Abstract
IntroductionHeart failure (HF) increases sensitivity to drug-induced QT interval lengthening and torsade de pointes. We have previously demonstrated that microRNA (miR) 362-3p is upregulated in patients with HF and decreases hERG-related current. We tested the hypothesis that circulating miR-362-3p predicts sensitivity to drug-induced QT interval lengthening.MethodsPatients with HF [preserved (n=10) or reduced (n=2) ejection fraction] and a group without HF (n=10) matched by age and sex were enrolled in a prospective, parallel-group study. Following a baseline day of ECG monitoring, IV ibutilide 0.003 mg/kg was administered over 10 minutes and serial blood samples were collected for determination of serum ibutilide (HPLC/MS) and miR 362-3p (qPCR) with time-matched ECGs for measurement of Fridericia-corrected QT (QTF) intervals. Non-linear mixed-effects modeling was used to link ibutilide concentrations to ΔΔQTF intervals with the influence of age, sex, weight, race, heart failure status, and miR-362-3p assessed.ResultsA 3-compartment model with proportional residual error linked to an Emax model with an effect compartment best described the ibutilide concentration-ΔΔQTF relationship. In the final covariate model, HF status predicted maximum ibutilide-induced QTF lengthening (Emax), while serum miR 362-3p significantly predicted the ibutilide concentration associated with half-maximal QTF lengthening (EC50) [ΔOFV = 5.23; P < 0.05]. The EC50 was strongly negatively correlated with miR-362-3p expression (R=0.93; P<0.0001). Simulations of high, medium, and low miR 362-3p expression levels revealed significant differences in ibutilide sensitivity with median EC50 of 0.03, 0.12, and 0.17 ng/mL, respectively (Figure).ConclusionsCirculating miR-362-3p expression is associated with enhanced sensitivity to drug-induced QT interval lengthening. Further assessment of miR 362-3p to predict drug-induced QT lengthening is warranted.