Plasma homocysteine level and myocardial infarction: how high is high enough to need intervention?

Several studies have shown the association of acute myocardial infarction with high plasma homocysteine levels. (1-4) These studies involved different populations and have involved different study designs. However, retrospective studies tend to show a higher degree of positive association with hyperhomocystinemia than prospective studies. In some studies, no association was found. (5,6) In this issue of the Journal, Marouf et al (7) showed a mild increase in plasma homocysteine levels in a group of patients with acute myocardial infarction in a case control study.

These patients have normal serum, vitamin [B.sub.12] and red cell folate levels, excluding the two important causes of hyperhomocystinemia. Certain important polymorphism-like thermolabile MTHFR and cystathionine [beta] synthases were not studied in these populations, which could have given better insight into the problem. The strongest indication that hyperhomocystinemia is an important predictor of arterial and venous thrombosis comes from experimental studies in the gene knock-out animals. (8,9) There is an uneven distribution of [B.sub.12] and folate deficiency worldwide. In developing countries such as India, subclinical forms of this deficiency may be substantial, as shown in one of the studies of young acute MI patients, where folic acid is given for 2 weeks and normalized homocysteine levels occur in more than 50% of the subjects. The authors have discussed how increased homocysteine in plasma can bring about endothelial injury, dysfunction and thrombosis. However, we still need a large prospective study to see whether supplementation of folic acid/[B.sub.12]/vitamin [B.sub.6] reduces the incidence of acute MI significantly in a cohort of patients.

The case published in this issue has several interesting features. One-third of these patients had a family history of acute myocardial infarction, 13% had a family history of stroke, 20% had previous MI and one-third of the patients had a family history of diabetes. Hyperhomocystinemia reported in these groups of patients is relatively mild. Other prothrombotic factors like protein C, S, AT-III, APC-R, and antiphospholipid antibodies were not significantly different in these populations when compared with controls. Hence it is possible that these patients have other genetic or environmental variables to account for their heart attacks. Sixty-two percent of the patients reported in this case were smokers. Smoking has also been shown to be associated with hyperhomocystinemia in some studies.

How hyperhomocystinemia causes vascular disease is an area of intense study. Endothelial injury and stress, decreased bioavailability of nitric oxide, oxidative stress leading to the formation of toxic peroxy nitrite, association of hyperhomocystinemia with higher circulating levels of asymmetric dimethyl arginine (ADMA) which inhibit the production of nitric oxide and promote uncoupling of e-NOS, protein modification by S-thiolation, and decreased expression of thrombomodulin in aortic endothelium leading to functional protein C deficiency have all been implicated to a varying degree. (10) However, the relative importance of each of the factors in the pathogenesis of vascular disease in humans remains to be worked out.

Another area pointed out by Marouf et al is the relationship of high homocysteine levels with lowered glomerular filtration rate (GFR). Renal disease is known to increase plasma homocysteine levels and the patients described in this case were approximately a decade older than the control patients and would be expected to have a comparative reduction of GFR.

In the final analysis, it may be said that even after the adjustment of many variables, a modest elevation of plasma homocysteine levels (3[micro]mol/L) was associated with a 10% higher incidence of cardiovascular events and a 20% higher incidence of stroke in some studies. (2) Hence the link between modest hyperhomocystinemia and vascular disease seems to be strong, but what remains to be seen are the pathophysiological studies which will allow early intervention.

References

1. Lentz SR, Haynes WG. Homocysteine: is it a clinically important cardiovascular risk factor? Clev Clin J Med 2004;71:729-734.

2. Homocysteine studies Collaboration. Homocysteine and risk of ischemic heart disease and stroke: a meta analysis. JAMA 2002;288:2015-2022.

3. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta analysis. Br Med J 2002;325:1202.

4. Khare A, Shetty S, Ghosh K, et al. Evaluation of markers of endothelial damage in cases of young myocardial infarction. Atherosclerosis 2005;180:375-380.

5. Cattaneo M. Hyperhomocysteinemia, atheroscelrosis and thrombosis. Thromb Haemost 1999;81:165-176.

6. Christen WG, Ajani UA, Glynn RJ, et al. Blood levels homocysteine and increased risk of cardiovascular disease: causal or casual? Arch Intern Med 2000;160:422-434.

7. Marouf R, Zubaid M, Mojiminiyi OA, et al. Determinants of plasma homocysteine in relation to hematological and biochemical variables in patients with acute myocardial infarction. South Med J 2006;99:811-816.

8. Gilfix BM. Hyper homocysteinemia: genetic determinants and selected mouse models. Clin Invest Med 2003;26:121-132.

9. Wang H, Jiang X, Yang F, et al. Hyperhomocysteinemia accelerates atherosclerosis in cystathionine beta-synthase and apolipoprotein E double knock-out mice with and without dietary perturbation. Blood 2003; 101:3901-3907.

10. Lentz SR. Mechanisms of homocystenie-induced atherothrombosis. J Thromb Haemost 2005;3:1646-1654.

Learning is not attained by chance, it must be sought for with ardor and
attended to with diligence.
--Abigail Adams

Kanjaksha Ghosh, MD, MRCPI, MRCP (UK), FRC, Path (Lond), FACP, FICP, FAMS, FNASC

From the Institute of Immunohematology, KEM Hospital Campus, Parel, Mumbai, India.

Reprint requests to Kanjaksha Ghosh, MD, MRCPI, MRCP (UK), FRC, Path (Lond), FACP, FICP, FA, MS, FNASC, Institute of Immunohematology, 13th Floor, New Multistored Building, KEM Hospital Campus, Parel, Mumbai, 400 012 India. Email: [e-mail]

Accepted April 20, 2006.