The bicuspid aortic valve (BAV) is a congenital heart defect which is characterized by the formation of two aortic leaflets instead of the normal three leaflets within the tricuspid aortic valve ... Show moreThe bicuspid aortic valve (BAV) is a congenital heart defect which is characterized by the formation of two aortic leaflets instead of the normal three leaflets within the tricuspid aortic valve (TAV). Whilst all BAV patients have a bicuspid valve, extended patient monitoring has revealed a large variation of disease progression trajectories during a patient’s lifetime. This large variation troubles clinical decision making due to the uncertain proliferation of BAV disease. More knowledge of the biological mechanisms underlying BAV could address that uncertainty and thus help stratify patient risk with more accuracy. Therefore this thesis aims to advance our current understanding regarding the biological impact and developmental mechanisms underlying congenital BAV and BAV related aortopathy. Show less
The research described in this thesis focuses on the use of both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to understand cardiac lineage development and disease. To... Show moreThe research described in this thesis focuses on the use of both embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) to understand cardiac lineage development and disease. To investigate the possibility of studying inherited cardiac diseases, we compared pluripotent stem cell-derived cardiomyocytes by investigating both a mouse and human model of a complex cardiac overlap syndrome caused by a mutation in the gene SCN5A. We demonstrated that both ESC- and iPSC-derived cardiomyocytes can recapitulate the characteristics of the disease. Furthermore this thesis describes a detailed protocol to differentiate human pluripotent stem cells to cardiomyocytes that was applied in the study comparing hESC- and hiPSC- derived cardiomyocytes at several time points during cardiac differentiation. We targeted fluorescent marker GFP to one allele of NKX2-5 in a human iPSC line that now matched a similar human ESC reporter line previously generated in the laboratory. This offered the opportunity to obtain cardiomyocytes and their precursors at different time points during the differentiation and determine the true degree of similarity between both pluripotent stem cell sources. Additionally the same hESC- and hiPSC-derived cardiomyocytes were compared to a unique set of foetal heart samples. Show less
The aim of this thesis is to review the current knowledge on atrioventricular septal defect (AVSD) (Part 1), to study the pathogenesis of AVSD (Part 2) and finally to analyze cardiac outcome long... Show moreThe aim of this thesis is to review the current knowledge on atrioventricular septal defect (AVSD) (Part 1), to study the pathogenesis of AVSD (Part 2) and finally to analyze cardiac outcome long-term after AVSD correction (Part 3). Studies are performed with novel imaging techniques. In part 2 it is made plausible that AVSD is a sliding scale and that patients with Down syndrome without AVSD also have abnormalities of the membranous septum and atrioventricular valves. High frequency ultrasound in mouse embryos shows to be a promising technique to study cardiovascular flow in early stages of heart development. In a mouse model with disturbed VEGF signalling, the heart rate is reduced and the sinoatrial node develops abnormally. Finally, in part 3 of this thesis, 4DFlow MRI data reveals that patients with an abnormal left atrioventricular valve (LAVV) after AVSD correction have aberrant intra-cardiac flow patterns. During diastole the inflow into the left ventricle is directed more towards the lateral wall, more towards the apex and vortex formation is abnormal. During systole the dynamic and eccentric regurgitation of the LAVV disturbs the normal recirculating flow patterns in the left atrium.4DFlow MRI can be used to reliably quantify flow over the LAVV. Show less
Many studies in developmental biology rely on the construction and analysis of models. This research presents a broad view of modelling approaches for developmental biology, with a focus on... Show moreMany studies in developmental biology rely on the construction and analysis of models. This research presents a broad view of modelling approaches for developmental biology, with a focus on computational methods. An overview of modelling techniques is given, followed by several case studies. Using 3D reconstructions, the heart development of the turtle is examined, with special attention to heart looping and the development of the outflow tract. Subsequently, an ontology system is presented in which anatomical, developmental and physiological information on the vertebrate heart is modelled. Finally, two Petri net models are discussed, which model the developmental process of gradient formation, both in a qualitative and quantitative manner. Show less
Boogerd, C.J.J.; Wong, L.Y.E.; Boogaard, M. van den; Bakker, M.L.; Tessadori, F.; Bakkers, J.; ... ; Barnett, P. 2011
While the embryonic heart is developing and maturing towards its four-chambered form, the cardiac conduction system (CCS) is developing as well. The CCS will provide the heart with the required... Show moreWhile the embryonic heart is developing and maturing towards its four-chambered form, the cardiac conduction system (CCS) is developing as well. The CCS will provide the heart with the required wiring system to ensure the properly orchestrated contraction of the myocardial chambers. In both the young and adult population rhythm disturbances or cardiac arrhythmias can occur. Electrophysiological studies have shown that these events do not occur randomly in the heart but rather at anatomical predilection sites. This thesis presents our results on the morphological as well as electrophysiological changes that occur during heart development, specifically in the developing sinoatrial and atrioventricular node. By studying the developmental changes we aim to increase our knowledge on the mechanism underlying arrhythmias. Show less
The processes of heart development, in which a primitive heart tube transforms into a specialized organ with two atria and ventricles divided by septa, are not only important for the understanding... Show moreThe processes of heart development, in which a primitive heart tube transforms into a specialized organ with two atria and ventricles divided by septa, are not only important for the understanding of congenital heart defects. These processes also give more insight for the development of heart regeneration therapies. The aim of this thesis was two fold. In the first part, we described the expression pattern of PDGF-A, -C and their receptor PDGFR-_ in the avian heart. Additionally, we studied mouse embryos in which the Pdgfr_ gene was mutated. These data show new insights into the role of PDGFR in a gene regulatory network which supports the development of cardiac structures. The second part of this thesis focused on the process of EMT in human adult EPDC and the role of the EPDC in the differentiation of cardiomyocytes. We gained more insight into the factors involved in EMT of the adult epicardium and showed that EPDCs are indispensible for proper integration of cardiomyocytes into a synchronously beating syncythium. These results might be beneficial for endogenous regulated cell-based cardiac repair. Show less
