Ranolazine shortens repolarization in patients with sustained inward sodium current due to type-3 long-QT syndrome.
BACKGROUND
One form of the hereditary long-QT syndrome, LQT3-Delta KPQ, is associated with sustained inward sodium current during membrane depolarization. Ranolazine reduces late sodium channel current, and we hypothesized that ranolazine would have beneficial effects on electrical and mechanical cardiac function in LQT3 patients with the SCN5A-DeltaKPQ mutation.


METHODS
We assessed the effects of 8-hour intravenous ranolazine infusions (45 mg/h for 3 hours followed by 90 mg/h for 5 hours) on ventricular repolarization and myocardial relaxation in 5 LQT3 patients with the SCN5A-Delta KPQ mutation. Changes in electrocardiographic repolarization parameters from before to during ranolazine infusion were evaluated by time-matched, paired t-test analyses. Cardiac ultrasound recordings were obtained before ranolazine infusion and just before completion of the 8-hour ranolazine infusion.


RESULTS
Ranolazine shortened QTc by 26 +/- 3 ms (P < 0.0001) in a concentration-dependent manner. At peak ranolazine infusion, there was a significant 13% shortening in left ventricular isovolumic relaxation time, a significant 25% increase in mitral E-wave velocity, and a meaningful 22% decrease in mitral E-wave deceleration time compared with the baseline. No adverse effects of ranolazine were observed in the study patients.


CONCLUSIONS
Ranolazine at therapeutic concentrations shortened a prolonged QTc interval and improved diastolic relaxation in patients with the LQT3-Delta KPQ mutation, a genetic disorder that is known to cause an increase in late sodium current.
Moss
Arthur J
AJ
Division of Cardiology, Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642-8653, USA. heartajm@heart.rochester.edu
Zareba
Wojciech
W
Schwarz
Karl Q
KQ
Rosero
Spencer
S
McNitt
Scott
S
Robinson
Jennifer L
JL
D000083:Acetanilides / Q000008:administration & dosage*; D000293:Adolescent; D000328:Adult; D004562:Electrocardiography / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006329:Heart Conduction System / Q000187:drug effects / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000188:drug therapy* / Q000503:physiopathology*; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics*; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines / Q000008:administration & dosage*; D000069458:Ranolazine; D012964:Sodium / Q000378:metabolism*; D015222:Sodium Channels / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
D000083:Acetanilides; D004791:Enzyme Inhibitors; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010879:Piperazines; C568320:SCN5A protein, human; D015222:Sodium Channels; D012964:Sodium; D000069458:Ranolazine