Stem cell therapy has raised enthusiasm as a potential treatment for cardiovascular diseases. However, questions remain about the in vivo behavior of the cells after transplantation and the... Show moreStem cell therapy has raised enthusiasm as a potential treatment for cardiovascular diseases. However, questions remain about the in vivo behavior of the cells after transplantation and the mechanism of action with which the cells could potentially alleviate disease symptoms. The objective of the research as described in this thesis was to visualize survival, proliferation, and migration of embryonic (ESC) and adult stem cells using non-invasive molecular imaging techniques in small animal models of cardiovascular diseases. The major findings can be described as follows: (1) Non-invasive bioluminescence imaging is a validated tool to monitor donor cell survival, proliferation, migration, and misbehavior; (2) ESC are a potential source for true regenerative therapy; (3) ESC form teratomas; (4) Adult stem cell survival is short-lived, but of all cells currently used in the clinic, mononuclear cells show the most prolonged survival; (5) Transplantation of mononuclear cells can preserve cardiac function in the short term after myocardial infarction in mice; (6) Compared to other measurements of murine cardiac function, Micro-CT is a superior method to assess cardiac geometry and function; and (7) Transplantation of mononuclear cells in peripheral artery disease is hampered by dismal cell survival and homing. These findings illustrate the current challenges for optimizing stem cell therapy for cardiovascular disease. 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
Cardiovascular disease is the principal cause of mortality in patients with type 2 diabetes mellitus. The present thesis describes a study, designed at a time-point when no primary prevention trial... Show moreCardiovascular disease is the principal cause of mortality in patients with type 2 diabetes mellitus. The present thesis describes a study, designed at a time-point when no primary prevention trial had yet been performed to investigate the effects of statin therapy on patients with type 2 diabetes without cardiovascular disease. We have performed a randomized, double-blind placebo-controlled trial in 250 type 2 diabetic patients without manifest cardiovascular disease. The aim of the study was to study non-invasively the effect of two year statin therapy on the vessel wall. We found no effect of two year statin therapy on carotid IMT as a reflection of the progress of atherosclerosis. We found no effect on endothelial function as assessed by FMD. The effect of statin therapy on CRP, as a marker for low grade inflammation, was only significant in a high- risk subgroup with the metabolic syndrome and a high LDL-cholesterol. There was no effect of two-year statin therapy on the prevalence of silent myocardial ischemia. In spite of these findings, we observed a lower cardiovascular event rate in patients on statin therapy, which is in line with other clinical trials. Show less
Cardiovascular diseases are the major cause of morbidity and mortality in western societies. The most common clinical manifestations are stroke and acute myocardial infarction and in both ailments... Show moreCardiovascular diseases are the major cause of morbidity and mortality in western societies. The most common clinical manifestations are stroke and acute myocardial infarction and in both ailments atherosclerosis is the underlying culprit. Atherosclerosis is a lipid-mediated chronic inflammatory disease, which is accompanied by leukocyte infiltration into the vessel wall. The migration of leukocytes from the circulation to the vessel wall is directed by a specific class of proteins, the chemokines. Therefore it is likely that chemokines have a distinctive role in leukocyte homeostasis at specific stages of atherosclerotic disease progression and during ischemia-reperfusion injury. This thesis encompasses of number of human and experimental mouse studies on the role of chemokines in cardiovascular diseases and atherosclerosis, from which several new targets were identified. For instance it is evident that patients with high levels of the chemokine CCL3 are 10 times more likely to develop severe cardiovascular events in the future. In conclusion, the research described in this thesis provided novel candidates that might be of value for the early prediction of high risk patients. Moreover, the identified candidates may also represent valuable targets for modulation of leukocyte homeostasis in the plaque that could improve atherosclerotic plaque progression and stability. 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
The research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_... Show moreThe research described in this thesis focussed on the role of apolipoproteins in lipid metabolism, inflammation and bacterial sepsis, with specific emphasis on apoCI. From studies in human APOC1_-transgenic and apoc1-/- mice, we were able to identify apoCI as a potent inhibitor of triglyceride hydrolysis by inhibiting lipoprotein lipase. Since APOC1 mice have thus increased VLDL levels, and VLDL protects against bacterial infection, we studied whether apoCI could play a role in inflammation and infection. We found that apoCI was able to bind lipopolysaccharide (LPS), the main toxic component of Gram-negative bacteria. Interestingly, although other apolipoproteins which have been studied have anti-inflammatory properties, we found that apoCI is a pro-inflammatory protein. By enhancing the biological response towards LPS and Gram-negative bacteria, apoCI dose-dependently improved the anti-bacterial attack, and protected against intrapulmonal Klebsiella pneumoniae-induced sepsis. Consistent with these experimental findings we also found that subjects with high plasma apoCI levels were less prone to infection-related mortality during follow-up, independent of plasma lipid levels. Likewise, survivors of severe sepsis showed higher plasma apoCI levels as compared to non-survivors, again independent of lipid levels. Taken together, our findings indicate that apoCI is an important determinant of the inflammatory response in mice and humans. Show less
