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

Ehud Chorin, Dan Hu, Charles Antzelevitch, Aviram Hochstadt, Luiz Belardinelli, David Zeltser, Hector Barajas-Martinez, Uri Rozovski, Raphael Rosso, Arnon Adler, Jesaia Benhorin, Sami Viskin

Research output: Contribution to journalArticlepeer-review

23 Scopus citations


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.

Original languageEnglish
JournalCirculation: Arrhythmia and Electrophysiology
Issue number10
StatePublished - 1 Oct 2016


FundersFunder number
National Heart, Lung, and Blood InstituteR01HL047678


    • action potential
    • bradycardia
    • long-QT syndrome
    • ranolazine
    • torsade de pointes


    Dive into the research topics of 'Ranolazine for Congenital Long-QT Syndrome Type III: Experimental and Long-Term Clinical Data'. Together they form a unique fingerprint.

    Cite this