Homocysteine, folate and risk of atherosclerosis: From bench to bedside

In this study, endothelial-dependent dilation of brachial artery (EDD) and carotid intima-media thickness (IMT) measured by high-resolution ultrasound were used as surrogate markers of atherosclerosis. We aimed to investigate: (1) The major determinants of total plasma homocysteine (tHcy) and the interaction between genetic and environmental factors; (2) The association of homocysteine with the severity and extent of coronary atherosclerosis in coronary artery disease (CAD); (3) The impact of homocysteine on the accelerated atherosclerosis in predialysing chronic renal failure (PRF); (4) The independent impact of folate deficiency on arterial endothelial function and early atherosclerosis. (5) The role of inflammation in homocysteine-related atherosclerosis; (6) The benefit of folate supplementation on brachial EDD in CAD and predialysing renal failure.;Firstly we studied 636 Chinese patients with angiographically documented CAD. Plasma creatinine, folate, vitamin B12 and methylenetetrahydrofolate reductase (MTHFR) TT genotype were independently correlated to tHcy with significant interaction between folate and TT genotype. Additionally, elevated level of tHcy (≥10 mumol/l) was independently associated with severe coronary atherosclerosis documented by Gensini score (adjusted odds ratio = 1.6, 95% CI 1.2--2.4).;Subsequently we recruited 258 PRF patients. Of these patients, 64.3% had plasma tHcy greater than 15mumol/l. Smoking, plasma folate, vitamin B12 and plasma creatinine were the major independent determinants of tHcy in PRF, while hypertension, overweight/obesity, smoking and elevated plasma tHcy (≥20mumol/1, upper tertile, adjusted OR = 1.9, 95% CI 1.0--3.4), but not folate were the major determinants of accelerated carotid atherosclerosis.;Based on the results, we concluded that (1) In CAD patients, plasma folate, vitamin B12, MTHFR C677T mutation are the major determinants of plasma homocysteine. Plasma folate status is especially determinative in TT subjects; (2) Elevated plasma homocysteine is independently associated with coronary atherosclerosis in CAD and carotid atherosclerosis in predialysing chronic renal failure; (3) Homocysteine may trigger vascular inflammation, impair arterial endothelial function and accelerate formation of atherosclerosis in asymptomatic community model; (4) Folate has independent vascular-protective effects. Folate deficiency predisposes to arterial endothelial dysfunction and intima-media thickening in the asymptomatic community; (5) Folic acid supplementation improves arterial endothelial function in CAD and in predialysing chronic renal failure, independent of its homocysteine-lowering effect. (Abstract shortened by UMI.).