How we wish to be cited:
Öhlin H. Homocysteine, vitamin therapy, and coronary heart disease [evaluation]. Rondel 2006; 26. URL: http://www.rondellen.net

  Introduction

Homocysteine is produced by the demethylation of the essential amino acid methionine. A main part of methionine is provided by food. Methionine is the precursor of S-adenosylmethionine (SAM), the dominating methyl donor of the body. In a following step of the methionine cycle, homocysteine is remethylated to form methionine again.

Moderately elevated homocysteine levels, 15-30 micromoles/L, may be due to inborn errors of metabolism in the MTHFR gene, deficiency of vitamin B12 and/or folate, and impaired renal function. It should be emphasised that overt vitamin deficiency usually causes higher elevations of plasma homocysteine.

The genetic disorders of homocystinuria with serum levels of homocysteine in the range 300-500 micromoles/L are associated with dislocation of the lenses of the eyes (ectopia lentis), osteoporosis, Marfan-like features, mental retardation, convulsions, and thromboembolic events during the first decades of life. The survival of those who respond to high doses of pyridoxine (vitamin B6), 40-100 mg daily, is dramatically improved.

In 1969, McCully presented the hypothesis that homocysteine is linked to vascular disease. In 1976, Wilcken & Wilcken published the homocysteine model, stating that moderately elevated levels of plasma homocystein might cause coronary artery disease. The objective of the present studies was to investigate whether the role of homocysteine in coronary artery disease is causal or casual.

Homocysteine and subtle renal dysfunction

Patients with coronary heart disease were studied, 59 with elevated levels of plasma homocysteine, 34 with low-normal levels. Patients with elevated homocysteine had higher serum concentrations of cystatin C, a marker for glomerular filtration rate, than patients with low-normal homocysteine. Nevertheless, there was a wide overlapping of cystatin C concentrations in the two groups. The correlation between homocysteine and cystatin C was not strengthened by homocysteine lowering from 18 to 10 micromoles/L. Our findings suggest that subtle renal dysfunction is not a major determinant of elevated plasma homocysteine.

Homocysteine and oxidative stress

Patients with coronary artery disease and moderately elevated plasma homocysteine had a lowered ratio of reduced to total Homocysteine in plasma, which might reflect increased oxidative activity or decreased reducing capacity in plasma. Vitamin therapy normalised homocysteine levels but redox status remained unchanged.

Homocysteine and asymmetric dimethylarginine (ADMA)

ADMA, an endogenous inhibitor of nitric oxide synthase, was not increased in patients with coronary artery disease and elevated homocysteine. Substantial reduction of homocysteine levels by vitamin treatment did not affect the levels of ADMA.

Homocysteine and lipid peroxidation

Patients with coronary artery disease and elevated levels of plasma homocysteine had elevated levels of isoprostanes, markers of lipid peroxidation. This increase remained unaffected by homocysteine lowering with vitamins, suggesting that homocysteine per se does not affect lipid peroxidation.

Homocysteine and low-grade inflammation

Two out of eight markers of inflammatory activity were elevated in the patient group with moderately elevated homocysteine. The finding suggests an association between hyperhomocysteinaemia and low-grade inflammation.

Conclusion

The present findings are compatible with the results of the intervention studies VISP, NORVIT, and HOPE-2 (see e.g. 1) – the association between  coronary artery disease and moderately elevated homocysteine appears to be casual, not causal.

Dr Hans Öhlin
Department of Cardiology
University Hospital of Lund
SE-221 85 Lund , Sweden
E-mail: hans.ohlin@med.lu.se

Reference

1.       Norberg B. Provocative proposal – global guidelines for oral vitamin B12 therapy [editorial]. Rondel 2006; 26. URL: http://www.rondellen.net/publisher26_eng.htm

Published October 17, 2006