Abstract
Cardiovascular disease due to premature atherosclerotic disease is the major cause of death in Western Societies. Key factors in the origin of premature atherosclerotic disease are lipid disturbances. Although classic lipid parameters predict cardiovascular disease in a huge amount, novel factors in the development of atherosclerosis prove to have an
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increasing role. Remnants of triglyceride-rich particles for example exhibit high atherogenic properties, in parallel with LDL-cholesterol and triglycerides. In this thesis, both patients with heterozygous familial hypercholesterolemia and patients with disturbances in their somatotropic axes (adult-onset growth hormone deficiency and acromegaly) have an exaggerated postprandial response concerning remnant-like particles (RLP). Disturbances in the somatotropic axes and cardiovascular mortality are reflected by a U-curve. Recent literature showed changes in the homeostatic balance of somatotropic axes (pituitary GH axis, superposed on paracrine/autocrine IGF systems) during ageing, but also in more cardiovascular disease related clinical features, such as type II diabetes. The origin of this exaggerated postprandial RLP-C response depends on the population tested but was detected on several levels, such as a decreased activity of lipoprotein lipase, increased insulin resistance and a low expression of hepatic LDL receptors In addition, semi-endpoints of atherosclerotic disease, such as intima media thickness and endothelial function, were closely related to plasma RLP-C levels. Moreover, the postprandial RLP-C response in adult-onset growth hormone deficiency was associated to the increased postprandial pro inflammatory response. In addition to the relationship of the somatotropic balance with a proatherogenic phenotype, a similar relationship was observed with a prodiabetic phenotype (impaired insulin secretion and increased de-novo glucose synthesis). The effect of GH therapy on the balance of gluconeogenesis (GNG) and glycogenolysis in GH deficient subjects was studied with use of latest stable isotope techniques and showed a compensatory response with the synthesis of de-novo glucose during GH therapy. A close relation was found between GNG and IGF-II (an important component of the IGF system, especially in prenatal life, which is 66% genetically determined in its variability of plasma expression). In a case report, the effect of especially high circulating levels of GH, and in a less amount IGF, on the cardiac performance was evident in an overt acromegalic patient.
In conclusion, this thesis gave rise to evidence that RLP is a lipid parameter that further completes an atherogenic lipid phenotype and that disturbances in the somatotropic axis are closely related to the expression of both a proatherogenic and a prodiabetic phenotype. A further analysis may therefore increase knowledge about the key role of GH or components of the IGF system in atherogenesis or atherosclerosis related clinical features.
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