Adiposity, adipocytokines & microvesicles in the etiology of vascular disease

Abstract

Vascular disease, in this thesis the terms vascular and cardiovascular are used interchangeably, is the number 1 cause of death worldwide. In 2008, 30% of all mortality had a vascular origin. Vascular mortality rates after a first manifestation of vascular disease are decreasing in Western society, which is attributable to better disease awareness, better preventive strategies and better healthcare systems. As mortality rates are decreasing, the number of patients surviving their first vascular event is increasing rapidly. These patients with manifest vascular disease are at increased risk for subsequent vascular disease as well as vascular or all-cause mortality. Despite traditional vascular risk factors explain the risk for these subsequent event largely, these patients remain subject to substantial residual risk. In addition, traditional risk factors for subsequent vascular disease might a distinct impact on the occurrence of subsequent vascular disease. Therefore it is of upmost importance to gain better understanding of the risk for subsequent vascular events or mortality in patients with manifest vascular disease. In chapter 2, the association between three different general and abdominal adiposity parameters (BMI, waist circumference and abdominal adipose tissue ultrasound) and subsequent vascular events and mortality was assessed in patients with clinically manifest vascular disease. We also aimed to explore this association for various phenotypes of recently diagnosed vascular disease as studies suggest that the association between adiposity and clinical events in these patients depends on the type of vascular disease. To elaborate on the associations described in this chapter, we aimed to qualify rather than quantify adipose tissue function (or dysfunction) by measuring a prespecified set of adipocytokines and to evaluate the risk for vascular events and mortality in chapter 3. Although numerous adipocytokines induce inflammation, atherosclerosis, fibrosis, thrombosis, insulin resistance and diabetes, based on in vivo and in vitro studies, the most extensively studied adipocytokine, adiponectin, has been accredited a protective role in the development of these conditions. In chapter 4 we meta-analyze evidence regarding the relation between plasma concentrations of adiponectin and the risk for future CHD and stroke, the two most common manifestations of vascular disease. As obesity is a risk factor for vascular diseases and diabetes and has been linked to both structural and functional disturbances of the brain we assessed if adipocytokines are associated with structural brain measurements in chapter 5. Prevention of vascular disease has a larger impact on the health and welfare of a population than any treatment of proven value that can be administered after a vascular event has occurred. Modifiable lifestyle factors could play a substantial role in the prevention of stroke, as they contribute substantially in the risk for primary or subsequent stroke. Therefore we aimed to overview the evidence regarding the role that modifiable lifestyle factors have on primary or subsequent stroke in chapter 6. There is a growing body of evidence indicating that microvesicles play an important role in the etiology of vascular disease. However, vascular research thus far has focused upon the quantity of microvesicles. In chapter 7 we evaluate the relation between the quality of microvesicles, specifically their transmembrane or cytosolic protein levels and the risk for vascular events and mortality. As vascular disease and cognitive decline share important risk factors and patients with vascular disease are at risk for cognitive decline, we assessed whether microvesicle protein levels, were associated with structural brain changes in chapter 8. Finally, in chapter 9 the main findings of the studies described in this thesis are discussed.