Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data

The basic defect in long-QT syndrome type III (LQT3) is an excessive inflow of sodium current during phase 3 of the action potential caused by mutations in the SCN5A gene. Most sodium channel blockers reduce the early (peak) and late components of the sodium current (I_Na and I_NaL), but ranolazine preferentially reduces I_NaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A.

We performed an experimental study of ranolazine in TSA201 cells expressing the D1790G mutation. We then performed a long-term clinical evaluation of ranolazine in LQT3 patients carrying the D1790G mutation. In the experimental study, I_NaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of I_NaL of the SCN5A-D1790G channel without reducing peak I_Na significantly. In the clinical study, among 8 patients with LQT3 and confirmed D1790G mutation, ranolazine had no effects on the sinus rate or QRS width but shortened the QTc from 509±41 to 451±26 ms, a mean decrease of 56±52 ms (10.6%; P=0.012). The QT-shortening effect of ranolazine remained effective throughout the entire study period of 22.8±12.8 months. Ranolazine reduced the QTc at all heart rates but less so during extreme nocturnal bradycardia. A type I Brugada ECG was never noticed.

Ranolazine blocks I_NaL in experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3 patients.

URL: https://clinicaltrials.gov; Unique identifier: NCT01728025.