Cardiac clockwork

This thesis explores how the timing of different processes in heart cells can lead to rhythm disorders and influence the effects of therapies. It uses advanced computer models that include both fast changes in ion channel opening and closing and slower changes related to the transport of the ion channels within the heart muscle cell. These models simulate how factors such as temperature, drugs or fast heart rates affect the heart’s electrical activity over time and how these modulators can sometimes have opposing effects at short versus long time points. This is important to consider because many treatments are taken over longer periods of time. The thesis also translates cellular findings to the level of heart tissue. For example, simulations of short QT syndrome showed that L-carnitine or a new gene therapy can prevent dangerous re-entrant activity in virtual tissue, although the gene therapy only works well when its effects are spread widely through the tissue. Finally, the trafficking and tissue-level models are combined to examine the therapeutic targeting of specific potassium channels in atrial fibrillation. Thus, by combining both fast and slow effects, this research provides new insights for predicting and treating heart rhythm problems.