Safety and efficacy of drug therapy in human heart

We applied a Systems Medicine approach to the investigation of drug-induced effects on the human heart using computational modelling and simulation combined with experimental and clinical investigation. Specifically, we are interested in investigating the following research questions:

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We focus our investigations in 3 important disease conditions, which include acute myocardial ischaemia, atrial fibrillation and hypertrophic cardiomyopathy. In all cases, pharmacological therapy exhibits limited efficacy due to drug cardiotoxicity, which is a major concern for society, clinicians, regulators and industry. Drug-induced arrhythmias are more likely to occur in patients with a diseased heart, but drug safety screening is routinely conducted in healthy animal models. Therefore, little is known about how drug-induced ionic alterations modulate the human diseased pro-arrhythmic substrate to either decrease or increase arrhythmic risk.

Our Systems Medicine approach exploits synergies of combining computational, experimental and clinical research building on the expertise brought together by the Computational Cardiovascular Science team and collaborators. Mathematical models of human non-diseased and disease human atrial and ventricular models are constructed, based on the largest human ventricular experimental database available worldwide. Simulation studies are conducted to investigate how established and recently-proposed anti-arrhythmic targets alter the likelihood of initiation, establishment and spontaneous termination of arrhythmias in human nondiseased and diseased ventricles. In collaboration with pharmaceutical companies, we evaluate the predictive capacity of our computational models and biomarkers for drug safety and efficacy screening with respect to animal experiment-based methodologies.