Ehud Chorin1, Dan Hu1, Charles Antzelevitch1, Aviram Hochstadt1, Luiz Belardinelli1, David Zeltser1, Hector Barajas-Martinez1, Uri Rozovski1, Raphael Rosso1, Arnon Adler1, Jesaia Benhorin1, Sami Viskin2. 1. From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.). 2. From the Tel Aviv Sourasky Medical Center and Sackler School of Medicine, Tel Aviv University, Israel (E.C., A.H., D.Z., U.R., R.R., A.A., J.B., S.V.); Masonic Medical Research Laboratory, Utica, NY (D.H., C.A., H.B.-M.); Cardiovascular Research Program, Lankenau Institute for Medical Research, Wynnewood, PA (C.A.); and Gilead Sciences, Inc, Foster City, CA (L.B.). samiviskin@gmail.com.
Abstract
BACKGROUND: 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 (INa and INaL), but ranolazine preferentially reduces INaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A. METHODS AND RESULTS: 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, INaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of INaL of the SCN5A-D1790G channel without reducing peak INa 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. CONCLUSIONS: Ranolazine blocks INaL in experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3 patients. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT01728025.
BACKGROUND: 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 (INa and INaL), but ranolazine preferentially reduces INaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A. METHODS AND RESULTS: 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 LQT3patients carrying the D1790G mutation. In the experimental study, INaL was significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of INaL of the SCN5A-D1790G channel without reducing peak INa 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. CONCLUSIONS:Ranolazine blocks INaL in experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3patients. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov; Unique identifier: NCT01728025.
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