Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: Insights from a RyR2 R4496C knock-in mouse model

Nian Liu, Barbara Colombi, Mirella Memmi, Spyros Zissimopoulos, Nicoletta Rizzi, Sara Negri, Marcello Imbriani, Carlo Napolitano, F. Anthony Lai, Silvia G. Priori

Research output: Contribution to journalArticlepeer-review


Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited disease characterized by life threatening arrhythmias and mutations in the gene encoding the ryanodine receptor (RyR2). Disagreement exists on whether (1) RyR2 mutations induce abnormal calcium transients in the absence of adrenergic stimulation; (2) decreased affinity of mutant RyR2 for FKBP12.6 causes CPVT; (3) K201 prevent arrhythmias by normalizing the FKBP12.6-RyR2 binding. We studied ventricular myocytes isolated from wild-type (WT) and knock-in mice harboring the R4496C mutation (RyR2). Pacing protocols did not elicit delayed afterdepolarizations (DADs) (n=20) in WT but induced DADs in 21 of 33 (63%) RyR2 myocytes (P=0.001). Superfusion with isoproterenol (30 nmol/L) induced small DADs (45%) and no triggered activity in WT myocytes, whereas it elicited DADs in 87% and triggered activity in 60% of RyR2 myocytes (P=0.001). DADs and triggered activity were abolished by ryanodine (10 μmol/L) but not by K201 (1 μmol/L or 10 μmol/L). In vivo administration of K201 failed to prevent induction of polymorphic ventricular tachycardia (VT) in RyR2 mice. Measurement of the FKBP12.6/RyR2 ratio in the heavy sarcoplasmic reticulum membrane showed normal RyR2-FKBP12.6 interaction both in WT and RyR2 either before and after treatment with caffeine and epinephrine. We suggest that (1) triggered activity is the likely arrhythmogenic mechanism of CPVT; (2) K201 fails to prevent DADs in RyR2 myocytes and ventricular arrhythmias in RyR2 mice; and (3) RyR2-FKBP12.6 interaction in RyR2 is identical to that of WT both before and after epinephrine and caffeine, thus suggesting that it is unlikely that the R4496C mutation interferes with the RyR2/FKBP12.6 complex.

Original languageEnglish
Pages (from-to)292-298
Number of pages7
JournalCirculation Research
Issue number3
Publication statusPublished - Aug 2006


  • Cardiac electrophysiology
  • Ryanodine receptor
  • Sudden death
  • Transgenic mice
  • Ventricular tachycardia

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


Dive into the research topics of 'Arrhythmogenesis in catecholaminergic polymorphic ventricular tachycardia: Insights from a RyR2 R4496C knock-in mouse model'. Together they form a unique fingerprint.

Cite this