Effects of flecainide in patients with new SCN5A mutation: Mutation-specific therapy for long-QT syndrome?

• Published in: Circulation (New York, N.Y.) N.Y.), 2000-04, Vol.101 (14), p.1698-1706
• Main Authors: BENHORIN, J, TAUB, R, GOLDMIT, M, KEREM, B, KASS, R. S, WINDMAN, I, MEDINA, A
• Format: Article
• Language: English
• Subjects: Anti-Arrhythmia Agents - therapeutic use; Antiarythmic agents; Biological and medical sciences; Cardiovascular system; Case-Control Studies; Electrocardiography; Female; Flecainide - therapeutic use; Heart - drug effects; Heart - physiopathology; Heterozygote; Humans; Injections, Intravenous; Lidocaine - therapeutic use; Long QT Syndrome - drug therapy; Long QT Syndrome - genetics; Long QT Syndrome - physiopathology; Male; Medical sciences; Mutation; NAV1.5 Voltage-Gated Sodium Channel; Pedigree; Pharmacology. Drug treatments; Sodium Channels - genetics
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/01.CIR.101.14.1698

Mutations in the cardiac sodium channel gene (SCN5A) can cause one variant of the congenital long-QT syndrome. The effects of some of these mutations on the alpha-subunit channel properties can be blocked by type Ib antiarrhythmic drugs. Recently, we have described a new SCN5A mutation (D1790G) that affects the channel properties in a manner suggesting that sodium blockers of the Ib type will be ineffective in carriers of this mutation. Hence, the ECG effects of flecainide-acetate, a type Ic sodium blocker, were evaluated in carriers of this mutation. Eight asymptomatic mutation carriers and 5 control subjects were studied. Intravenous lidocaine was tested first in only 2 mutation carriers and had no significant effect on any ECG parameter. Flecainide significantly shortened all heart rate-corrected repolarization duration parameters only in carriers and not in control subjects: QT(c) shortened by 9.5% (from 517+/-45 to 468+/-36 ms, P=0.011), and the S-offset to T-onset interval shortened by 64.7% (from 187+/-88 to 66+/-50 ms, P=0.0092). Flecainide also normalized the marked baseline repolarization dispersion in most mutation carriers. These effects among carriers were maintained during long-term (9 to 17 months) outpatient flecainide therapy with no adverse effects. This report is the first to describe SCN5A mutation carriers who significantly responded to flecainide therapy yet did not respond to lidocaine. These results have important implications for long-QT allele-specific therapeutic strategies.