doi: 10.1161/01.CIR.0000136200.18448.37
(Circulation. 2004;110:e37-e38.)
© 2004 American Heart Association, Inc.
Correspondence |
Institute of Medical Chemistry and Biochemistry, Medical University of Innsbruck, Innsbruck, Austria
To the Editor:
With great interest we read the article by Zylberstein and coworkers,1 in which the authors conclude that homocysteine is an independent risk factor for myocardial infarction, in particular fatal myocardial infarction in middle-aged women. Follow-up investigations, especially long-term follow-up studies, are certainly better suited to assess the role of homocysteine in the pathogenesis of disease. However, the question of whether homocysteine itself is responsible for disease progression in vascular diseases is not yet answered; a causality between moderate hyperhomocysteinemia and atherogenesis remains to be demonstrated. This point is also discussed by the authors,1 whereas the point that homocysteine is an independent risk factor for myocardial infarction and vascular disease requires some comment.
In studies focusing on patients with coronary heart disease, neurodegenerative diseases, and autoimmune disease, we found that moderate hyperhomocysteinemia closely correlates with increased cellular immune activation.2 Moreover, in vitro production of homocysteine was found in peripheral blood mononuclear cells on stimulation with mitogens.3 These results point to a role of immune activation in the development of moderate hyperhomocysteinemia. Inflammation and cellular immune activation are crucially involved in atherogenesis4 and are also established as confounding risk factors for vascular diseases. A link between the pathogenesis of moderate hyperhomocysteinemia and the immunopathogenesis of atherosclerosis is very likely and would take together both concepts. Both events could relate to the overwhelming production of reactive oxygen species by activated macrophages within cellular immune activation. Antioxidants are depleted and oxidative stress develops. Decreased concentrations of antioxidants and vitamins are often encountered in patients suffering from chronic disease, and B-vitamins, folic acid, and vitamin B12 are known to be prone to oxidation.2,5 Thus, hyperhomocysteinemia may develop secondary to immune activation.
References
- Zylberstein DE, Bengtsson C, Bjorkelund C, et al. Serum homocysteine in relation to mortality and morbidity from coronary heart disease: a 24-year follow-up of the population study of women in Gothenburg. Circulation. 2004; 109: 601–606.
[Abstract/Free Full Text]
- Schroecksnadel K, Frick B, Winkler C, et al. Hyperhomocysteinemia and immune activation. Clin Chem Lab Med. 2003; 41: 1438–1443.[CrossRef][Medline]
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- Schroecksnadel K, Frick B, Wirleitner B, et al. Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells. Clin Exp Immunol. 2003; 134: 53–56.[CrossRef][Medline]
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- Libby P. Inflammation in atherosclerosis. Nature. 2002; 420: 868–874.[CrossRef][Medline]
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- McCaddon A, Regland B, Hudson P, et al. Functional vitamin B(12) deficiency and Alzheimer disease. Neurology. 2002; 58: 1395–1399.
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Response
Sahlgrenska Academy, Göteborg University, Göteborg, Sweden
Department of Laboratory Medicine, Ullevål University Hospital, Oslo University, Oslo, Norway
We would like to thank Drs Tsuda and Nishio as well as Dr Schroecksnadel et al for their interest in the recently published results from the Population Study of Women in Göteborg.1 We agree fully with Schroecksnadel and co-workers that even a statistically independent association between homocysteine and cardiovascular endpoints in an observational study is not proof of a direct causal association. Given the complex metabolic mechanisms involving homocysteine, it is more likely that this metabolite represents an intermediary factor in the causal web eventually resulting in overt disease. For this reason, we are also studying potential mechanisms including a possible mediating role of asymmetric dimethylarginine (ADMA), as suggested by Drs Tsuda and Nishio in their letter. Specifically, blood samples collected at the baseline of our population study are currently being analyzed with respect to ADMA levels, and we hope that these data will provide some insight into the excess myocardial infarction incidence and mortality among women with elevated homocysteine. In this context, plasma homocysteine levels have been observed to be a statistical predictor of other end points, including dementia.2 Moreover, elevated homocysteine has been observed to be associated with high ADMA and low levels of nitric oxide in patients with Alzheimer’s dementia.3 Epidemiological studies such as ours1 represent one level of evidence in disentangling causal relationships. The observed associations have to be complemented by other types of research aiming at exposure variables and genetic polymorphisms affecting the homocysteine levels and potential molecular biological mechanisms.
References
- Zylberstein DE, Bengtsson C, Bjorkelund C, et al. Serum homocysteine in relation to mortality and morbidity from coronary heart disease: a 24-year follow-up of the population study of women in Gothenburg. Circulation. 2004; 109: 601–606.
[Abstract/Free Full Text]
- Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer’s disease. N Engl J Med. 2002; 346: 476–483.
[Abstract/Free Full Text]
- Selley ML. Increased concentrations of homocysteine and asymmetric dimethylarginine and decreased concentrations of nitric oxide in the plasma of patients with Alzheimer’s disease. Neurobiol Aging. 2003; 24: 903–907.[CrossRef][Medline]
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