Interplay between ventricular electrical and mechanical activity as a trigger for torsades de pointes in drug-induced long-QT 2 syndrome
Notice bibliographique
Résumé
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
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».