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Mutant ryanodine receptors in catecholaminergic polymorphic ventricular tachycardia generate delayed

Jere Paavola1, Matti Viitasalo, Päivi J Laitinen-Forsblom

  • 1Minerva Foundation Institute for Medical Research, FIN-00290, Helsinki, Finland.

European Heart Journal
|March 10, 2007
PubMed
Abstract

Insights

Mutations in cardiac ryanodine receptors (RyR2s) cause catecholaminergic polymorphic ventricular tachycardia (CPVT). Increased RyR2 sensitivity to cAMP leads to spontaneous calcium release, explaining CPVT arrhythmias during stress.

Area of Science:

  • Cardiovascular Research
  • Molecular Cardiology
  • Genetics of Arrhythmias

Background:

  • Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a life-threatening arrhythmia linked to cardiac ryanodine receptor (RyR2) mutations.
  • These mutations cause gain-of-function defects in RyR2, but the precise cellular mechanisms of arrhythmogenesis remain unclear.

Purpose of the Study:

  • To investigate the cellular mechanisms underlying CPVT arrhythmias caused by RyR2 mutations.
  • To determine if altered RyR2 function in response to cAMP contributes to delayed afterdepolarizations (DADs) observed in CPVT patients.

Main Methods:

  • Monophasic action potentials (MAPs) were recorded from CPVT patients and controls during epinephrine infusion.
  • Wild-type and mutant RyR2s (P2,328S, V4,653F) were expressed in HEK 293 cells.
  • Subcellular calcium (Ca2+) release events were monitored using confocal microscopy and Fluo-3 fluorescence.

Main Results:

  • CPVT patients exhibited DADs and ventricular premature complexes during epinephrine infusion, unlike controls.
  • Mutant RyR2-expressing cells showed spontaneous Ca2+ release events (sparks and waves) at lower cAMP concentrations compared to wild-type RyR2.
  • Dioctanoyl-cAMP triggered Ca2+ release in both mutant and wild-type RyR2 expressing cells, but with increased propensity in mutants.

Conclusions:

  • DADs in CPVT patients are associated with premature action potentials.
  • Abnormal RyR2s have an increased propensity to generate spontaneous Ca2+ waves upon cAMP stimulation, leading to DADs.
  • Enhanced RyR2 sensitivity to cAMP likely explains CPVT arrhythmias during stress.

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