Antifibrillatory effect of ranolazine during severe coronary stenosis in the intact porcine model

BackgroundClinical evidence suggests that the antianginal agent ranolazine has antiarrhythmic properties, but its effects on vulnerability to ventricular fibrillation (VF) and T-wave alternans (TWA) during coronary artery stenosis have not been measured.ObjectiveWe investigated whether the antiarrhythmic effect of ranolazine during acute coronary stenosis could be quantified by measuring VF threshold and TWA magnitude.MethodsElectrode catheters placed in the left ventricular apex were used to determine VF threshold during ventricular pacing at 130 beats/min, and TWA was quantified from epicardial electrograms using modified moving average method (N = 18). Left anterior descending coronary flow was reduced with a balloon occluder by 75% for 10 minutes. The IKr blocker E-4031 was used to distinguish effects of late INa and IKr inhibition by ranolazine.ResultsBefore stenosis, ranolazine and E-4031 increased VF threshold from 32 ± 4 mA to 46 ± 4 mA (mean ± SEM), P = .02, and from 33 ± 5 mA to 40 ± 9 mA, P = .02, respectively. During stenosis, ranolazine increased VF threshold from 19 ± 2 mA to 33 ± 3 mA (P = .02), whereas E-4031 decreased VF threshold from 21 ± 3 mA to 15 ± 3 mA (P = .02). The ischemia-induced increase in TWA was suppressed by ranolazine but not by E-4031, consistent with effects of these agents on VF threshold.ConclusionRanolazine exerts significant antifibrillatory effects during coronary stenosis through direct effects on cardiac electrical properties independent of coronary flow. Ranolazine's antifibrillatory action during myocardial ischemia does not appear to be mediated by blockade of IKr but rather by inhibition of late INa. TWA changes paralleled vulnerability to VF as indicated by VF threshold testing.