long-term efficacy study of sodium channel blocker in lqt3 patients

Conditions: Long QT Syndrome

Summary: the purpose of this study is to determine whether late sodium channel blockade might be effective in shortening the qtc interval in various lqt3 mutations and be considered as a safe therapeutic option for lqt3 patients.

long qt syndrome (lqts) is a genetic disorder characterized by prolongation of the qt interval in the electrocardiogram (ecg) and a propensity to torsade de pointes ventricular tachycardia frequently leading to syncope, cardiac arrest, or sudden death usually in young otherwise healthy individuals. the long qt syndrome is caused by mutations of predominantly potassium and sodium ion channel genes or channel-related proteins. the most common types of lqts affect: the slow delayed rectifier potassium repolarization channel (kcnq1; lqt1) resulting in a reduction in iks current; the rapid delayed rectifying potassium repolarization channel (kcnh2; lqt2) resulting in a reduction in ikr current; and the sodium channel (scn5a; lqt3) resulting in an increase in late ina current. among positively genotyped patients, lqt1 and lqt2 account for about 90% of lqts cases, whereas lqt3 accounts for about 5% to 8% of cases. lqt3 patients represent a challenging cohort of patients. unlike patients with lqt1 and lqt2 form of this disorder, the lqt3 patients have high lethality of cardiac events with 1 in 5 patients dying suddenly during their first syncopal or arrhythmic event. in childhood (age 0-18) in the analysis of 1,404 patients, lqt3 was found to be associated with significantly higher risk of aborted cardiac arrest or death than lqt1 and lqt2. a similar pattern is observed in lqts patients after age 40 in whom lqt3 patients show the highest risk. optimal therapy in lqt3 patients remains controversial. there are data showing that sodium current blockers including mexiletine and flecainide shorten qtc duration in lqt3 patients. ranolazine is a selective late sodium current inhibitor that has been also showed to reduce qtc in dkpq mutation and d1790g mutation patients. however, data on long-term effectiveness of ranolazine are limited. this single-blinded study evaluated a long-term effects of ranolazine on qtc duration in lqt3 patients with various lqt3 mutations. enrolled subjects are treated for 1 months with matching placebo and next for subsequent 5 months with ranolazine with ecg recorded at baseline, 1 , 2, and 6 months of follow-up.

Eligibility criteria:
inclusion criteria: * genotyped positive for lqt3 (scn5a) mutation * age 21 years or older * not currently taking an antiarrhythmic drug (beta blockers are allowed) * enrolled in lqts registry exclusion criteria: * age less than 21 years * not confirmed to have an lqt3 mutation * significant co-morbidity that would preclude subject's safe participation in this study * females who are pregnant or nursing * females of childbearing age who are not using acceptable method of birth control * evidence of prior sensitivity to ranolazine * hepatic or renal disease that might adversely affect ranolazine excretion * currently taking strong cyp3a inhibitors * currently taking p-gp inhibitors * currently taking cyp3a inducers * in vitro studies of specific mutation show no effect of ranolazine on late sodium current kinetics or show repolarization prolongation

Keywords: ranolazine clinical trial