Ranolazine for Congenital Long-QT Syndrome Type III

The long-QT syndrome (LQTS) type III (LQT3) is the third most common variant of the congenital LQTS. LQT3 differs from the more common (LQT1 and LQT2) variants of LQTS by important clinical and electrophysiological characteristics: (1) Patients with LQT3 develop arrhythmias less often, but these are more likely to be lethal when they ultimately occur. (2) In contrast to LQT1 and LQT2 patients, who develop arrhythmias primarily during stress or sudden startling, patients with LQT3 typically develop arrhythmias at rest, often while asleep. (3) Experimental models of LQTS suggest that heart rate slowing is particularly arrhythmogenic in LQT3 and β-adrenergic stimulation (rather than β-blockade) is antiarrhythmic in LQT3. Consequently, clinicians are often reluctant to initiate β-blocker therapy in patients with LQT3 who are not protected from bradycardia by cardiac pacing. The basic electrophysiological defect in LQT3 is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Thus, sodium channel blockers, including lidocaine, mexiletine, and flecainide, have been tested in LQT3. Specifically, in a large family with LQT3 caused by the D1790G mutation described in Israel, Benhorin et al demonstrated impressive QT-shortening effects with flecainide therapy. The enthusiasm to treat LQT3 patients with flecainide lessened, however, after reports of flecainide-induced Brugada pattern in patients with LQT3. Concern about this potentially proarrhythmic effect of flecainide in LQT3 increased when the same D1790G mutation described by Benhorin et al in patients with LQT3 was recognized in patients with a spontaneous type I Brugada ECG in the absence of drug therapy. Ranolazine is a relatively new medication (approved for the treatment of angina pectoris) that has unique electrophysiological properties. As opposed to other sodium channel blockers, which reduce both the early (peak) and late components of the sodium current (I Na and I NaL , respectively)