Interplay between ventricular electrical and mechanical activity as a trigger for torsades de pointes in drug-induced long-QT 2 syndrome
Bibliographic record
Abstract
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
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".