A strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy... Show moreA strong correlation exists between abdominal aortopathy and atherosclerosis. In thoracic aortopathy however, the prevalence of atherosclerosis and its role in the etiology of thoracic aortopathy remained unknown. This thesis therefore studied the cardiovascular disease burden within this patient group. These results showed that the prevalence of atherosclerosis (i.e. cardiovascular disease burden), in contrast to abdominal aortopathy, is not increased within the thoracic aortopathy population. Show less
Acute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is... Show moreAcute cardiovascular syndromes, including myocardial infarction or stroke, are the principal cause of death in the Western society. The main underlying pathology of cardiovascular diseases is atherosclerosis, which is caused by the accumulation of lipids and inflammatory cells in the vessel wall, in so-called atherosclerotic plaques. Current therapies mainly target the disturbed lipid homeostasis, but recent clinical trials have shown a clear benefit in treating patients with anti-inflammatory drugs. However, more specific targeting is required to avoid unwanted side effects. In this thesis, we have generated a detailed atlas of all the cells present in human atherosclerotic plaques using a novel state-of-the-art technique called single-cell RNA sequencing. This data set can be applied as a powerful tool to select potential drug targets with a functional relevance for atherosclerosis. We showed that the majority of the immune cells in the human atherosclerotic plaque consisted of T cells. Subsequently, we identified a pro-inflammatory population of T cells that likely responds to a plaque-derived antigen, suggesting that atherosclerosis has an autoimmune-like component. Finally, we have applied our single-cell atlas to define and validate targets to intervene with the recruitment and activation of mast cells and other immune cells in atherosclerosis. Show less
With ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is... Show moreWith ageing populations, the prevalence of age-related disorders such as dementia is on the rise. As there is currently no curable treatment for dementia, the vascular component of dementia is increasingly recognised as a key modifiable cause. This thesis aims to investigate biological pathways between risk factors of cardiometabolic disease and cognitive function, in a population of older adults at increased risk of cardiovascular disease (CVD). We hypothesise that changes in physiological functioning caused by (sub)clinical CVD are possible mediators within the pathway leading to cognitive dysfunction. In the first part of this thesis, we studied electrocardiogram-based intervals and serum cardiac biomarkers (such as troponin) in relation to cognitive function. In the second part of this thesis, we studied the interplay of body mass index and serum leptin, loss of body weight and body weight variability, as well as metabolomics-based health scores in relation to cognitive function. We found that various cardiometabolic risk factors are associated with worse cognitive function. The results of this thesis strongly suggest that subclinical changes in cardiometabolic health may exist before cognitive dysfunction becomes apparent. Treating these cardiometabolic risk factors may be of benefit to future cognitive health. Show less
In the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the... Show moreIn the first part of this thesis we focus on the genetic determinants of lipid metabolism as atherogenic dyslipidemia is major component of cardiometabolic disease and consequently of CVD. In the second part of the thesis, we study the age-related changes of cardiometabolic risk factors over the life course across four generations. In this thesis, we aimed to gain new insights into the underlying pathophysiology of cardiometabolic disease and the long-term and cumulative exposure of its risk factors over the life course, thereby facilitating the search for preventive and curative strategies of cardiometabolic disease. In the first part of this thesis, we focused on the genetic determinants of lipid metabolism during both fasting and postprandial states. In the second part, we studied the age-related changes of cardiometabolic risk factors, in particular of body weight, overweight and obesity, over the life course across four generations. An important finding of the thesis is that obesity has worsened in the younger generations, reaching almost double the prevalence of older generations. However, after midlife the levels of obesity levelled off, which could be a reason why the adverse shift in obesity was not associated with unfavourable changes in cardiometabolic risk factors. We also found out that some genes effect body weight differently at different ages, which suggests that gene-environment interactions play an important role in body weight and consequently in obesity. Show less
In this thesis we observe that prescription rates of lipid-lowering drugs and antithrombotic medication in secondary prevention in old age are low. According to focus-group discussions with general... Show moreIn this thesis we observe that prescription rates of lipid-lowering drugs and antithrombotic medication in secondary prevention in old age are low. According to focus-group discussions with general practitioners highly individualized care with the ultimate aim to improve quality of life, might largely explain these low prescription rates; however, improvements might be expected from structured follow up, and tailored, age-specific guidelines, reflecting the heterogeneity of clinical practice. In very old age we observed that the severity of the cardiovascular disease history is associated with unfavourable prognosis, not only with regard to (recurrent) cardiovascular disease/mortality, but also with regard to future disability and cognitive decline. Of four newer cardiovascular risk markers N-terminal pro B-type natriuretic peptide (NT-proBNP) was the strongest predictor of cardiovascular events/mortality in secondary cardiovascular prevention in very old age. NT-proBNP was also associated with cognitive and functional decline. Finally NT-proBNP predicted treatment effect of pravastatin. In order to improve patient care in older age, the following actions are recommended: vigorous ICPC coding and pro-active follow-up of all older patients with a history of cardiovascular disease. Finally, optimisation of secondary cardiovascular prevention is advised by individualised risk prediction and consciously weighing all pros and cons of preventive treatment. Show less
Current therapies for patients with atherosclerosis are targeted primarily on reducing blood cholesterol, but this fails to prevent a large number of cardiovascular events.95 In order to identify... Show moreCurrent therapies for patients with atherosclerosis are targeted primarily on reducing blood cholesterol, but this fails to prevent a large number of cardiovascular events.95 In order to identify new therapeutic strategies for treating atherosclerosis, it is important to study the interactions between the cells that make up the atherosclerotic lesion. This thesis describes the role of endothelial cells and macrophages during lesion formation, as well as the expression patterns of sterol sensors in vascular smooth muscle cells present in the lesion. These new insights contribute to our understanding of atherosclerosis open up new avenues of atherosclerosis research Show less
Cardiovascular disease is an important problem in the western world and identification of individuals at risk of cardiovascular disease and identification of patients with cardiovascular disease... Show moreCardiovascular disease is an important problem in the western world and identification of individuals at risk of cardiovascular disease and identification of patients with cardiovascular disease who are at risk of complications is important in order to reduce morbidity and mortality. This thesis shows the potential of MRI for risk stratification in cardiovascular disease. MRI enables assessment of morphology and function of the aortic vessel wall, which is important since the thickness and stiffness of the aortic vessel wall are related with coronary artery disease and cardiovascular events. Furthermore, the potential of MRI for visualization of the coronary arteries and assessment of coronary artery flow is explored. Although, this technique is not yet routinely used, ongoing research may in the future make MRI a valuable technique for detection of coronary artery disease. In addition, it is demonstrated that MRI is an excellent technique for detection and quantification of valve regurgitation. MRI also allows for quantification of scar tissue and contractile reserve in patients with ischemic cardiomyopathy enabling assessment of viability, which is important for optimization of treatment and prognosis. Finally, it is demonstrated that infarct size and infarct tissue heterogeneity measured with MRI are important predictors for long-term survival. Show less
The aim of this thesis was to study cardiovascular risk management in old age, in order to facilitate the development of age specific guidelines. In part one the current status of cardiovascular... Show moreThe aim of this thesis was to study cardiovascular risk management in old age, in order to facilitate the development of age specific guidelines. In part one the current status of cardiovascular prevention in old age is described, including a study into general practitioners__ attitudes and perceived barriers in this respect. The second part explores the incremental value of routine-ECGs for cardiovascular risk management in older persons from the general population, beyond existing information from medical records. The third part focuses on primary prevention, exploring the performance of classic risk factors, and some new biomarkers, in predicting cardiovascular mortality in very old people from the general population. It was concluded that a homocysteine level alone accurately identifies those at high risk of cardiovascular mortality, whereas classic risk factors included in the Framingham risk score do not. Next, in various age strata from age 55 years onwards, the association between blood pressure and mortality was studied. Finally, a systematic review into the diagnostic accuracy of natriuretic peptides for the diagnosis of chronic heart failure in older persons from the general population was performed, followed by a study in a cohort of nonagenarians into the prognostic value of NT-proBNP. A general discussion is provided, including directions for future research. Show less
With the use of combinatorial phage display, solid phase peptide synthesis and a multidiscipline of molecular and cellular assays in vascular biology, the research described in this thesis has... Show moreWith the use of combinatorial phage display, solid phase peptide synthesis and a multidiscipline of molecular and cellular assays in vascular biology, the research described in this thesis has resulted in the identification of two novel peptides targeting to SR-AI and CD40 respectively which hold promise as targeted contrast agents for the diagnosis of atherosclerosis symptom. In addition, a peptide named VIVIT and its derivatives had been discovered and synthesized which constitute a more selective and less toxic drug candidate than currently used immunosuppressant cyclosporine A or FK506, leading to new generation immunosuppressants and therapeutics for autoimmune diseases such as rheumatoid arthritis or allograft transplantation and cardiovascular disorders including atherosclerosis, restenosis and cardiac hypertrophy. Show less
The main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e.... Show moreThe main cause of cardiovascular disease (CVD) is atherosclerosis. Several genes that affect atherosclerosis development have been identified by the use of genetically modified mice (i.e. transgenic and knock-out mouse models). Many of these genes exert their role in atherosclerosis development as a result of effects on lipoprotein metabolism and inflammation. Transgenic mouse models have also been proven to be suitable for evaluating the mechanisms underlying the anti-atherosclerotic action of experimental drugs aimed to reduce atherogenic lipoprotein levels. However, thus far no suitable animal model was present to evaluate the mechanism of action of anti-atherosclerotic effect of HDL-raising therapeutic strategies. In this thesis, we further explored the role of apolipoprotein CI (apoCI) and cholesteryl ester transfer protein (CETP) in lipoprotein metabolism, inflammation, and atherosclerosis. Furthermore, we developed a mouse model that will be suitable for testing potential high-density-lipoprotein (HDL) raising therapies as a novel strategy to treat CVD. Show less
