Homocysteine and Cardiovascular Risk: The Perils of Reductionism in a Complex System

[摘要] Patients with genetic defects causing severe hyperhomocysteinemia have a high rate of mortality from cardiovascular diseases at an early age, irrespective of the specific genetic lesion. Long-term therapy with B vitamins or betaine in patients with homocystinuria due to cystathionine β-synthase deficiency decreases homocysteine and reduces the rate of vascular events by 90%. Kilmer McCully studied the vascular pathology in young patients who died with homocystinuria and in 1969 proposed that a moderate increase in circulating homocysteine could be involved in the pathogenesis of vascular occlusive disease in the general population, i.e., the so-called homocysteine theory of atherosclerosis. This theory was investigated in the early 1990s in many clinical and epidemiologic studies. A metaanalysis of studies of homocysteine concentration and vascular risk concluded that an increase of 0.68 mg/L (5 μmol/L) in plasma homocysteine had an impact on cardiovascular risk that was equivalent to a 19-mg/dL (0.5-mmol/L) increase in total cholesterol. In general, the risk estimates from the prospective studies are weaker than those obtained from case–control and cross-sectional studies (1, 2), yet they clearly support plasma homocysteine as an independent cardiovascular risk factor.The possible role of homocysteine in the development of vascular disease inspired research on the biochemical and molecular effects on the vasculature of homocysteine and the determinants of circulating homocysteine concentrations. Experimental studies revealed numerous homocysteine effects relevant to the pathogenesis of vascular disease, including induction of endothelial dysfunction, inhibition of biological methylation through accumulation of S -adenosylhomocysteine, homocysteinylation and posttranslational modification of proteins, increased oxidant stress, and decreased availability of nitric oxide (1). In addition, plasma homocysteine positively correlates with a variety of biochemical parameters, clinical traits, and lifestyle factors associated with increased cardiovascular risk, including dyslipidemia, increased blood pressure, impaired renal function, a sedentary …

[学科分类] 过敏症与临床免疫学