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Drug induced TdP risks classification assay using electro-mechanical models of human ventricle based on CiPA
Aulia Khamas Heikhmakhtiar1,2, Ali Ikhsanul Qauli3, Yunendah Nur Fu'adah4
1Department of Biomedical Engineering, Kumoh National Institute of Technology, 61 Daehak-ro (yangho-dong), Gumi, Gyeongbuk, 39177 Republic of Korea.
An integrated electromechanical model improves prediction of drug-induced cardiac toxicity, specifically Torsade de Pointes (TdP) risk. This advanced model enhances classification accuracy using action potential, calcium, and tension profiles for safer drug development.
Area of Science:
- Cardiovascular Pharmacology
- Computational Biology
- Drug Safety Assessment
Background:
- Predicting drug-induced cardiac toxicity, particularly Torsade de Pointes (TdP), is crucial for pharmaceutical development.
- Existing frameworks like CiPA provide a basis for risk assessment but can be enhanced.
- Electromechanical coupling in myocytes plays a significant role in cardiac function and dysfunction.
Purpose of the Study:
- To develop and evaluate an integrated electromechanical model for improved TdP risk assessment.
- To extend the existing CiPA framework by incorporating mechanical properties of myocytes.
- To compare the predictive performance of different electromechanical models against established electrophysiological models.
Main Methods:
- Integration of human electrophysiological models (CiPAORdv1.0, ORD, ToR) with a mechanical ventricle model (Land).
- Observation of 27 parameters including net current (qNet), inward current (qInward), action potential, intracellular calcium, and tension profiles.
- Ordinal logistic regression used for training with 12 drugs and validation with 16 unseen drugs, following FDA protocols.
Main Results:
- The electromechanical models significantly improved TdP risk classification across action potential, calcium transient (Cai), and tension profiles.
- The CiPAORdv1.0 + Land model maintained qNet performance while enhancing classification using APD50, APD90, CaD90, Catri, titi, and EMW.
- Specific improvements were noted for ToR + Land (CaTD50, CaD50,tp) and ORD + Land (Vmax, CaTD90, CaD90,tp, Catri, titi) models.
Conclusions:
- Integrated electromechanical ventricular models offer a distinct advantage over purely electrophysiological models for TdP risk assessment.
- Coupled models demonstrate enhanced TdP classification performance based on action potential duration (APD), calcium dynamics, and mechanical tension.
- Further model optimization and expanded drug datasets are recommended to improve interpretability and predictive accuracy for TdP risk.
