Abstract 9171: An Increase in Late Sodium Current Causes Junctional Tachycardia in Mice Expressing an LQT3 SCN5A Mutant Na+ Channel
Background: Junctional tachycardia (JT) is predominantly seen in young patients, where it is associated with significant morbidity and mortality and poor response to drug therapy. We documented JT in mice with the cardiac gain-of-function SCN5A mutation N1325S and its inhibition by ranolazine, suggesting that enhancement of the late Na+ current (late INa) is a novel cause of JT.
Methods: In N1325S mutant and wild type mice, an eight-channel surface ECG was recorded weekly for 15 weeks. Intracardiac electrograms from catheterization of intact animals and studies of isolated hearts were performed.
Results: JT occurred in an age-dependent manner in N1325S mutant but not in wild type mice. The number of N1325S mice with JT increased from 0 % at 3 weeks or less of age to 13.7, 46.6, 79.3, 89.1 and 100 % at 4, 5, 7, 10 and 15 weeks of age, respectively, and heart rate (HR) increased from 520±22 bpm at 5 weeks to 598±14 bpm at 15 weeks (n=58, p<0.01). In contrast, in littermate wild type mice HR was 463±12 bpm and sinus rhythm was maintained. HR was significantly higher at all ages in N1325S mice with JT than in wild type mice (n=45, p<0.01). JT in N1325S mouse isolated hearts and in intact animals could not be terminated by programmed atrial stimulation (n=7), suggesting that reentry is unlikely to be the mechanism underlying the JT. In isolated hearts, the late INa inhibitors ranolazine (1-30 µM, n=6), TTX (0.1-1 µM, n=8) and flecainide (0.1-1 µM, n=3) slowed the rate of the JT and converted JT to sinus rhythm in a concentration-dependent manner. Results from the intracardiac EP study confirmed the JT in N1325S mice, and the JT was terminated by intraperitoneal administration of ranolazine (15-30 mg/kg).
Conclusion: The gain-of-function cardiac SCN5A mutation N1325S is associated with JT in mice. An enhanced late INa is a novel mechanism for JT. Drugs that inhibit late INa may be effective in treating JT in patients with enhanced late INa.
- Arrhythmias, treatment of
- Supraventricular tachycardia
- Sodium channel
- Transgenic models
- © 2011 by American Heart Association, Inc.