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Section III

Hyperhomocysteinemia and

Atherosclerosis

330 Enoka P. Wijekoon et al.

less severe increases in plasma homocysteine may pose a risk. Since then, a plethora of prospective, retrospective, and cross-sectional studies have appeared that link moderate hyperhomocysteinemia to atherosclerotic disease. These studies show that patients with coronary, cerebrovascular, or peripheral arterial occlusive disease have mean plasma total homocysteine (tHcy) levels greater than control subjects. Kang et al. [2] reported mean plasma tHcy to be significantly higher both in male and female patients with coronary artery disease when compared to controls with angiographically normal coronary arteries. Since cross-sectional studies deal with patients who already exhibit disease characteristics, they do not answer the question whether hyperhomocysteinemia gives rise to the coronary artery disease or vice versa [3]. Two large prospective studies address this question. The Physicians’ Health Study, which studied male physicians in the USA, showed that a plasma homocysteine concentration of only 1.7 mol/L or 12% greater than the upper normal level was associated with a 3.4-fold increase in the risk of myocardial infarction [4]. The Tromso study, which investigated over 21,000 subjects between the ages of 12 and 61, showed an increase in the relative risk for coronary heart disease of 1.32 after adjusting for possible confounders [5]. Meta-analyses confirm homocysteine’s status as an independent risk factor although they disagree on its strength. A meta-analysis of 27 studies relating homocysteine to coronary, cerebrovascular, and peripheral arterial vascular disease showed a very strong relationship between these diseases and tHcy [6]. It was concluded that a 5 mol/L increment in tHcy was comparable to a 0.5 mmol/L increment in cholesterol in increasing the incidence of coronary artery disease. A more recent meta-analysis that examined 30 prospective and retrospective studies confirmed that increased plasma homocysteine is an independent predictor of ischemic heart disease but of only moderate strength [7]. The same group [8] has reported a meta-analysis of the MTHFR 677TT polymorphism, which tends to increase plasma homocysteine, particularly in the context of low folate. They found that individuals with the MTHFR 677TT genotype had a significantly higher risk of cardiovascular disease especially when found in conjunction with a low-folate status. The uncertainty about the degree of risk associated with elevated plasma homocysteine may be attributed to a number of factors, but Stamm and Reynolds [9] have emphasized one important factor: tHcy in plasma may not be the most appropriate marker of cardiovascular disease risk. In particular, risk may be more closely linked either to cellular homocysteine or to a particular component of plasma homocysteine.

There are certain situations in which the risk attributable to homocysteine may be elevated. Certainly, there is evidence that hyperhomocysteinemia is a stronger risk factor in patients with type 2 diabetes [10] and in patients with existing coronary disease. In this latter group, Nygard et al. [11] found a direct relationship between plasma homocysteine levels and overall mortality; at 4 years, Kaplan–Meier estimates of mortality were 3.8% for patients with tHcy levels less than 9 mol/L, 8.6% for patients with homocysteine