Rick Schreurs

13 General introduction patients with CRT [41, 42]. To our believe, better understanding of this signal might lead to improvements in the optimization algorithm. Animal studies Animals have long been used to study dyssynchrony and resynchronization using pacemakers. The LBBB has been described in monkeys and pigs in a manner that is comparable to humans. In other animals like ox and sheep, the bundles are significantly thicker and their branches extend much more towards the epicardium compared to the human situation. In rabbit hearts the left ‘bundle’ is more a group of fine sheets covering the subendocardial tissue [43]. To study CRT in animals a model with sufficient amount of interventricular dyssynchrony is preferable. In pigs RV pacing (to mimic LBBB) or LBBB increases QRS duration by only 50% [44] and the increase is even less in goats. The most optimal species is the dog, in which a doubling of QRS duration can be seen during LBBB which is comparable to human. Percutaneous radiofrequency ablation of the LBBB in canine hearts results in a model perfectly suited to study the effects of CRT [45-48]. Computational modeling of the heart Computer models provide a description of situations through simulations, based on assumed relations and simulation conditions. This provides a level of control that is not always physically or ethically possible in animals or clinical studies, which raises the opportunity to study new insights in the context of CRT [49]. In the current thesis CircAdapt was used to study the influence of various pacemaker settings on hemodynamic outcome. CircAdapt is a model that consists of various modules representing not only the atria, ventricles and myocardial tissue, but also pericardium, heart valves, large blood vessels and systemic and pulmonary circulation [50, 51]. The CircAdapt model is able to simulate cardiac pacing and to describe the physiology and physics of AV-coupling and the mechanical and electrical interaction of the ventricles. The model has been extensively used to generate additional insights of existing clinical and animal experimental data or to form new hypotheses in the context of cardiac pacing [52-55]. General aims and outline of the thesis The research presented in this thesis has two main aims. The first aim is to examine if CRT improves cardiac function in patients with prolonged PR-interval and whether first-degree AV-block (AV dromotropathy) might therefore be a new indication for CRT. The second aim is to explore new ways of optimizing pacemaker settings in CRT and relate them to hemodynamic outcome. After this general introduction, chapter 2 reviews the electrophysiological and hemodynamic changes that occur during CRT in both patient and animal studies. It elaborates on electro- mechanics of dyssynchrony and how CRT reverses this. Furthermore, it focusses on the acute hemodynamic improvements that can be seen due to CRT and on the long-term reverse remodeling of the heart. It reviews the influence of various pacing modalities and 1