title: Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data.
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 (INaand INaL), but ranolazine preferentially reduces INaL. We, therefore, evaluated the effects of ranolazine in LQT3 caused by the D1790G mutation in SCN5A.
  
  
  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, INaLwas significantly higher in D1790G than in wild-type channels expressed in the TSA201 cells. Ranolazine exerted a concentration-dependent block of INaLof the SCN5A-D1790G channel without reducing peak INasignificantly. 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 INaLin experimental models of LQT3 harboring the SCN5A-D1790G mutation and shortened the QT interval of LQT3 patients.
  
  
  BACKGROUND
  URL: https://clinicaltrials.gov; Unique identifier: NCT01728025.
authors.affiliation: 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.).
authors.forename: Ehud
authors.initials: E
authors.lastname: Chorin
authors.affiliation: 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.).
authors.forename: Dan
authors.initials: D
authors.lastname: Hu
authors.affiliation: 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.).
authors.forename: Charles
authors.initials: C
authors.lastname: Antzelevitch
authors.affiliation: 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.).
authors.forename: Aviram
authors.initials: A
authors.lastname: Hochstadt
authors.affiliation: 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.).
authors.forename: Luiz
authors.initials: L
authors.lastname: Belardinelli
authors.affiliation: 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.).
authors.forename: David
authors.initials: D
authors.lastname: Zeltser
authors.affiliation: 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.).
authors.forename: Hector
authors.initials: H
authors.lastname: Barajas-Martinez
authors.affiliation: 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.).
authors.forename: Uri
authors.initials: U
authors.lastname: Rozovski
authors.affiliation: 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.).
authors.forename: Raphael
authors.initials: R
authors.lastname: Rosso
authors.affiliation: 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.).
authors.forename: Arnon
authors.initials: A
authors.lastname: Adler
authors.affiliation: 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.).
authors.forename: Jesaia
authors.initials: J
authors.lastname: Benhorin
authors.affiliation: 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.
authors.forename: Sami
authors.initials: S
authors.lastname: Viskin
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004562:Electrocardiography; D005260:Female; D006801:Humans; D007557:Israel; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D010641:Phenotype; D000069458:Ranolazine / Q000627:therapeutic use*; D026941:Sodium Channel Blockers / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D000069458:Ranolazine
keywords: action potential; bradycardia; long-QT syndrome; ranolazine; torsade de pointes