"Genes, Vitamins, Homocyst(e)ine And Cardiovascular Diseases"

February 14, 1998

Background information on presentation by M.R. Malinow, M.D., Oregon Regional Primate Research Center and Oregon Health Sciences University, at AAAS symposium on "Gene-Diet Interactions in Coronary Heart Disease"

Homocysteine (Hcy) is an amino acid generated in the body from the metabolism of methionine, an essential amino acid ingested with food. Homocysteine, normally exported from body cells into blood, occurs in all humans, and probably in all animals. Homocysteine in the blood is the sum of several molecular species, called total homocysteine (tHcy) or homocyst(e)ine [H(e)].

The interest of the scientific community in homocysteine is illustrated by the number of publications dealing with that subject. Figure 1 shows the rate of publications listed in MedLine under Homocysteine/blood since 1966. It indicates that the annual rate of publications has increased about 168-fold in the last 31 years. If such a trend continues, would homocysteine be "the cholesterol of the next century"?

Although it is difficult to know exactly why this surge in interest, it likely stems from the fact that blood concentration of homocyst(e)ine is elevated in 10-40% of people with heart attack, stroke or peripheral atherosclerosis (atherosclerosis in leg blood vessels). Thus, blood homocyst(e)ine may be a risk factor for atherosclerosis, in a similar fashion as smoking, high blood pressure and high cholesterol levels.

Several other reasons for this interest also are probably important. For instance, Figure 2 shows that the risk of death was 6.5 times higher over the course of 4.6 years in patients with coronary heart disease having levels of plasma homocyst(e)ine > 15.0 pmol/L, compared to those patients with homocyst(e)ine below 9 pmol/L.

Figure 3 shows that there is no threshold for the risk of having heart attack according to homocyst(e)ine levels, or as defined more precisely, the risk is graded across the entire distribution of blood homost(e)ine levels. This characteristic is also shared with another, independent risk factor, i.e., blood cholesterol levels.

There are several potential mechanisms that are associated with elevated homocysteine levels. The most common is probably an insufficient intake of folic acid or of vitamin B-6, as demonstrated by Dr. Selhub and his colleagues in subjects from the Framingham Study (Selhub, et al, JAMA 1993;270:2693-98). Moreover, many investigators have demonstrated that folic acid supplementation lowers homocyst(e)ine levels in most individuals, sometimes requiring additional supplementation of vitamins B-6 and B-12. We have demonstrated that the decrease of blood homocyst(e)ine by folic acid supplementation depends in part on the individual's genetic background (shown in Figure 4).

Much is known on potential mechanisms on how homocyst(e)ine damages arteries and favors thrombosis, as well as on the fact that elevated levels of homocyst(e)ine are usually corrected with vitamin supplementation. However, it is not known whether adequate diet, diet fortification or vitamin supplementation may prevent or beneficially affect the evolution of atherosclerotic diseases.

The National Institutes of Health is supporting a current study that may determine whether vitamin supplementation will alter the course of atherosclerotic diseases; results are expected to be available probably within the next 5 years. Until this pivotal study is completed, it would be advisable that the population consumes a diet rich in green-leaf vegetables, fruits and legumes in order to increase folate intake and lower homocyst(e)ine levels. Legends for figures:

Figure 1. Shows the annual rate of publications listed in MedLine under "Homocysteine/blood." The rate in the last period is 168-fold higher than in the initial period (data up to December 1997).

Figure 2. Results of a prospective study conducted in Norway in 587 men and women with coronary heart disease. After a median follow-up of 4.6 years, 3.8% of patients with initial homocyst(e)ine levels below 9 pmol/L have died, as compared with 24.7% of those with initial homocyst(e)ine levels > 15 pmol/L (Nygaard, et al. N Engl J Med 1997; 337:230).

Figure 3. Results of an observation conducted in Northern France in 229 subjects with history of myocardial infarction and in 315 controls. The odds ratios for having had a myocardial infarction in those with homocyst(e)ine levels > 17.2 pmol/L were 6.06 times higher than in those with homocyst(e)ine < 9.8 pmol/L. The graph shows that the risk was progressive across the entire distribution of homocyst(e)ine concentration, i.e., without a threshold (adapted from Malinow et at, Atherosclerosis 1996;125:27).

Figure 4. Changes in homocyst(e)ine levels brought about by daily doses of 1 or 2 mg of folic acid during 3 weeks. Subjects were habitual users of multivitamins (n=99) or non-users of multivitamins (n=143). Subjects were sorted by the genotypes of an enzyme [methylenetetrahydrofolate reductase (MTHFR)], which catalyzes the synthesis of the active form of circulating folic acid in blood. The frequency of homozygotes "wild type" (C/C in nucleotide 677 of the gene) was about 40%, of heterozygotes (C/T) about 50%, and of homozygotes for the mutation (T/T) about 10% (not shown in the figure). C=cytosine; T=thymine. The basal levels of homocyst(e)ine levels due to the intake of folic acid was larger in the homozygotes for the mutation compared to the other genotypes.

Note to reporters: This is one of four fact sheets about the symposium presentation. News release also available. Contact: 214-706-1340.

American Heart Association

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