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Homocysteine and vascular disease: 2006 and the jury is still out
The fact that elevated plasma levels of homocysteine are associated with vascular disease and thrombosis is now in little doubt, but the nature of this relationship remains unclear. Does high homocysteine cause disease or is it merely a marker?
It is going on 40 years since the link between homocystinuria and premature vascular disease was first observed by Harvard pathologist Kilmer McCully, MD. His homocysteine theory of atherosclerosis was first met with skepticism, but subsequent reports from case-control and cross-sectional studies linking hyperhomocysteinemia to cerebral, coronary and peripheral vascular diseases has kindled a growing interest in the association. Most convincingly, positive results of several prospective studies emerged to put homocysteine squarely on the list of suspects for cardiovascular risk.
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![Ralph Green, MD, PhD, FRCPath [photo]](images/hot/200601/Green.jpg)
Add to this the fact that low intakes and blood levels of the B vitamins, folate, B6 and B12 are common and correctable causes of hyperhomocysteinemia and the field burgeoned. More than 10,000 indexed papers have been published on homocysteine since McCully’s observation. Last year alone, there were two international meetings on this amino acid. Still, we are not much closer to the central questions: Does a high level of homocysteine promote vascular disease or thrombosis and does lowering of homocysteine ameliorate the risk of these diseases?
The folate story
It has been eight years since the U.S. government mandated fortification of all grain and cereal products with folic acid as a public health measure to reduce the risk of neural tube defect pregnancies.
It was anticipated that this would result in the lowering of homocysteine levels in the population at large. It was also predicted, from a large meta-analysis, that improved folate nutrition, whether through homocysteine lowering or not, would reduce between 13,500 and 50,000 deaths from coronary artery disease.
Gathering the data to substantiate this prediction has proved difficult, however, as the control data set is historical and much has changed since 1998, apart from folic acid fortification. The use of statins and other lipid-lowering measures as well as improved hypertension control are prime examples.
A glimmer of encouragement has come from epidemiological data first reported at the Saarbrucken Homocysteine Conference last April and further refined at the Milan Meeting on Homocysteine three months later, where Quanhe Yang, PhD, from the CDC, reported that the death rate from stroke in the United States and Canada has declined more rapidly since the introduction of folic acid fortification. In England and Wales, where there is no fortification program, the rate of decline in stroke mortality has remained unchanged over this period. Even so, the link with folate and with homocysteine is only circumstantial and this report awaits peer review publication.
In the era of folic acid fortification, vitamin B12 deficiency has emerged as the most common correctable cause of hyperhomocysteinemia among the elderly, according to a report from a group at the University of California, Davis.
Should we lower homocysteine?
In 2001, researchers published the results of a Swiss placebo-controlled, double-blind, interventional study, which used a combination of vitamin B12, folic acid and vitamin B6 to lower homocysteine in patients following angioplasty in The New England Journal of Medicine. Homocysteine levels and the rate of restenosis dropped in the group that received the vitamin combination compared with the controls.
Three years later, a larger multicenter study with a similar design was also published in The New England Journal of Medicine. This study, however, reported diametrically opposite results, with shorter time to restenosis in the group receiving vitamins.
Even more dramatic in the ongoing homocysteine debate was the news that emerged from a large interventional study reported at the European Society of Cardiology Meeting held in Stockholm, Sweden last September.
Researchers designed the NORVIT study, a three and a half-year, double-blind, placebo-controlled trial on 3,749 patients suffering acute myocardial infarction, to compare folic acid or vitamin B6 alone with a combination of both vitamins — all groups receiving folic acid also got B12 — with patients who received no vitamins. Endpoints included fatal and nonfatal myocardial infarction or stroke and other causes of death.
Vitamins lowered homocysteine by 28%, but the rate of recurrent myocardial infarction was significantly higher: 21% in the group receiving folic acid and B6 compared with placebo controls. A disturbing finding was that death from cancer showed a higher, though not significant, trend in the groups that received folic acid, raising the specter that folate might feed an established tumor. This possibility is certainly not inconsistent with the known efficacy of folate antagonists in treating cancer.
The NORVIT study gives pause to reconsider the wisdom of indiscriminate use of vitamin supplements in patients with established disease. Some caution is advised in extrapolating the results too far to include primary prevention through the use of vitamin supplements to lower homocysteine and vascular disease risks. Here, the data are not yet in and the jury is still out.
Perhaps future research and more international meetings will be required to provide substantive answers.
About the author:
- Ralph Green MD, PhD, FRCPath, is a professor in and chair of the department of pathology and laboratory medicine at the University of California, Davis in Sacramento, Calif., and a member of Hem/Onc Today’s editorial board.