Plasma homocysteine, atheromatous vascular disease and platelet function

Cardiovascular disease is the major cause of death in man. The prevalence of cardiovascular disease varies in different ethnic groups, which implies variation of risk factors between different populations. Some new risk factors have emerged recently, which may also contribute to the prevalence of cardiovascular disease. Among these the total homocysteine level (tHcy) in plasma/serum has created much interest and has been regarded as an important and independent risk factor for cardiovascular disease. Plasma tHcy levels are less well elucidated in Chinese populations compared to the populations in the US and in Europe. Therefore, we performed serial investigations on plasma tHcy and explored its role in Chinese subjects for the purpose of evaluating its importance in atherosclerosis in Hong Kong Chinese. In a sample of 65 Hong Kong Chinese diabetic patients, 23 were identified as having presented with peripheral vascular disease (PVD) based on ankle brachial systolic pressure ratio. The presence of PVD in these patients showed associations with age, systolic blood pressure, plasma/serum creatinine, fibrinogen, tHcy, sialic acid, urine albumin/creatinine ratio, and vitamin C. Plasma tHcy levels were significantly higher in patients with PVD compared to those without PVD. However, this difference no longer existed after adjustment for the degree of nephropathy. Plasma tHcy levels did not appear to contribute independently to the prevalence of PVD in Hong Kong Chinese diabetics. Its importance requires further evaluation.; In another approach, we assessed the effects of homocysteine on platelet function in vitro and established a model of mild to moderate hyperhomocysteinaemia in vivo by methionine loading for evaluating the effects of homocysteine on platelet function, endothelial function and parameters of oxidative stress. Homocysteine at physiologically elevated concentration did not induce spontaneous platelet aggregation in vitro, however, at this concentration it did potentiate platelet aggregation induced by physiological agonists. However, this potentiation of platelet aggregation was not likely to occur through fibrinogen binding to platelet IIb/IIIa receptor and neither was it accompanied by platelet α granular secretion measured by flow cytometry and plasma platelet specific proteins β-thromboglobulin and platelet factor 4.; In in vivo studies, acute elevation of tHcy levels produced evidences of damage to the endothelium and platelet activation. The decrease of fibrinogen binding to platelets and platelet P-selectin expression seen after placebo and possibly caused by nitroglycerin used in the experiments, were neutralised in the subjects who received methionine loading. Activation and damage to the endothelium, evidenced by elevation of Von Willebrand factor (vWF) and plasminogen activator inhibitor 1 (PAI-1), were observed in the subjects after methionine loading. All these changes in the subjects in the methionine loading group were not accompanied by changes in indices of oxidative stress. However, in vivo, we do not identify fibrinogen binding and P-selectin expression changes caused by the damage of endothelium or by elevation of tHcy levels. From the results summarised above, elevation of plasma tHcy may be involved in atherosclerogenesis possibly through the activation of platelets either directly or through the damage to the endothelium.