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Updated: Jul 16, 2025
In Silico Clinical Trials for Cardiovascular Disease
Published on: May 27, 2022
HPC Framework for Performing in Silico Trials Using a 3D Virtual Human Cardiac Population as Means to Assess
Jazmin Aguado-Sierra1,2, Renee Brigham3, Apollo K Baron4
1Barcelona Supercomputing Center, Barcelona, Spain. jazmin.aguado@bsc.es.
Insights
A new computational framework enables in-silico clinical trials for cardiac drug safety. This virtual heart model accurately predicts pro-arrhythmic risk, reducing animal testing and accelerating drug development.
Area of Science:
- Computational biology
- Cardiovascular research
- Pharmacology
Background:
- Traditional drug cardiotoxicity testing relies on animal models and lengthy clinical trials.
- Assessing pro-arrhythmic risk, particularly with drug combinations, remains a challenge.
- Existing in-silico methods often lack detailed anatomical and physiological representation.
Purpose of the Study:
- To develop and validate a high-performance computational framework for in-silico clinical trials.
- To assess the pro-arrhythmic risk of hydroxychloroquine and azithromycin, alone and in combination.
- To investigate drug-induced QT-prolongation and arrhythmia mechanisms in a virtual human heart model.
Main Methods:
- Utilized 3D biventricular human heart models with phenotypic and sex-specific variations.
- Performed electrophysiology simulations to analyze pseudo-ECGs, calcium dynamics, and activation patterns.
- Validated in-silico findings with in-vitro experiments on reanimated swine hearts using Visible Heart® methodology.
Main Results:
- The in-silico trials accurately predicted pro-arrhythmic risk (21.8% vs. 21% clinical risk).
- Identified transmural heterogeneity in action potential prolongation as a key mechanism for drug-induced arrhythmias.
- Demonstrated that common phenotype variants lead to distinct drug-induced arrhythmogenic outcomes.
Conclusions:
- The computational framework provides a rapid and reliable method for in-silico drug cardiotoxicity trials.
- This approach effectively reproduces complex cardiac electrophysiology in diverse virtual populations.
- The study highlights the potential to reduce animal use and accelerate clinical trial timelines for drug safety assessment.
Abstract:
Following the 3 R's principles of animal research-replacement, reduction, and refinement-a high-performance computational framework was produced to generate a platform to perform human cardiac in-silico clinical trials as means to assess the pro-arrhythmic risk after the administrations of one or combination of two potentially arrhythmic drugs. The drugs assessed in this study were hydroxychloroquine and azithromycin. The framework employs electrophysiology simulations on high-resolution three-dimensional, biventricular human heart anatomies including phenotypic variabilities, so as to determine if differential QT-prolongation responds to drugs as observed clinically. These simulations also reproduce sex-specific ionic channel characteristics. The derived changes in the pseudo-electrocardiograms, calcium concentrations, as well as activation patterns within 3D geometries were evaluated for signs of induced arrhythmia. The virtual subjects could be evaluated at two different cycle lengths: at a normal heart rate and at a heart rate associated with stress as means to analyze the proarrhythmic risks after the administrations of hydroxychloroquine and azithromycin. Additionally, a series of experiments performed on reanimated swine hearts utilizing Visible Heart® methodologies in a four-chamber working heart model were performed to verify the arrhythmic behaviors observed in the in silico trials.The obtained results indicated similar pro-arrhythmic risk assessments within the virtual population as compared to published clinical trials (21% clinical risk vs 21.8% in silico trial risk). Evidence of transmurally heterogeneous action potential prolongations after providing a large dose of hydroxychloroquine was found as the observed mechanisms for elicited arrhythmias, both in the in vitro and the in silico models. The proposed workflow for in silico clinical drug cardiotoxicity trials allows for reproducing the complex behavior of cardiac electrophysiology in a varied population, in a matter of a few days as compared to the months or years it requires for most in vivo human clinical trials. Importantly, our results provided evidence of the common phenotype variants that produce distinct drug-induced arrhythmogenic outcomes.
