The direct actions of flecainide on the human cardiac ryanodine receptor: keeping open the debate on the mechanism of action of local anesthetics in CPVT

Godfrey L. Smith*, Niall MacQuaide

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Citations (Scopus)


Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare but particularly disabling disease that manifests as spontaneous transition to VT associated with increased sympathetic activity. In 2 variants of this disease (CPVT1 and CPVT2), the abnormal electric activity of the heart is associated with genetic defects in the coding of either the ryanodine receptor (type 1) or a related sarcoplasmic reticulum (SR) protein, calsequestrin (type 2). For those cases (20%–30%) unresponsive to β-blocker treatment there were few options available to mitigate the risk of VT/VF (ventricular tachycardia/ventricular fibrillation). However, an article published by the Knollman group1 in 2009 indicated that these individuals may respond to the class 1 antiarrhythmic drug flecainide, which has an anesthetic action via inhibition of INa. The article provided evidence that in the case of CPVT, its antiarrhythmic action was not via inhibition of INa, but instead via inhibition of the activity of the cardiac ryanodine receptor (RyR2) and subsequent reduction in the proarrhythmic release of Ca2+ during diastole. This interpretation was supported by further work by the Knollman and his collaborators,2,3 in particular, the demonstration of direct effects of flecainide and the related more potent local anesthetic R-propafenone3 on SR Ca2+ release in permeabilized cardiac muscle preparations. However, the interpretation of this result is controversial. Two independent groups4,5 have failed to reproduce the effects of flecainide on RyR2 activity in either normal ventricular myocardium5 or a mouse model of CPVT1.4 The first group reported effects of flecainide that are entirely consistent with a direct action on the excitability of cardiac muscle via INa,4 whereas the second produced evidence that the antiarrhythmic effect is by depressed Na+ influx through INa and the subsequent effects on cytoplasmic Ca2+ via the Na+/Ca2+ exchanger.5 To date this issue remains unresolved. A detailed mechanistic view of the action of flecainide is essential to design new strategies to counter CPVT. RyR2 inhibition may be a suitable target for drug design, but the form of inhibition is unclear because a novel drug known to depress RyR2 (JTV 519) has been reported to be ineffective at suppressing the CPVT phenotype in some cases.6 This makes a detailed analysis of the interaction of flecainide with RyR2, a priority for advancement in this area.
Original languageEnglish
Pages (from-to)1284-1286
Number of pages3
JournalCirculation Research
Issue number8
Publication statusPublished - 10 Apr 2015


  • Animals
  • Anti-Arrhythmia Agents/pharmacology
  • Flecainide/pharmacology
  • Humans
  • Male
  • Myocytes, Cardiac/drug effects
  • Ryanodine Receptor Calcium Release Channel/drug effects
  • Tachycardia, Ventricular/drug therapy
  • Voltage-Gated Sodium Channel Blockers/pharmacology
  • Heart
  • Ryanodine receptor calcium release channel
  • Sarcoplasmic reticulum
  • Polymorphic catecholergic ventricular tachycardia
  • Editorials
  • Flecainide


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