Bellamy, Michael Francis; (2000) Homocysteine and endothelial function. Doctoral thesis (M.D), UCL (University College London).

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Abstract

Dysfunction of the endothelium is an early event in the pathophysiology of atherosclerosis. Elevated plasma homocysteine (Hey) is a risk factor for vascular disease which may be mediated by endothelial injury. The thesis describes a series of clinical and laboratory experiments to investigate the relationship between Hey and endothelial function. Non-invasive measurement of endothelial dysfunction in humans was assessed in the forearm as an impaired increase in brachial artery diameter during reactive hyperaemia (shear stress-induced, nitric oxide-mediated vasodilatation). Responses were compared with endothelium-independent vasodilatation following sublingual glyceryl trinitrate. Flow-mediated brachial artery dilatation (FMD) using this method, was shown to be an endothelium-dependent mechanism and normal values for the population established with the addition of regression modelling to define an appropriate index to represent endothelium-dependent and -independent responses. An association between hyperhomocysteinaemia and FMD was demonstrated in (i) homozygous homocystinuria, (ii) following an acute elevation of plasma Hey after oral methionine loading (an effect that was partially reversed by the prior oral administration of vitamin C), and (iii) in subjects with low B12/folate status (where elevated Hcy resulted from impaired remethylation). However, in a cross-sectional population study across the range of Hcy concentrations no correlation between Hcy and FMD was observed. In healthy subjects with mild hyperhomocysteinaemia, oral folic acid supplementation (5mg daily for 6 weeks) enhanced FMD and lowered Hcy, providing preliminary evidence that folate may have beneficial cardiovascular effects in adults with elevated Hcy levels. In vitro, endothelium-dependent relaxation in isolated rabbit aortic rings to both receptor-dependent and -independent agonists was impaired by Hcy. Prior incubation with antioxidants and the intracellular superoxide scavenger, Tiron, attenuated the inhibitory effect of Hcy supporting the hypothesis that Hcy-related endothelial injury may be mediated in part by oxidative stress and alterations in intracellular redox status.

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