Safety and efficacy of anti-arrhythmic drug therapy in acute myocardial ischaemia in human. An integrative, multiscale and mechanistic investigation

The most common cause of mortality in the UK is Sudden Cardiac Death, subsequent to lethal arrhythmias and in 80% of cases associated to acute myocardial ischemia. 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 ischemic patients, but drug safety screening is routinely conducted in healthy animal models. Therefore, little is known about how drug-induced ionic alterations modulate the human ischemic elecrophysiological (EP) substrate to either decrease or increase arrhythmic risk. The main aim is to unravel key mechanisms underlying the EP response of human ventricles to anti-arrhythmic drugs in non-diseased versus acutely-ischemic conditions. A Systems Biology Approach is proposed to exploit synergies of computational, experimental and clinical research building on the unique expertise of the team. Mathematical models of human non-diseased and ischemic ventricular EP are being constructed, based on the largest human ventricular EP experimental database available worldwide.

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. This research develops translational aspects of the Applicants research towards clinical and industrial applications, and contribute to provide reliable computational methods for drug screening.