Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

Area of Science:

• Cardiovascular Pharmacology
• Drug Safety and Toxicology
• Electrophysiology

Background:

• Current models like stem cell-derived cardiomyocytes (SC-CMs) for assessing drug-induced pro-arrhythmic risk, particularly Torsades de Pointes (TdP), show limitations due to immature phenotypes and false positive predictions.
• There is a need for more predictive preclinical models using mature human cardiac tissue to accurately assess drug-induced cardiac risks.

Purpose of the Study:

• To evaluate the efficacy of a human ventricular trabeculae (hVT) action potential (AP) based model in assessing drug-induced pro-arrhythmic risk.
• To compare the predictive performance of the hVT model against human SC-CMs for drug-induced TdP risk.

Main Methods:

• Human ventricular trabeculae from organ donors were used to assess the effects of 15 reference drugs (8 torsadogenic, 5 non-torsadogenic) on AP parameters at 1 and 2 Hz.
• A pro-arrhythmic score was calculated based on drug-induced changes in AP duration, triangulation, variability, and early afterdepolarizations.
• The ratio of testing concentration to human therapeutic unbound Cmax was calculated to assess clinical translation, with analysis performed at a ratio of 10.

Main Results:

• The hVT AP-based model correctly identified 7 out of 8 torsadogenic drugs and 4 out of 5 non-torsadogenic drugs at a Cmax ratio of 10.
• The model demonstrated excellent performance with sensitivity, specificity, positive predictive value, and negative predictive values of 0.88, 0.8, 0.88, and 0.8, respectively, at a ratio of 10.
• The hVT model showed superior predictive performance compared to human SC-CM models in differentiating torsadogenic from non-torsadogenic drugs.

Conclusions:

• The hVT AP-based model, integrated with a pro-arrhythmic score, effectively differentiates torsadogenic from non-torsadogenic drugs.
• This model offers a more accurate and reliable preclinical assessment of drug-induced pro-arrhythmic risk compared to current SC-CM models.
• The hVT model holds significant potential for improving drug safety evaluations and reducing the incidence of TdP.