Lay summary
Aim: Our general aim is to better understand what causes heart rhythm disorders (arrhythmias) by using an interdisciplinary approach combining computer simulations and biological experiments.Background: Heart disease is a major cause of morbidity and mortality. During disease, arrhythmias are frequent. They result from an abnormal electrical activity in the heart and can precipitate cardiac failure, cause stroke and lead to sudden death. Cardiac contraction is triggered by an electrical excitation wave (action potential, AP), which is generated in the sinoatrial node (pacemaker) and conducted from cell to cell across the entire heart. Many arrhythmias are caused by disorders of action potential conduction. Conduction relies on a multitude of ion currents flowing through various channels in the cell membranes, on currents passing between adjacent cells and on the microscopic architecture of cardiac tissue. Conduction is then determined by the dynamic interactions between all these actors. The dynamics of conduction are extremely complex, which explains why the prevention and the treatment of arrhythmias still represent a great challenge. A deeper understanding of cardiac electrical activity is therefore necessary for the development of new and more efficient clinical strategies.Methodology: To gain this understanding, one must consider all individual actors and all their mutual interactions by using integrative approaches. For this purpose, we use mathematical models to reconstruct conduction in computer simulations. In this way, we gain direct insight into phenomena which cannot be addressed experimentally and better understand, for example, the effects of drugs and the effects of cardiac tissue structure on conduction. In turn, experiments serve to refine the models and to verify the hypotheses that are based on them. We use patterned cultures of cardiac cells grown on microelectrode arrays. While the patterned growth technique permits to control the architecture of cardiac tissue, microelectrode arrays permit to monitor conduction patterns during extended periods of time.Projects: One of our projects focused on the rate-dependent mechanisms of slow conduction and conduction block. These two phenomena lead to reentry, a phenomenon underlying serious arrhythmias (e.g., fibrillation). We also investigated oscillations of conduction during reentry in rings of cardiac tissue to evaluate what makes this pathological rhythm stable or unstable. In another project, we investigated the beat-to-beat variability of spatiotemporal dynamics of spontaneously active cardiac cell cultures, an in vitro model of a pacemaker. In a further work, we explored how pacing cardiac tissue at intervals varying randomly from beat to beat provides additional information about conduction dynamics compared to pacing at predefined intervals. Finally, in collaboration with other research groups, we investigated how congenital ion channel mutations (e.g., the Brugada syndrome) put carrier patients at risk of life-threatening arrhythmias.