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 (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://ichgcp.net/clinical-trials-registry/NCT01728025" title="See in ClinicalTrials.gov">NCT01728025.

Keywords: action potential; bradycardia; long-QT syndrome; ranolazine; torsade de pointes.

© 2016 American Heart Association, Inc.

Figures

Figure 1

Effect of ranolazine on late sodium current (INa) of SCN5A-D1790G channels. A: Representative original traces depicting late INa recorded before and after increasing concentrations of ranolazine. B: Dot plot showing late INa as a % of peak INa in WT and SCN5AD1790G channels (n = 22 and 5, p < 0.05). C. Concentration–response relationship of the effect of ranolazine to inhibit late INa in SCN5A-D1790G channels. D. Representative traces depicting peak INa recorded before and after ranolazine. E: Normalized I-V relationship of the effect of 10 μM ranolazine on peak INa in SCN5A-D1790G channels. F: Dot plot of blocking effect of 10 μM ranolazine on peak INa of SCN5A-D1790G mutant (n = 5, p > 0.05).

Figure 2

QTc values (during resting ECG) before and during ranolazine therapy in 8 patients with LQT3. Each line represents QTc values of a single patient at baseline and during follow-up. Patient 6 (orange line) discontinued ranolazine after the 1-month follow-up and declined to come for follow-up ECG. Patient 1 (blue line) discontinued ranolazine after the 6 months follow-up and her QTc returned to her baseline values. Patient 4 (purple line) temporarily stopped ranolazine after the 12 months follow-up visit so his QTc increased (even above his baseline QTc), only to significantly decrease again after he restarted ranolazine.

Figure 3

Effects of ranolazine on the QTc during resting ECG and during nocturnal bradycardia. Resting ECG (A) and 12-lead Holter recording during maximal sinus bradycardia at night (C) in the same patient in the absence of drugs. Note that the baseline electrocardiogram, although showing a long QT interval (QTc 549 msec during sinus rate of 60/min) is not representative of the severe QT prolongation recorded during nocturnal bradycardia, when the QTc increases to 566 msec with distinctly abnormal T-waves. Panels B and D show ECG recordings during ranolazine therapy in the same patient. Note that ranolazine shortens the QT interval not only during resting ECG (B) but also during nocturnal bradycardia, partially normalizing the nocturnal T-wave morphology (E).

Figure 4

QT-shortening effects of ranolazine at different heart rates. Box plots of the QT (panel A) and QTc (panel B) during different heart-rates in Holter recordings. The colored boxes (blue at baseline and red during ranolazine therapy) represent the interquartile range (25th to 75th percentiles); the thick black line in the box is the 50th percentile, and the bars represent the range of results excluding outliers. Open circles indicate outliers and * signs indicate extreme outliers. The ΔQT (QT at baseline minus QTc during ranolazine) and the ΔQTc for the different heart rate categories, including the calculated high and low 95% confidence intervals, are shown in panels C and D, respectively. Note that the ΔQTc is greater during sinus tachycardia than during nocturnal sinus bradycardia (4D).

Figure 5

QT-shortening effects of different sodium channel blockers in LQT3. The data on flecainide and mexiletine are as reported by the groups of Benhorin and Priori, whereas data on ranolazine are from the present study. Although direct comparison between the QT shortening effects of flecainide, mexiletine and ranolazine has not been performed, the similar baseline QT values (blue columns in all three studies) suggest that all three drugs shorten the QT interval in LQT3 patients to a similar degree (red columns). Values shown for mexiletine represent the median values rather than the mean.