The studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular... Show moreThe studies described in this thesis focus on gene therapeutic strategies to target pathological vascular wall remodeling after PT(C)A or bypass surgery. Inflammatory processes and extracellular proteases, both activated by mechanical and vascular injury caused by these interventions, are thought to contribute largely to the development of post-angioplasty restenosis and vein graft disease. Therefore, viral and non-viral gene therapy techniques were used in these studies to deliver genes encoding protective as well as inhibiting proteins in order to modulate the inflammatory cascade (i.e. IL-10 and the MCP-1/CCR-2 pathway) in the first part of this thesis and the plasminogen activator and MMP-system in the second part. Finally, the expression of several involving genes was blocked locally by RNA interference techniques in the last part of this thesis. The possibilities and effects of these gene therapy applications were studied in cell cultures, in a human saphenous vein organ culture model and in two mouse models of restenosis and vein graft disease. Altogether, these studies provided more insight into the pathophysiology of post-interventional remodeling and several potential therapeutic strategies were assessed. Show less
The aim of this thesis was to explore the relation between visceral obesity and the accompanying metabolic disturbances, systemic inflammation and the atherosclerotic process. A newly developed... Show moreThe aim of this thesis was to explore the relation between visceral obesity and the accompanying metabolic disturbances, systemic inflammation and the atherosclerotic process. A newly developed magnetic resonance vessel wall imaging technique was implemented in phenotyping patients and as a therapeutic endpoint in a randomised controlled setting. A three step approach was chosen for this purpose. First, the magnetic resonance black blood vessel wall imaging technique at the magnetic field strength of 3 Tesla was developed and validated. Secondly, phenotyping of viscerally obese subjects was performed with special attention for the role of systemic inflammation and atherosclerosis. Finally, in the setting of a randomised controlled trial, the impact of reducing visceral obesity and systemic inflammation with lifestyle intervention and rosiglitazone treatment (PPARg agonist) on the progression of atherosclerosis was assessed. Show less
In summary, in this thesis it becomes clear that the intrauterine environment created by the mother during pregnancy not only has beneficial effects on the developing embryo / fetus. Although it is... Show moreIn summary, in this thesis it becomes clear that the intrauterine environment created by the mother during pregnancy not only has beneficial effects on the developing embryo / fetus. Although it is too early to draw definite conclusions, the first results of this research line show that maternal apoE-deficiency, in contrast to maternal Ldlr-deficiency, adversely affects the offspring, not only in late fetal stages but also in adult life. Our data indicate that the inflammatory status of the mother and the lack of maternal apoE itself may attribute to the increased cardiovascular disease risk observed in the adult offspring. Hypercholesterolemia and oxidative stress possibly play a more regulatory role. In a first attempt to elucidate the underlying mechanism we show that maternal apoE-deficiency leads to changes in the histone triple-methylation modifications in the vascular wall of the offspring. Thi s can be considered an important lead that needs to be investigated further. It does not mean, however, that we are close to complete elucidation of the underlying mechanism. A lot of research is needed to accomplish this and it is needed. Why? The fact that a hit so early in life exerts negative effects on cardiovascular disease risk in adulthood is worrisome. If we could succeed in elucidating the exact role of epigenetics in this process and are able to translate these data to the human situation, possibly we could reduce the incidence of cardiovascular disease. Show less
The main objective of this thesis was to study the association between nutritional status and survival in end-stage renal disease patients who are maintained on a chronic dialysis treatment. Where... Show moreThe main objective of this thesis was to study the association between nutritional status and survival in end-stage renal disease patients who are maintained on a chronic dialysis treatment. Where as obesity is an established risk factor for morbidity and mortality in the general population, many survival studies in hemodialysis patients have indicated reverse associations of obesity with mortality. We showed, however, that the association between BMI and mortality in the hemodialysis population was similar, and not reversed compared with the general population of equal baseline age and duration of follow-up. Independent from BMI, weight loss and muscle mass depletion were both associated with an increased mortality risk in hemodialysis patients. Furthermore, we observed an interaction effect between protein-energy wasting, inflammation and cardiovascular disease, resulting in excess mortality in chronic dialysis patients. Finally, compared with a normal nutritional status, the short-term impact of protein-energy wasting on mortality appeared more important than the long-term effect. The results of this thesis emphasize the importance of maintaining a good nutritional status in chronic dialysis patients. The nutritional status of dialysis patients should be assessed regularly, at least every 6 months. In clinical practice, the 7-point Subjective global assessment can be used for this. Show less
Atherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i... Show moreAtherosclerosis is a multifactorial disease of the large arteries and the leading cause of morbidity and mortality in industrialized countries. There is ample evidence that hypercholesterolemia (i.e. elevated plasma levels apo-B-containing lipoproteins) is a major causative factor in atherogenesis. It is equally clear that atherogenesis has an inflammatory component which is thought to drive the progression of the disease. However, while the lipid component in atherosclerosis development is relatively well-understood, the origin and exact contribution of the inflammatory component remains largely unknown. The aim of this thesis is to further define and delineate the contribution of the inflammatory component to the atherosclerotic process and to elucidate the link between cholesterol and inflammation in atherosclerotic lesion formation and progression. The studies of this thesis show that, besides plasma cholesterol, inflammation contributes to a substantial extent to atherogenesis. Intervention strategies directed at lowering apoB-containing lipoproteins and reducing inflammation may therefore be more effective than current lipid-lowering strategies. Direct experimental evidence for this assumption mainly comes from animal experiments as described in this thesis. Human intervention studies are necessary to evaluate whether these findings can also be translated to the human situation. Show less
