Ranolazine reduces repolarization heterogeneity in symptomatic patients with diabetes and non–flow-limiting coronary artery stenosis

Abstract

Background: Experimental evidence suggests that ranolazine decreases susceptibility to ischemia-induced arrhythmias independent of effects on coronary artery blood flow. Objective: In symptomatic diabetic patients with non–flow-limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, we explored whether ranolazine reduces T-wave heterogeneity (TWH), an electrocardiographic (ECG) marker of arrhythmogenic repolarization abnormalities shown to predict sudden cardiac death. Methods: We studied all 16 patients with analyzable ECG recordings during rest and exercise tolerance testing before and after 4 weeks of ranolazine in the double-blind, crossover, placebo-controlled RAND-CFR trial (NCT01754259). TWH was quantified without knowledge of treatment assignment by second central moment analysis, which assesses the interlead splay of T waves in precordial leads about a mean waveform. Myocardial blood flow (MBF) was measured by positron emission tomography. Results: At baseline, prior to randomization, TWH during rest was 54 ± 7 μV and was not altered following placebo (47 ± 6 μV, p =.47) but was reduced by 28% (to 39 ± 5 μV, p =.002) after ranolazine. Ranolazine did not increase MBF at rest. Exercise increased TWH after placebo by 49% (to 70 ± 8 μV, p =.03). Ranolazine did not reduce TWH during exercise (to 75 ± 16 μV), and there were no differences among the groups (p =.95, ANOVA). TWH was not correlated with MBF at rest before (r2 =.07, p =.36) or after ranolazine (r2 =.23, p =.06). Conclusions: In symptomatic diabetic patients with non-flow-limiting coronary artery stenosis with diffuse atherosclerosis and/or microvascular dysfunction, ranolazine reduced TWH at rest but not during exercise. Reduction in repolarization abnormalities appears to be independent of alterations in MBF.