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LE Magazine July 1997

The Dangerous Link Between Homocysteine and Heart Attacks

Life Extension magazine republishes abstracts on health and longevity topics in each issue, drawn from research papers originally published in science and medical journals throughout the world.

Human homocysteine catabolism: Three major pathways and their relevance to development of arterial occlusive disease

Dudman NP; Guo XW; Gordon RB; Dawson PA; Wilcken DE Centre for Thrombosis and Vascular Research, University of New South Wales, Prince Henry Hospital, Little Bay, Australia. J Nutr (U.S.) Apr 1996, 126 (4 Suppl) p1295S-300S.

Two separate metabolic pathways that methylate homocysteine to methionine are known in humans, utilizing, respectively, 5-methyltetrahydrofolate and betaine as methyl donors. Deficiency of the folate-dependent methylation system is linked to hyper homocystinemia. Our data suggest that this deficiency leads to concurrent metabolic down-regulation of homocysteine transsulfuration that may contribute to hyperhomocystinemia. By contrast, no instances have been reported of hyperhomocystinemia resulting from deficiencies of betaine-dependent homocysteine methylation.

Long-term betaine supplementation of 10 patients who had pyridoxine-resistant homocystinuria and gross hyperhomocystinemia due to deficiency of cystathionine beta-synthase activity caused a substantial lowering of plasma homocysteine, which has now been maintained for periods of up to 13 years. Betaine had to be taken regularly because the effect soon disappeared when treatment was stopped. In conclusion, depressed activity of the transsulfuration pathway may contribute to hyperhomocystinemia because of primary deficiencies of enzymes of either the transsulfuration or of the folate-dependent methylation pathways. Stimulation of betaine-dependent homocysteine remethylation causes a commensurate decrease in plasma homocysteine that can be maintained as long as betaine is taken.

an independent risk factor for vascular disease

Clarke R; Daly L; Robinson K; Naughten E; Cahalane S; Fowler B; Graham I Department of Cardiology, Adelaide Hospital, Dublin, Ireland. N Engl J Med (U.S.) Apr 25 1991, 324 (17) p1149-55.

Background: Hyperhomocystinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency.

Methods: We first established a diagnostic criterion for hyperhomocystinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92-percent sensitive and 100-percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age.

Results: Hyperhomocystinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocystinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocystinemia.

Conclusions: Hyperhomocystinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.

A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians

Stampfer MJ; Malinow MR; Willett WC; Newcomer LM; Upson B; Ullmann D; Tishler PV; Hennekens CH Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA.
JAMA (U.S.) Aug 19 1992, 268 (7) p877-8

Objective: To assess prospectively the risk of coronary heart disease associated with elevated plasma levels of homocyst(e)ine. DESIGN: Nested case-control study using prospectively collected blood samples. Setting: Participants in the Physicians' Health Study. Participants: A total of 14,916 male physicians, aged 40 to 84 years, with no prior myocardial infarction (MI) or stroke provided plasma samples at baseline and were followed up for 5 years. Samples from 271 men who subsequently developed MI were analyzed for homocyst(e)ine levels together with paired controls, matched by age and smoking.

Main Outcome Measure: Acute MI or death due to coronary disease. Results: Levels of homocyst(e)ine were higher in cases than in controls (11.1 +/- 4.0 [SD] vs 10.5 +/- 2.8 nmol/mL; P =.03). The difference was attributable to an excess of high values among men who later had MIs. The relative risk for the highest 5 percent vs. the bottom 90 percent of homocyst(e)ine levels was 3.1 (95 percent confidence interval, 1.4 to 6.9; P = .005). After additional adjustment for diabetes, hypertension, aspirin assignment, Quetelet's Index, and total/high-density lipoprotein cholesterol, this relative risk was 3.4 (95 percent confidence interval, 1.3 to 8.8) (P = .01). Thirteen controls and 31 cases (11 percent) had values above the 95th percentile of the controls.

Conclusions: Moderately high levels of plasma homocyst(e)ine are associated with subsequent risk of MI, independent of other coronary risk factors. Because high levels can often be easily treated with vitamin supplements, homocyst(e)ine may be an independent, modifiable risk factor.

Prospective study of serum total homocysteine concentration and risk of stroke in middle-aged men

Perry IJ; Refsum H; Morris RW; Ebrahim SB; Ueland PM; Shaper AG Department of Public Health, Royal Free Hospital School of Medicine, London, UK. Lancet (ENGLAND) Nov 25 1995, 346 (8987) p1395-8

Moderate hyper homocystinemia is common in the general population and has been linked with cardiovascular disease. However, there are no data from prospective, population-based studies. We examined the association between serum total homocysteine (tHcy) concentration and stroke in a nested case-control study within the British Regional Heart Study cohort. Between 1978 and 1980 serum was saved from 5,661 men, aged 40-59 years, randomly selected from the population of one general practice in each of 18 towns in the UK.

During follow-up to December 1991, there were 141 incident cases of stroke among men with no history of stroke at screening. Serum tHcy was measured in 107 cases and 118 control men (matched for age-group and town, without a history of stroke at screening, who did not develop a stroke or myocardial infarction during follow-up). THcy concentrations were significantly higher in cases than controls (geometric mean 13.7 [95 percent CI 12.7-14.8] vs. 11.9 [11.3-12.6] mumol/L; p = 0.004). There was a graded increase in the relative risk of stroke in the second, third, and fourth quarters of the tHcy distribution (odds ratios 1.3, 1.9, 2.8; trend p = 0.005) relative to the first.

Adjustment for age-group, town, social class, body-mass index, hypertensive status, cigarette smoking, forced expiratory volume, packed-cell volume, alcohol intake, diabetes, high-density lipoprotein cholesterol, and serum creatinine did not attenuate the association. These findings suggest that tHcy is a strong and independent risk factor for stroke.

Treatment of mild hyperhomocystinemia in vascular disease patients

Franken DG; Boers GH; Blom HJ; Trijbels FJ; Kloppenborg PW Department of Medicine, University Hospital Nijmegen, The Netherlands.
Arterioscler Thromb (U.S.) Mar 1994, 14 (3) p465-70.

Mild hyperhomocystinemia is recognized as a risk factor for premature arteriosclerotic disease. A few vitamins and other substances have been reported to reduce blood homocysteine levels, but normalization of elevated blood homocysteine concentrations with any of these substances has not been reported. Therefore, we screened 421 patients suffering from premature peripheral or cerebral occlusive arterial disease by oral methionine loading tests for the presence of mild hyperhomocystinemia. Thirty-three percent of patients with peripheral, and 20 percent of patients with cerebral occlusive arterial disease, were identified with mild hyperhomocystinemia (14 percent of the men, 34 percent of the premenopausal women, and 26 percent of the postmenopausal women). Mildly hyperhomocystinemic patients were administered vitamin B6 250 mg daily. After 6 weeks methionine loading tests were again assessed to evaluate the effect of treatment. Patients with non-normalized homocysteine concentrations were further treated with vitamin B6 250 mg daily and/or folic acid 5 mg daily and/or betaine 6 g daily, solely or in any combination. Vitamin B6 treatment normalized the afterload homocysteine concentration in 56 percent of the treated patients (71 percent of the men, 45 percent of the premenopausal women, and 88 percent of the postmenopausal women). Further treatment resulted in a normalization of homocysteine levels in 95 percent of the remaining cases. Thus, mild hyperhomocystinemia, which is frequently encountered in patients with premature arteriosclerotic disease, can be reduced to normal in virtually all cases by safe and simple treatment with vitamin B6, folic acid and betaine, each of which is involved in methionine metabolism.

Effect of betaine on S-adenosylmethionine levels in the cerebrospinal fluid in a patient with methylenetetrahydrofolate reductase deficiency and peripheral neuropathy

Kishi T; Kawamura I; Harada Y; Eguchi T; Sakura N; Ueda K; Narisawa K; Rosenblatt DS Department of Pediatrics, Hiroshima University School of Medicine, Japan.
J Inherit Metab Dis (NETHERLANDS) 1994, 17 (5) p560-5

A 16-year-old Japanese girl with 5,10-methylenetetrahydrofolate reductase deficiency showed peripheral neuropathy. There were no significant responses to vitamin B6, vitamin B12 or folate, given alone or in combination. With the addition of betaine monohydrate, she has been free from gait disturbance and muscle weakness. The concentration of S-adenosylmethionine in cerebrospinal fluid, which was undetectable before receiving betaine monohydrate, increased to about the normal level 24 months after treatment with betaine monohydrate.

Picamilon Enhances Blood Flow

Novyi tserebrovaskuliarnyi preparat Picamilon

Mirzoian RS; Gan'shina TS
Farmakol Toksikol (USSR) Jan-Feb 1989, 52 (1) p23-6

Picamilon, a sodium salt of N-nicotinoyl-gamma-aminobutyric acid, was shown to induce a significant increase of cerebral blood flow in conscious cats. Picamilon was found to inhibit neurogenic spasms of cerebral vessels, that were followed by suppression of tonic activity and reflectory discharges in sympathetic nerves. Picamilon led to restoration of the initial condition of cerebral hemodynamics disturbed by a previous administration of serotonin.

Results of Picamilon therapy of patients with open-angle glaucoma

Kolomoitseva E.M.; Ermakova V.N.; Abdulkadyrova M.Zh. Mosk. NI Institut Glaznykh Boleznej, Minzdravmedproma Rossii,
Moskva Russian Federation Vestnik Oftalmologii (Russian Federation), 1994, 110/4 (4-7).

Administration of Picamilon, a cerebrovascular and nootropic drug, to patients with primary open-angle glaucoma with normalized intraocular pressure and declining visual function resulted in improvement of the central and peripheral visual fields manifesting by improvement of individual sensitivity threshold, decreased area and intensity of scotomas; the treatment had a favorable effect on light sensitivity and vision acuity in some patients. No noticeable effect on arterial pressure was observed. The drug did not reduce the intraocular pressure.

Thymic Protein A

Induction of T-cell maturation by a cloned line of thymic epithelium (TEPI)

Beardsley TR; Pierschbacher M; Wetzel GD; Hays EF
Proc Natl Acad Sci USA (U.S.) Oct 1983, 80 (19) p6005-9

A cloned cell line of thymic origin has been characterized as epithelial in nature. A description of the procedures for derivation and cloning of the cell line includes use of epidermal growth factor. The thymic epithelial (TEPI) cell line is Ia antigen positive, forms desmosomes, and produces an extracellular fibronectin matrix. The supernatant from confluent monolayers of TEPI was tested for its ability to promote thymocyte functional activity. TEPI supernatant (TEPI SN) was demonstrated to greatly enhance the response of peanut agglutinin-positive thymocytes to alloantigen, as measured by cell-mediated lympholysis.

Furthermore, preincubation of peanut agglutinin-positive thymocytes with TEPI SN prior to allostimulation resulted in marked enhancement, thus distinguishing it from interleukin-2. Finally, TEPI SN was demonstrated to induce interleukin-2 production by peanut agglutinin-positive thymocytes in the presence of concanavalin A. This activity was demonstrated not to be due to interleukin-1, which is absent in TEPI SN. Preliminary biochemical analysis indicates that the biological activity is associated with a Mr 50,000 entity. The data suggest that TEPI produces a soluble factor capable of inducing function of an immature thymocyte subpopulation into an IL 2 producer.

Immunologic effects of human thymic stromal grafts and cell lines

Hays EF; Beardsley TR
Clin Immunol Immunopathol (U.S.) Dec 1984, 33 (3) p381-90.

These experiments report a method of preparing stromal remnants from human thymus. The remnants were composed of epithelial cells, fibroblasts and macrophages. They were grafted under the renal capsule of nude mice. Some of the grafts were reconstituted with lymphocytes to obtain the microscopic morphology of the thymus. The mice with reconstituted grafts survived in a conventional environment, had increased numbers of T cells in their spleen, and showed improvement of T-cell mediated immunologic function.

This was measured by a positive allogeneic effect, a mixed lymphocyte reaction, and cell-mediated lysis. In vitro cell lines were established from thymic remnants of two separate individuals. These lines grew as attached monolayers. One of them was composed of fibroblasts. The other had an epithelial morphology. This epithelial cell line (HT-7) was shown to produce factors which promoted thymocyte differentiation in vitro.