Inhibition of Cardiac Ca2+ Release Channels (RyR2) Determines Efficacy of Class I Antiarrhythmic Drugs in Catecholaminergic Polymorphic Ventricular Tachycardia
Küçük Resim Yok
Tarih
2011
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
Lippincott Williams & Wilkins
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Background-Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by mutations in the cardiac ryanodine receptor (RyR2) or calsequestrin (Casq2) and can be difficult to treat. The class Ic antiarrhythmic drug flecainide blocks RyR2 channels and prevents CPVT in mice and humans. It is not known whether other class I antiarrhythmic drugs also block RyR2 channels and to what extent RyR2 channel inhibition contributes to antiarrhythmic efficacy in CPVT. Methods and Results-We first measured the effect of all class I antiarrhythmic drugs marketed in the United States (quinidine, procainamide, disopyramide, lidocaine, mexiletine, flecainide, and propafenone) on single RyR2 channels incorporated into lipid bilayers. Only flecainide and propafenone inhibited RyR2 channels, with the S-enantiomer of propafenone having a significantly lower potency than R-propafenone or flecainide. In Casq2(-/-) myocytes, the propafenone enantiomers and flecainide significantly reduced arrhythmogenic Ca2+ waves at clinically relevant concentrations, whereas Na+ channel inhibitors without RyR2 blocking properties did not. In Casq2(-/-) mice, 5 mg/kg R-propafenone or 20 mg/kg S-propafenone prevented exercise-induced CPVT, whereas procainamide (20 mg/kg) or lidocaine (20 mg/kg) were ineffective (n = 5 to 9 mice, P < 0.05). QRS duration was not significantly different, indicating a similar degree of Na+ channel inhibition. Clinically, propafenone (900 mg/d) prevented ICD shocks in a 22-year-old CPVT patient who had been refractory to maximal standard drug therapy and bilateral stellate ganglionectomy. Conclusions-RyR2 cardiac Ca2+ release channel inhibition appears to determine efficacy of class I drugs for the prevention of CPVT in Casq2(-/-) mice. Propafenone may be an alternative to flecainide for CPVT patients symptomatic on beta-blockers. (Circ Arrhythm Electrophysiol. 2011;4:128-135.)
Açıklama
Anahtar Kelimeler
class I antiarrhythmic drugs, propafenone, RyR2, catecholaminergic polymorphic ventricular tachycardia, flecainide, ranolazine, tetrodotoxin, quinidine, procainamide, disopyramide, lidocaine, mexiletine
Kaynak
Circulation-Arrhythmia and Electrophysiology
WoS Q Değeri
Q1
Scopus Q Değeri
Cilt
4
Sayı
2
