Homocysteine, B-Vitamins, and the Risk of Cardiovascular Disease

Homocysteine is an amino acid involved in folate and methionine metabolism and is a potentially modifiable risk factor for cardiovascular disease. Scientific publications on homocysteine, B-vitamins, and the risk of cardiovascular disease have increased exponentially over the last decade, and hence there is a need for periodic summaries of the current theories and evidence. We invited experts to prepare critical reviews on various aspects of this topic for a special issue of Seminars in Vascular Medicine on homocysteine, B-vitamins, and the risk of cardiovascular diseases. With the accumulation of knowledge, it has become harder for individuals working alone to make an effective contribution in basic pathophysiological research and in epidemiology, not just because of the number of individuals to be studied and range of assays to be analyzed but also because of the need for a multidisciplinary approach required to address research questions. Advances in the epidemiological discoveries on this topic have emerged from multidisciplinary collaborations involving inborn errors of metabolism and neural tube and other congenital defects: European Union COMAC study, BIOMED Homocysteine and holoTC demonstration projects, Homocysteine Studies Collaboration, Homocysteine Lowering Trialists’ collaboration, B-Vitamin Treatment Trialists Collaboration, and the MTHFR studies collaboration. In addition, basic pathophysiological and applied clinical science is also more and more becoming a multidisciplinary, multicenter type of scientific activity. Thus, the chief credit for progress in this field is owed to those investigators who agreed to work together in multidisciplinary collaborations to solve the relevant research questions.

This review commences with an examination of the biochemistry of the enzymes involved in homocysteine metabolism and polymorphisms for the genes encoding the enzymes involved in homocysteine metabolism and the role of folate in the body for methylation and DNA synthesis. The roles of vitamin and other dietary determinants of homocysteine are examined in both healthy and diseased populations. Considerable progress had been made in our understanding of the mechanisms for the atherogenic effects of elevated homocysteine levels, and these are reviewed separately in experimental animal models and in human studies. In recent years, it has become apparent that disease associations with vitamin levels occur not just at low vitamin levels but also at levels previously considered “normal.” This review examines the concepts of cobalamin deficiency and the utility of various laboratory tests to aid clinicians to recommend vitamin B₁₂ therapy.

The importance of adequate intake of folate for prevention of neural tube defects is well established, and folic acid fortification strategies have been shown to be highly effective in reducing the risk of neural tube defects. Nevertheless, many European countries have deferred a decision to introduce fortification because of concerns of possible masking of vitamin B₁₂ deficiency in older people. This review includes a proposal for combined fortification of folic acid with vitamin B₁₂ to address the possible hazards of folic acid fortification and possibly solve this problem.

Homocysteine assays are used in a clinical setting to predict the risk of venous thromboembolism, cardiovascular disease, and cognitive impairment. Dietary supplementation with B-vitamins lowers homocysteine levels, and hence it may be expected that supplementation with these vitamins may reduce the risk of venous thromboembolism, cardiovascular disease, and cognitive decline, respectively. Large trials of B-vitamin supplements in people with prior stroke, coronary heart disease, end-stage renal disease, and venous thromboembolism are currently assessing whether lowering homocysteine levels may reduce the risk of disease in the respective populations. Some, but not all, epidemiologists are persuaded that the association of homocysteine with vascular disease is causal and that folic acid should be administered to everyone aged 55 years or greater in combination with other cardioprotective medications as a “polypill.” The issue of whether B-vitamin supplementation reduces the risk of cardiovascular disease remains unresolved, and the results of ongoing randomized trials are eagerly anticipated. This review examines the design and power of the large-scale trials of B-vitamins for prevention of vascular diseases. Most experts await the results of such trials before recommending B-vitamins for the prevention of cardiovascular diseases.

We thank all the authors for their contributions as well as our colleagues who enthusiastically gave their time and talents to critically evaluate these review articles. We also acknowledge the individual investigators who participated in the multidisciplinary collaborations that are summarized in these articles. We hope that readers will find the articles as informative and useful as we have.