Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition.

BACKGROUND: The prevalence of genetic risk factors has not been systematically evaluated in the setting of complete atriventricular (AV) block complicated by long QT syndrome (LQTS). OBJECTIVE: This study was performed to determine to what extent acquired LQTS in the context of AV block has a genetic substrate. METHODS: Among 420 recipients of pacemakers implanted over a 3-year period, we identified retrospectively 29 patients with complete AV block and a QT interval >600 ms in duration. A second study group included 22 randomly selected patients who had AV block and a QT interval <600 ms. Normal controls were 100 consecutive individuals without medical history. Genetic studies screening for HERG, KCNQ1 KCNE1, KCNE2, and SCN5A mutations were performed. RESULTS: We identified four mutations on genes encoding potassium channels in five patients with AV block and acquired LQTS. These mutations were not found among patients with AV block and a QT interval <600 ms in duration or in healthy volunteers. Functional expression of three HERG mutations (R328C, R696C, and R1047L) had a dominant negative effect on wild-type I(Kr). One KCNE2 mutation (R77W) identified in a patient treated with flecainide did not alter I(Kr). CONCLUSIONS: This study showed that complete AV block complicated by LQTS was associated with HERG mutations in 17% of cases. Further studies are needed to identify factors, genetic or environmental, which may be implicated in bradycardia-related abnormalities of ventricular repolarization.

The impact of acute myocardial ischemia on the ventricular defibrillation threshold during chronic oral azimilide therapy.

The effects of chronic oral azimilide therapy on the ventricular defibrillation threshold (DFT) during ischemia are unknown. The effects of azimilide on defibrillation efficacy under ischemic condition were investigated in a closed-chest animal model. Azimilide (20 mg/kg/d) was administered orally for 7 days to 10 pigs (20 to 25 kg). The control group (no treatment) comprised 15 pigs. A 2-lead defibrillation system was used. Each shock was delivered after 8 seconds of ventricular fibrillation. A step-up and step-down protocol was used to calculate mean DFT before and 10 minutes after coronary artery occlusion using an angioplasty balloon in the left descending artery. The basal DFT of the azimilide group did not differ from controls (20.8 +/- 4.8 versus 18.8 +/- 2.8; P = 0.33). After ischemia, the mean DFT of the azimilide-treated animals was similar to controls (21.8 +/- 5.2 versus 23.2 +/- 3.8 J; P = 0.54), despite significant lengthening of ventricular repolarisation (428.2 +/- 51.8 versus 494.1 +/- 46.6 msec; P = 0.005) and significant prolongation of the ventricular fibrillation cycle length (85.1 +/- 13 versus 104.7 +/- 24 msec; P < 0.04). Chronic oral azimilide treatment does not affect the DFT at baseline or during acute myocardial ischemia.