Homocysteine, B-vitamins and cardiovascular disease : epidemiologic evidence

<strong><em>Background</em></strong> Cardiovascular disease constitutes a major public health problem in the Netherlands and other Western countries. Elevated plasma homocysteine has attracted growing interest as a "new" risk factor for cardiovascular disease. Homocysteine is formed from the essential amino acid methionine. Defective Homocysteine, metabolism may lead to elevation of plasma total homocysteine (tHcy). Genetic enzyme deficiencies or inadequate intake of vitamins B _{<font size="-2">6</font>} , B _{<font size="-2">12</font>} , and folate, all important cofactors in homocysteine metabolism, may result in elevation of tHcy. Accumulation of tHcy can possibly promote atherosclerotic or thrombotic processes.<em><strong>Methods</strong></em> The epidemiologic studies presented in the thesis, aimed to find additional evidence for the hypothesis that elevated plasma tHcy is an independent risk factor for cardiovascular disease. We addressed various disease endpoints, with data of prospective and retrospective studies, from Dutch, European, and US populations. The role of the B-vitamins and of a genetic enzyme defect, predisposing to high tHcy levels, were studied.<em><strong>Results</strong></em> Overall, in line with other findings, most of our studies showed that elevated tHcy is an independent risk factor for cardiovascular disease. Results indicated that the risk increased with rising levels of tHcy, with no threshold effect. The estimated average % increase in risk for 5 μmol/L (about 1 SD) increase in fasting tHcy varied between 20% and 60% in the various studies. In a large European case-control study, we found that elevated tHcy was a strong risk factor in women, both in pre- and postmenopausal women.Folate concentrations in plasma or expressed per haematocrit, and dietary folate were found to be important determinants of plasma tHcy in several studies. In one of our studies, in concordance with findings of others, tHcy reached its nadir at a folate intake of 400 μg/day. Furthermore, we observed that homozygosity for a mutation in 5,10-methylenetetrahydrofolate reductase, in combination with low folate status, predisposed to particularly high tHcy levels, and may thereby increase risk of cardiovascular disease.<strong><em>Conclusions & implications</em></strong> Dietary folate intake of a large segment of the general population is lower than 400 μg/day, and tHcy may be generally increased. Several studies have already shown that elevated tHcy can be normalized by supplementation with folate, even at a dose of 650 μg/day. Thus, increased folate intake seems an important way to decrease tHcy in populations, thereby possibly reducing incidence of cardiovascular disease. Large-scale prevention trials are warranted to demonstrate the efficacy of tHcy-lowering, and the minimal folate intake required. At this moment, based on the available epidemiologic evidence, it is advisable to increase consumption of fruits and vegetables in the general population. Results from prevention trials will indicate whether additional measures, such as fortification of food or supplementation are justified as well.