Advancing Drug Risk Assessment with Tissue Models: Correlating QT Interval and APD90 Prolongation to Refine...

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.