Implications of the cardiomyocyte stress response on protein homeostasis in atrial fibrillation

Atrial fibrillation (AF) is the most common sustained tachyarrhythmia, which increases mortality. Elderly are often affected by this disease and due to the aging population the incidence of AF is expected to increase. The current treatments for AF have a low efficacy, due to the focus of these treatments on restoring a normal heart rhythm, but not on halting the damaging structural changes in cardiomyocytes. These structural changes encompass degradation of proteins needed for structure and contraction of the cardiomyocytes. The underlying mechanisms of the structural changes in AF are mostly unknown. Previous research showed that derailment of proteostasis (synthesis, function and degradation of proteins) is an important mediator in the structural changes in AF. In this thesis we show that AF activate specific stress-responsive and protein degradation pathways of the proteostasis network. The activation of these pathways contributes to the derailment of proteostasis in AF pathogenesis. Identification of these specific routes led to recognition of several novel therapeutic targets, which preserved cardiac proteostasis in the models used. Consequently, these targets may be exploited to reduce or even prevent AF pathogenesis.