In-silico clinical trial using high performance computational modeling of a virtual human cardiac population to assess drug-induced arrhythmic risk

Cardiotoxicity continues to be a major health issue worldwide due to the imperative need to access new or repurposed drugs that are safe and effective. Accessibility to affordable drugs is also key to ensure access to drugs to all patients who require them. In this work we propose a workflow for an in-silico clinical trial at the 3D biventricular human population level, to assess cardiac pro-arrhythmic risk after administration of a single or a combination of potentially cardiotoxic drugs. The proposed workflow aims at reproducing gender-specific ionic channel characteristics that determine different responses of patients to drug-induced arrhythmia. To that end a "normal" virtual population of human 3D hearts at rest and exercise/stress (increased heart rate) was analyzed under the influence of drugs, using computer electrophysiology simulations. The changes in ECG, calcium concentration as well as activation patterns on 3D geometry were evaluated for the signs of arrhythmia. Hydroxychloroquine and Azithromycin were used to demonstrate the workflow. Additionally a series of experiments on a reanimated swine heart utilizing Visible Heart(R) methodologies were performed to verify the arrhythmic behaviour observed in the in-silico trial. Our results showed similar results to the recently published clinical trials (21% clinical risk vs 21.8% in-silico trial risk). Evidence of transmurally heterogeneous action potential prolongation after a large dose of hydroxychloroquine was an observed mechanism of arrhythmia, both in the in-vitro and the in-silico model. The proposed workflow for the in-silico clinical drug cardiotoxicity trials allows reproducing the complex behavior of cardiac electrophysiology in a population and verifying drug-induced arrhythmic risk in a matter of a few days as compared to the in-vivo trials. Importantly, our results provided evidence of the normal phenotype variants that produce distinct drug-induced arrhythmogenic outcomes.