  • 1Center for Arrhythmia Research, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48108, USA. toddherr@umich.edu

Heart Rhythm
|June 12, 2010
PubMed
Abstract

Insights

Mutations in the cardiac ryanodine receptor (RyR2) cause inherited arrhythmias. This study found that Purkinje cells, not ventricular myocytes, are the primary source of these arrhythmias in a mouse model, due to more severe calcium handling defects.

Area of Science:

  • Cardiovascular Physiology
  • Cardiac Electrophysiology
  • Molecular Cardiology

Background:

  • Inherited arrhythmias can stem from mutations in the cardiac ryanodine receptor (RyR2).
  • The precise cellular origin of these arrhythmias remains unclear.
  • Previous studies suggest the His-Purkinje system, not ventricular myocytes, may be the source in the RyR2(R4496C) mouse model of catecholaminergic polymorphic ventricular tachycardia (CPVT).

Purpose of the Study:

  • To investigate whether ventricular myocytes or Purkinje cells are more significantly impacted by the RyR2(R4496C) mutation concerning calcium handling.
  • To identify the specific cardiac cell type responsible for arrhythmogenic activity in the RyR2(R4496C) mouse model.

Main Methods:

  • Utilized a genetic cross between the RyR2(R4496C) CPVT mouse model and Cx40(EGFP/+) transgenic mice to distinguish Purkinje cells (eGFP positive) from ventricular myocytes.
  • Employed calcium-sensitive probes to measure intracellular calcium dynamics in isolated Purkinje cells and ventricular myocytes.
  • Analyzed the rate and amplitude of spontaneous calcium release events in both cell types.

Main Results:

  • Purkinje cells from RyR2(R4496C) mice exhibited a significantly higher rate (approximately 2x) and amplitude (approximately 2-3x) of spontaneous calcium release compared to ventricular myocytes.
  • These findings were statistically significant (P < .05 for rate, P < .000001 for amplitude).

Conclusions:

  • The RyR2(R4496C) mutation more severely affects calcium handling in Purkinje cells than in ventricular myocytes.
  • These results confirm that arrhythmias in this CPVT model originate focally within the specialized conducting cells of the His-Purkinje system.

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