Cardiotoxicity: Supercomputer-based in silico studies by CompBioMed Core Partners aiming to make COVID-19 treatment safer for the heart

The use of certain drugs can disturb the rhythm at which hearts beat.  This disruption can have toxic effects on the heart, which are particularly dangerous for those with underlying medical conditions.  Two drugs which are known to have proarrhythmic effects are the antimalarial drugs azithromycin and hydroxychloroquine. Azithromycin and hydroxychloroquine are thought to be potentially effective for the treatment of COVID-19.  Little however is currently known about the effect of the drugs on the arrhythmic risk to patients who receive it as a COVID-19 therapy, which itself has been link to fatal consequences for people with underlying cardiovascular disease and to cardiac injury to some patients without underlying heart conditions.  There is also little known about the effect on the heart of using the drugs in combination.

Sufficient and conclusive test result and autopsy data are currently not available to evaluate the risks of using the drugs to treat COVID-19. Comprehensive computational cardiac models are however being employed to increase our understanding.  Computational modelling can provide a unique tool to allow models for the function of the heart to be developed, and assessments of the cardiotoxicity of drugs to be made to a high level of detail, without the need for lengthy and expensive clinical research.

Barcelona Supercomputing Centre (BSC), one of the core partners in the CompBioMed projects, is currently conducting research in collaboration with ELEM Biotech (ELEM) to assess the impact of the drugs on the human heart, to provide guidance for clinicians on dosages and risks.  The study is complementary to other efforts such as the WHO Solidarity project which is assessing the efficacy of drugs used in COVID-19 treatments more generally.  The in silicio trials being carried out by BSC and ELEM are addressing specific concerns around cardiac safety, especially when drugs are administered in combination, and to patients with different underlying medical conditions.  They are utilising Alya Red in their research, a multiscale model developed by BSC which performs cardiac electro-mechanics simulations, from tissue to organ level.

The state-of-the-art models being employed and developed by BSC and ELEM will also enable them to study the varied effects between groups of individuals.  COVID-19 has now infected a large spectrum of the demographics, to identify specific risk groups.  It also seems that males and females have different risks and propensities to drug-induced cardiac arrhythmias. The aim of the study is to analysis the effect of the antimalarial drugs on a range of simulated human hearts with a variety of comorbidities which may be present in an infected population.  The comorbidities will include such things as gender, ischemia, metabolite imbalances, and structural diseases.

Early results from the BSC/ELEM models have already identified how a conduction block may occur as an effect from action potential duration lengthening from the use of chloroquine.  The effect may also be increased during stress (at elevated heart around 150 bpm) and with high doses of the medication.  These and other results will be validated by the BSC and ELEM researchers against published experimental data on the pro-arrhythmic behaviour of the drugs as it becomes available.