Interplay between ventricular electrical and mechanical activity as a trigger for torsades de pointes in drug-induced long-QT 2 syndrome

Abstract Background Torsades de pointes (TdP) is a potentially lethal ventricular tachyarrhythmia occuring in congenital long-QT syndrome or acquired QT prolongation. Trigger mechanisms of TdP in the beating heart are still poorly understood, but electromechanical reciprocity likely contributes. Purpose (1.) Determining the timing of left-ventricular (LV) mechanical events at TdP induction in a large animal model, particularly the impact of LV filling; (2.) Delaying the onset of LV filling with the myosin activator omecamtiv mecarbil with the aim of preventing TdP. Methods In 9 anesthetized female Welsh mountain sheep, transthoracic echocardiography was performed, and LV pressure and surface ECG were measured. After baseline recordings, 1 mg/kg of omecamtiv mecarbil (OM) was given to delay the onset of diastolic LV filling. Following OM, long-QT syndrome type 2 (LQT2) was mimicked by the infusion of IKr blocker dofetilide (Dof) until TdP occurred or a maximum of 15 µg/kg was reached (Panel A). Data from seven additional sheep only treated with Dof before TdP induction were used as reference for TdP coupling intervals. Data are shown as mean±SD or median (25th to 75th percentile). Echocardiography-derived electromechanical window (EMW) was calculated by subtracting the QT time from the aortic-valve closure time. Results At baseline, the RR interval was 686±125 ms, QTc (Bazett) was 412±27 ms, and the EMW was -3 (-10 to 25) ms. After OM, RR and QTc remained unchanged, but the EMW was rendered more positive (88 (68 to 143) ms, p=0.004). The isovolumic relaxation time (IVRT, p=0.0002) and the mitral valve opening time (MVO, p=0.006) were also prolonged, indicating a delayed onset of passive LV filling upon OM. OM+Dof-treated animals that ultimately developed TdP (5/9, 9 µg/kg mean Dof dose at TdP induction) had a markedly different mechanical phenotype after OM with less positive EMW (74±11 vs. 135±34 ms, p=0.007), shorter IVRT (p=0.03), and shorter MVO (p=0.02), indicating a relatively earlier onset of passive LV filling in these animals. At the highest individual Dof dose per animal, no increase in RR intervals (p=0.71) was observed, but QTc was prolonged (p<0.0001, Panel B). The 5 animals that developed TdP upon OM+Dof did not differ from those resistant to TdP-induction in terms of RR (p=0.15) or QTc (p=0.72). However, tissue-doppler imaging of the LV revealed that TdP induction fell into the LV passive filling phase in all animals after OM+Dof, and TdP induction was separated from the T-wave unlike in classic R-on-T (Panel C). In OM+Dof vs. Dof-treated sheep, QTc before TdP onset did not differ between groups (p=0.80), but coupling intervals were significantly longer in OM+Dof-treated animals (656±43 vs. 549±54 ms, p=0.007). Conclusion Passive LV filling is involved as a mechanoelectrical trigger of TdP in this experimental model, and can be modulated with omecamtiv mecarbil.Figure