Modulators of ventricular arrhythmias in structurally normal and abnormal hearts

Sudden cardiac death (SCD) is a major cause of death in the Western world and it accounts for approximately 25% of cardiovascular deaths. SCD is mainly caused by ventricular arrhythmias (VA). For VA, the concurrence of a pre-existing arrhythmogenic condition (the substrate) and an initiating factor (the trigger) is required. Both trigger and substrate can be changed by modulating factors. This thesis focused on the arrhythmogenic substrate of VA and its modulators. For VA to occur, trigger, substrate and modulators have to be present, creating “the right situation at the right time” for VA to occur. For example, the arrhythmic substrate may be present in a patient for years on end, but will not lead to VA until an adequate trigger occurs. Despite having the same underlying disease, some patients are more at risk for VA than others. This thesis demonstrates that in various diseases, acquired or of genetic origin, an arrhythmogenic substrate is present. Therefore, triggers and modulation factors play a crucial role in the occurrence of VA. The thesis deals with patients with end-stage heart failure, with heart failure based on a phospholamban mutation, ischemic or dilated cardiomyopathy, with idiopathic VF, or with Brugada syndrome. In addition the potential pro-arrhythmic factors of stem cell therapy are studied. By thus enlarging the understanding of the components responsible for VA, this thesis ultimately aims to achieve a more accurate risk stratification and a better treatment for patients at risk for VA