TY - JOUR
T1 - Ranolazine for Congenital Long-QT Syndrome Type III
AU - Chorin, Ehud
AU - Hu, Dan
AU - Antzelevitch, Charles
AU - Hochstadt, Aviram
AU - Belardinelli, Luiz
AU - Zeltser, David
AU - Barajas-Martinez, Hector
AU - Rozovski, Uri
AU - Rosso, Raphael
AU - Adler, Arnon
AU - Benhorin, Jesaia
AU - Viskin, Sami
N1 - Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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 (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. 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, 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. Conclusions - Ranolazine blocks I NaL 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.
AB - 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 (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. 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, 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. Conclusions - Ranolazine blocks I NaL 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.
KW - action potential
KW - bradycardia
KW - long-QT syndrome
KW - ranolazine
KW - torsade de pointes
UR - http://www.scopus.com/inward/record.url?scp=84992109112&partnerID=8YFLogxK
U2 - 10.1161/CIRCEP.116.004370
DO - 10.1161/CIRCEP.116.004370
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AN - SCOPUS:84992109112
SN - 1941-3149
VL - 9
JO - Circulation: Arrhythmia and Electrophysiology
JF - Circulation: Arrhythmia and Electrophysiology
IS - 10
M1 - e004370
ER -