Anne-Marie Koop

14 increased pressure load of the right ventricle. However, these processes eventually leads to pathologic alternations contributing to the development of right ventricular failure.. 31 In the process of adaptive towards maladaptive hypertrophy, several signalling pathways are involved. Activation of Akt (also known as protein kinase B) is associated with a physiological hypertrophic response, 36,37 whereas activation of the calcineurin/nuclear factor activated T-cells (NFAT)-signaling predominantly induces pathological features. 38–42 The hypertrophic response may be accompanied by a shift in type of myosin heavy chains. In particular, slow twitch β -myosin heavy chains, which are more energy efficient, will relatively increase as compared to the fast twitch α -myosin heavy chains. 43 This resembles the fetal situation, but in the adult heart this finally contributes to maladaptation. Due to the increased afterload, more nutrients and oxygen will be required in order to meet the increased energy demand for contraction. 23 Contrary, increased pressure load impairs angiogenesis, with subsequent capillary rarefaction which is associated with RV failure. 44,45 Angiogenesis involves signalling cascades including vascular endothelial growth factor (VEGF), forkhead transcription factor (FOXO1) and hypoxia inducible factor 1α (HIF1α ), which may be initiated by metabolic remodelling. 46 In the pressure loaded RV specifically, activation of angiogenic signalling differs in various pressure overload animal models. 45,47,48 Also fibrosis is a characteristic feature of RV adaptation due to increased pressure load conditions. 33,49,50 Fibrosis embodies collagen disposition induced by fibroblasts activated by macrophages via transforming growth factor β , and affects cardiac stiffness, promotes arrhythmias and impairs oxygen diffusion to cardiomyocytes. 51–53 Fibrosis is in general considered as a pathological sign and contributes to further pathological remodelling. Hereby, the progression of remodelling correlates not only with the quantity but also the quality of fibrosis, expressed by type of fibrillar collagen and the degree of cross-linking. 54,55 Troughout the thesis, we have characterized various remodelling processes by the use of experimental models. Where previous studies mostly focussed on one particular time point, we aimed to characterize different stages of RV disease. In chapter 2 we demonstrate the differences between compensated RV dysfunction and clinical RV failure, whereas chapter 4 focusses on different timepoints in compensated RV dysfunction. Proper characterization at different time points and standardized methods will be pivotal for proper RV investigation.