Computational investigation of cardiac arrhythmias and drug effect: from ion channels to the surface electrocardiogram

The electrocardiogram (ECG) is the clinical test routinely used to diagnose and treat cardiac disorders. Despite the fact that many diagnostic and therapeutic decisions rely only upon interpretation of ECG patterns, the cellular and sub-cellular mechanisms underlying pathophysiological ECG changes remain mostly unclear. In this project we specifically aim at improving the currently existing knowledge of the mechanisms responsible for the generation and maintenance of cardiac arrhythmias, as well as of therapeutic approaches to prevent or terminate them. We propose to use a multi-scale approach that will enable us to characterize abnormalities from the ion channel level to the ECG as well as to determine the effects of pharmacological compounds on those abnormalities, both at preclinical and clinical stages. Specifically, we will develop and validate whole atrial and ventricular computational models and we will use them to simulate the electrical activity of the heart from the single cell to the whole cavity and, ultimately, to the ECG. Development and validation of the models will be based on available experimental and clinical data. Simulations will be run to investigate the causes and mechanisms responsible for the occurrence of cardiac arrhythmias. Pharmacological modeling and testing will also be conducted as part of the project, and hints for the development of new compounds will be provided.