| Summary: | Ventricular arrhythmias are a major cause of sudden cardiac death, which accounts for about 50% of cardiovascular mortality worldwide. Understanding the mechanisms underlying arrhythmias generations is crucial to improve its diagnosis and treatment. Cardiac Purkinje cells constitute the peripheral conduction system of the electrical stimulation in ventricles and are responsible for the correct contraction pattern of the heart. Experimental studies on animal models pointed out that drug actions, mutations or cardiac diseases might alter the electrical activity of Purkinje cells and lead to arrhythmia onsets. However, the pro-arrhythmic mechanisms in Purkinje cells are not entirely understood, and results obtained in animal studies do not always translate to humans, due to inter-species differences.
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The aim of this thesis is to develop an experimentally-informed computational framework to mechanistically investigate the role of human Purkinje cells in arrhythmia onset, and predict Purkinje cells electrophysiological response to pharmacological therapy. Multiscale simulations are used to identify the mechanisms underlying electrical abnormalities in human Purkinje cell and tissue models, as well as to evaluate drug safety and efficacy on cardiac Purkinje electrophysiology in humans, also accounting for biological variability.
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