Key result
Tissue APD90 models predict proarrhythmic risk better than isolated cells by correlating with in vivo QT.
Why the study?
Assessing arrhythmogenic drug potential has traditionally relied on in vivo QT interval prolongation, but this parameter alone may be limiting.
Does a tissue model measuring APD90 prolongation provide a more accurate representation of proarrhythmic risk compared to isolated cell models or in vivo QT interval alone?
Does a tissue model measuring APD90 prolongation provide a more accurate representation of proarrhythmic risk compared to isolated cell models or in vivo QT interval alone?
Tissue models measuring APD90 prolongation offer a more accurate and comprehensive approach to predicting drug-induced proarrhythmic risk than isolated cell models or relying solely on in vivo QT prolongation.
Tissue models may refine preclinical proarrhythmic screening; leaves open human validation before any practice change.
The assessment of the arrhythmogenic potential of drugs has traditionally relied on QT interval prolongation in vivo, but this parameter alone may be limiting. This study confirms the strong correlation between the median of APD90 (action potential duration at 90% repolarization) prolongation in tissue and QT interval prolongation, demonstrating that a tissue model provides a more accurate representation compared to an isolated cell model. The tissue model faithfully captures biological mechanisms, highlighting how cellular dynamics directly influence the organ's macroscopic behavior, as measured by the pseudo-ECG. From a regulatory perspective, integrating cellular biomarkers, such as APD90 prolongation, would offer a more reliable and comprehensive approach, preserving the information from the QT interval while enhancing the understanding of mechanisms underlying potentially lethal arrhythmias.Clinical Relevance- The adoption of cellular models and biomarkers can enhance the prediction of arrhythmogenic risk, reducing false positives and ensuring greater accuracy. Understanding pro-arrhythmic mechanisms, such as APD90 prolongation, opens new possibilities for personalized pharmacological therapies, taking into account individual electrophysiological variability. This approach supports the development of safer drugs that avoid triggering proarrhythmic mechanisms, while preserving therapeutic efficacy and improving the risk-benefit balance.
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Costi et al. (2025) studied Proarrhythmic risk. Tissue models vs. Isolated cell models was evaluated on Correlation between APD90 prolongation and QT interval prolongation. Tissue models assessing APD90 prolongation strongly correlate with in vivo QT interval prolongation, providing a more accurate representation of proarrhythmic risk than isolated cell models.
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