The major findings from this study are that ranolazine, a new antianginal agent with novel electrophysiologic properties, shortens the QTc interval and improves myocardial relaxation in LQT3 patients with the SCN5A-ΔKPQ mutation. Shortening of the QTc interval by ranolazine is concentration dependent. We do not have a good explanation for the non-significant rebound in the QT, QTc, QTpeak, Tpeak-Tend, and Tduration parameters above baseline values at 16 hours after the ranolazine infusion.
In 1995, Bennet et al. showed that the molecular mechanism for the LQT3-ΔKPQ form of LQTS was due to a persistent inward sodium current that prolongs the action potential with resultant QT prolongation in the surface electrocardiogram.2
Since ranolazine has been shown to inhibit the late sodium current with minimal effect on peak sodium current during the upstroke of the action potential in experimental LQT3 models,4
it was logical to study this drug in patients with ΔKPQ mutation. Thus, shortening of the QT interval with ranolazine in our patients with the LQT3-ΔKPQ mutation has mechanistic rationale, and the QTc reduction occurred within the therapeutic concentration of the drug used in the treatment of patients with angina. Ranolazine has only minimal effect on phase 0 of the ventricular action potential, and the QRS interval was not prolonged in the current study. The absence of a QRS prolonging effect with ranolazine is in contrast to the drug flecainide that has early and late sodium-channel blocking effects on the ventricular action potential and is associated with QRS widening in LQT3 patients with the ΔKPQ mutation.12
In a recent study, Ruan et al showed that the electrophysiologic properties of mexiletine as evaluated in cellular expression studies were correlated with the clinical QTc response in LQT3 patients.13
Prior cellular electrophysiologic studies have shown the benefit of ranolazine in experimental models of LQT314
, so our in vivo
QTc findings in LQT3 patients with the ΔKPQ mutation are in good alignment with the Raun findings even though we are using a different sodium-channel blocker.
Ranolazine has modest QT prolonging effects in coronary patients treated with this antianginal agent,15
possibly due to some inhibition of the delayed rectifier potassium current IKr.16
However, in large clinical trials ranolazine showed no proarrhythmic effect, but rather, had antiarrhythmic properties.15
In the current ranolazine study with LQT3 patients, there were no supraventricular or ventricular arrhythmias during the 8-hour intravenous infusion of ranolazine.
It has been hypothesized that an increase in late entry of sodium into the myocardial cell results in an increase in cytosolic calcium concentration,17
a factor that could contribute to electrical instability by triggering afterdepolarization-related ventricular arrhythmias. In addition, an increase in late sodium current causes intracelluar sodium–dependent calcium-overload that can result in a slowing of LV diastolic relaxation, i.e., a negative lusitropic effect. In the current study, the baseline resting ultrasound exam did not appear to be entirely normal in our LQT3 patients with findings suggestive of minor grade 1 diastolic dysfunction. During ranolazine infusion, left ventricular isovolumic relaxation time shortened, mitral E-wave deceleration time decreased, and mitral E-wave velocity increased when compared to baseline values, and these findings are consistent with a positive lusitropic action in this disorder.
This study was initiated as a pilot investigation to evaluate the effects of intravenous ranolazine in high-risk patients with the LQT3-ΔKPQ mutation. We only studied 5 patients in view of our prior positive study with oral flecainide in 5 patients with the same LQT3 mutation.18
Nevertheless, the small sample size, the study of only patients with the LQT3-ΔKPQ mutation, and the failure to study patients with the oral preparation are limitations that preclude any recommendation for use of ranolazine for management of patients with LQT3 mutations. A larger study with oral ranolazine needs to be done to determine the safety and efficacy of oral ranolazine for clinical use in LQT3 patients.