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Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model.

ABSTRACT: Bradycardia is a risk factor for the development of torsade de pointes (TdP). The aim of this work was to compare the importance of changes in heart rate and arterial blood pressure in the development of drug-induced TdP and to investigate the role of vagal influences.Experiments were performed in open-chest, pentobarbital-anaesthetized, male rabbits which were given clofilium (20, 60 and 200 nmol kg(-1) min(-1)) with rising doses of either phenylephrine (75, 150, 225 and 300 nmol kg(-1) min(-1)), angiotensin II (0.25, 0.5, 0.75 and 1 nmol kg(-1) min(-1)) or saline. A fourth group received phenylephrine and cloflium after bilateral vagotomy. ECGs, haemodynamics and epicardial monophasic action potentials were recorded.TdP occurred in 57% of rabbits given phenylephrine and clofilium. Replacement of phenylephrine with saline or angiotensin II reduced the incidence of TdP to 0 and 17%, respectively. Vagotomy prevented TdP in rabbits given phenylephrine and clofilium. Increases in blood pressure induced by phenylephrine and angiotensin II were similar. Bradycardia only occurred with phenylephrine and was reduced but not abolished by vagotomy. Neither short-term variability of repolarization nor action potential triangulation could predict TdP.These results indicate that reflex activation of vagal nerve activity is essential for the induction of drug-induced TdP in alpha1-adrenoceptor-stimulated anaesthetized rabbits. This implies that alterations in vagal activity may also precipitate episodes of drug-induced TdP in man and that this should be considered in selecting models used in drug development.

SUBMITTER: Farkas A

PROVIDER: S-EPMC2451051 | biostudies-other | 2008 Jul

REPOSITORIES: biostudies-other

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Project description:Drug-induced cardiotoxicity is one of the main causes of drug failure, which leads to subsequent withdrawal from pharmaceutical development. Therefore, identifying the potential toxic candidate in the early stages of drug development is important. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a useful tool for assessing candidate compounds for arrhythmias. However, a suitable model using hiPSC-CMs to predict the risk of torsade de pointes (TdP) has not been fully established. The present study aimed to establish a predictive TdP model based on hiPSC-CMs. In the current study, 28 compounds recommended by the Comprehensive in vitro Proarrhythmia Assay (CiPA) were used as training set and models were established in different risk groups, high- and intermediate-risk versus low-risk groups. Subsequently, six endpoints of electrophysiological responses were used as potential model predictors. Accuracy, sensitivity and area under the curve (AUC) were used as evaluation indices of the models and seven compounds with known TdP risk were used to verify model differentiation and calibration. The results showed that among the seven models, the AUC of logistic regression and AdaBoost model was higher and had little difference in both training and test sets, which indicated that the discriminative ability and model stability was good and excellent, respectively. Therefore, these two models were taken as submodels, similar weight was configured and a new TdP risk prediction model was constructed using a soft voting strategy. The classification accuracy, sensitivity and AUC of the new model were 0.93, 0.95 and 0.92 on the training set, respectively and all 1.00 on the test set, which indicated good discrimination ability on both training and test sets. The risk threshold was defined as 0.50 and the consistency between the predicted and observed results were 92.8 and 100% on the training and test sets, respectively. Overall, the present study established a risk prediction model for TdP based on hiPSC-CMs which could be an effective predictive tool for compound-induced arrhythmias.

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Importance of vagally mediated bradycardia for the induction of torsade de pointes in an in vivo model.

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