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Vol. 54, Issue 4, 599-618, December 2002
Laboratory of Pediatrics and Neurology, University Medical Center,
Nijmegen, The Netherlands (A.d.B., L.A.J.K., H.J.B.) and Department of
Chronic Disease Epidemiology, National Institute of Public Health and
the Environment, The Netherlands (A.d.B., W.M.M.V., D.K.).
I. Introduction
II. History of Homocysteine As a Risk Factor for Vascular Diseases
III. Homocysteine Metabolism
IV. Determinants of Homocysteine Concentration in the General
Population
A. Age and Sex
B. Supplemental and Dietary B Vitamin Intake
C. Lifestyle factors
1. Coffee.
2. Smoking.
3. Alcohol.
4. Physical Activity.
D. Genetics
E. Biological Coronary Heart Disease Risk Factors
V. Drugs and Diseases As Determinants of Homocysteine
Concentrations
A. Drugs Influencing the Homocysteine Concentration
1. Hormones.
2. Antiepileptic Drugs.
3. Methotrexate.
4. Nitrous Oxide.
5. Other Drugs That Have an Effect on the Homocysteine
Concentration.
B. Diseases That Influence the Homocysteine Concentration
1. Kidney Dysfunction.
2. Proliferating Diseases.
3. Rheumatoid Arthritis.
4. Endocrine Disorders.
5. Intestinal Diseases.
VI. Homocysteine and the Risk of Coronary Heart Disease
A. Inborn Errors
B. Retrospective, Cross-Sectional, and Prospective Epidemiological
Studies
C. Homocysteine and Thrombosis
D. Methylenetetrahydrofolate Reductase 677C>T Genotype and
Coronary Heart Disease
E. Mechanism by Which Homocysteine Increases the Risk of Coronary
Heart Disease
1. In Vitro Studies.
2. Studies in Patients with Homocystinuria.
3. Studies on Homocysteine and Endothelial Function.
4. Studies on Homocysteine and Endothelium-Derived Nitric
Oxide.
F. Intervention Trials
G. Conclusion about the Relationship between Homocysteine and
Coronary Heart Disease
VII. Directions for Future Research
VIII. Implications for Prevention and Treatment
Acknowledgments
References
Cardiovascular diseases (CVD), especially coronary heart disease (CHD), are the most important causes of death in industrialized countries. Increased concentrations of total plasma homocysteine (tHcy) have been associated with an increased risk of CHD. Assuming that this relation is causal, a lower tHcy concentration will reduce the occurrence and recurrence of CHD. Therefore, it is important to know which factors determine the tHcy concentration. In the general population, the most important modifiable determinants of tHcy are folate intake and coffee consumption. Smoking and alcohol consumption are also associated with the tHcy concentration, but more research is necessary to elucidate whether these relations are not originating from residual confounding due to other lifestyle factors. The most important nonmodifiable determinant is the 677 C>T polymorphism in the gene that encodes methylenetetrahydrofolate reductase (MTHFR), a regulating enzyme in homocysteine metabolism. Especially subjects with the homozygous form of this polymorphism (i.e., 677TT genotype) and a low folate status have elevated tHcy concentrations. Specific clinical conditions like the use of antiepileptic drugs or methotrexate, renal failure, cancer, rheumatoid arthritis, and hypothyroidism may lead to elevated tHcy concentrations. The available epidemiological evidence indicates that an increased tHcy concentration is not an important risk factor for CHD in healthy subjects. However, prospective studies, which included subjects at high risk of CHD, and secondary prevention trials with intermediary endpoints consistently show that elevations in the tHcy concentration may be an important risk factor in these subjects for a (recurrent) CHD event. The induction of vascular endothelial dysfunction by homocysteine may underlie this increased risk. Ongoing intervention trials will indicate whether homocysteine-lowering through vitamin supplementation, prevents CHD in the treatment groups.
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