Objective. —To determine the risk of elevated total homocysteine (tHcy) levels for arteriosclerotic vascular disease, estimate the reduction of tHcy by folic acid, and calculate the potential reduction of coronary artery disease (CAD) mortality by increasing folic acid intake. Data Sources. —MEDLINE search for meta-analysis of 27 studies relating homocysteine to arteriosclerotic vascular disease and 11 studies of folic acid effects on tHcy levels. Study Selection and Data Extraction. —Studies dealing with CAD, cerebrovascular disease, and peripheral arterial vascular disease were selected. Three prospective and six population-based case-control studies were considered of high quality. Five cross-sectional and 13 other case-control studies were also included. Causality of tHcy's role in the pathogenesis of vascular disease was inferred because of consistency across studies by different investigators using different methods in different populations. Data Synthesis. —Elevations in tHcy were considered an independent graded risk factor for arteriosclerotic vascular diseases. The odds ratio (OR) for CAD of a 5-μmol/L tHcy increment is 1.6(95% confidence interval [Cl], 1.4 to 1.7) for men and 1.8 (95% Cl, 1.3 to 1.9) for women. A total of 10% of the population's CAD risk appears attributable to tHcy. The OR for cerebrovascular disease (5-μmol/L tHcy increment) is 1.5 (95% Cl, 1.3 to 1.9). Peripheral arterial disease also showed a strong association. Increased folic acid intake (approximately 200 μg/d) reduces tHcy levels by approximately 4 μmol/L. Assuming that lower tHcy levels decrease CAD mortality, we calculated the effect of (1) increased dietary folate, (2) supplementation by tablets, and (3) grain fortification. Under different assumptions, 13 500 to 50 000 CAD deaths annually could be avoided; fortification of food had the largest impact. Conclusions. —A 5-μmol/L tHcy increment elevates CAD risk by as much as cholesterol increases of 0.5 mmol/L (20 mg/dL). Higher folic acid intake by reducing tHcy levels promises to prevent arteriosclerotic vascular disease. Clinical trials are urgently needed. Concerns about masking cobalamin deficiency by folic acid could be lessened by adding 1 mg of cobalamin to folic acid supplements. ( JAMA . 1995;274:1049-1057)

https://jamanetwork.com/journals/jama/articlepdf/389728/jama_274_13_028.pdf

A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes

An elevated level of total homocysteine (tHcy) in blood, denoted hyperhomocysteinemia, is emerging as a prevalent and strong risk factor for atherosclerotic vascular disease in the coronary, cerebral, and peripheral vessels, and for arterial and venous thromboembolism. The basis for these conclusions is data from about 80 clinical and epidemiological studies including more than 10,000 patients. Elevated tHcy confers a graded risk with no threshold, is independent of but may enhance the effect of the conventional risk factors, and seems to be a particularly strong predictor of cardiovascular mortality. Hyperhomocysteinemia is attributed to commonly occurring genetic and acquired factors including deficiencies of folate and vitamin B12. Supplementation with B-vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce an elevated tHcy level. Studies are now in progress to establish whether such therapy will reduce cardiovascular risk.

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Homocysteine and Cardiovascular Disease

In 1969, McCully made the clinical observation linking elevated plasma homocyst(e)ine concentrations with vascular disease.1 He reported autopsy evidence of extensive arterial thrombosis and atherosclerosis in two children with elevated plasma homocyst(e)ine concentrations and homocystinuria. On the basis of this observation, he proposed that elevated plasma homocyst(e)ine (hyperhomocyst(e)inemia) can cause atherosclerotic vascular disease. The term “homocyst(e)ine” is used to define the combined pool of homocysteine, homocystine, mixed disulfides involving homocysteine, and homocysteine thiolactone found in the plasma of patients with hyperhomocyst(e)inemia. Subsequent investigations have confirmed McCully's hypothesis, and it has recently become clear that hyperhomocyst(e)inemia is an independent risk factor . . .

Homocysteine and atherothrombosis

CONTEXT: It has been suggested that total blood homocysteine concentrations are associated with the risk of ischemic heart disease (IHD) and stroke. OBJECTIVE: To assess the relationship of homocysteine concentrations with vascular disease risk. DATA SOURCES: MEDLINE was searched for articles published from January 1966 to January 1999. Relevant studies were identified by systematic searches of the literature for all reported observational studies of associations between IHD or stroke risk and homocysteine concentrations. Additional studies were identified by a hand search of references of original articles or review articles and by personal communication with relevant investigators. STUDY SELECTION: Studies were included if they had data available by January 1999 on total blood homocysteine concentrations, sex, and age at event. Studies were excluded if they measured only blood concentrations of free homocysteine or of homocysteine after a methionine-loading test or if relevant clinical data were unavailable or incomplete. DATA EXTRACTION: Data from 30 prospective or retrospective studies involving a total of 5073 IHD events and 1113 stroke events were included in a meta-analysis of individual participant data, with allowance made for differences between studies, for confounding by known cardiovascular risk factors, and for regression dilution bias. Combined odds ratios (ORs) for the association of IHD and stroke with blood homocysteine concentrations were obtained by using conditional logistic regression. DATA SYNTHESIS: Stronger associations were observed in retrospective studies of homocysteine measured in blood collected after the onset of disease than in prospective studies among individuals who had no history of cardiovascular disease when blood was collected. After adjustment for known cardiovascular risk factors and regression dilution bias in the prospective studies, a 25% lower usual (corrected for regression dilution bias) homocysteine level (about 3 micromol/L [0.41 mg/L]) was associated with an 11% (OR, 0.89; 95% confidence interval [CI], 0.83-0.96) lower IHD risk and 19% (OR, 0.81; 95% CI, 0.69-0.95) lower stroke risk. CONCLUSIONS: This meta-analysis of observational studies suggests that elevated homocysteine is at most a modest independent predictor of IHD and stroke risk in healthy populations. Studies of the impact on disease risk of genetic variants that affect blood homocysteine concentrations will help determine whether homocysteine is causally related to vascular disease, as may large randomized trials of the effects on IHD and stroke of vitamin supplementation to lower blood homocysteine concentrations.

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Homocysteine and risk of ischemic heart disease and stroke: A meta-analysis

Context. —Elevated plasma homocysteine is a known risk factor for atherosclerotic vascular disease, but the strength of the relationship and the interaction of plasma homocysteine with other risk factors are unclear. Objective. —To establish the magnitude of the vascular disease risk associated with an increased plasma homocysteine level and to examine interaction effects between elevated plasma homocysteine level and conventional risk factors. Design. —Case-control study. Setting. —Nineteen centers in 9 European countries. Patients. —A total of 750 cases of atherosclerotic vascular disease (cardiac, cerebral, and peripheral) and 800 controls of both sexes younger than 60 years. Measurements. —Plasma total homocysteine was measured while subjects were fasting and after a standardized methionine-loading test, which involves the administration of 100 mg of methionine per kilogram and stresses the metabolic pathway responsible for the irreversible degradation of homocysteine. Plasma cobalamin, pyridoxal 5'-phosphate, red blood cell folate, serum cholesterol, smoking, and blood pressure were also measured. Results. —The relative risk for vascular disease in the top fifth compared with the bottom four fifths of the control fasting total homocysteine distribution was 2.2 (95% confidence interval, 1.6-2.9). Methionine loading identified an additional 27% of atrisk cases. A dose-response effect was noted between total homocysteine level and risk. The risk was similar to and independent of that of other risk factors, but interaction effects were noted between homocysteine and these risk factors; for both sexes combined, an increased fasting homocysteine level showed a more than multiplicative effect on risk in smokers and in hypertensive subjects. Red blood cell folate, cobalamin, and pyridoxal phosphate, all of which modulate homocysteine metabolism, were inversely related to total homocysteine levels. Compared with nonusers of vitamin supplements, the small number of subjects taking such vitamins appeared to have a substantially lower risk of vascular disease, a proportion of which was attributable to lower plasma homocysteine levels. Conclusions. —An increased plasma total homocysteine level confers an independent risk of vascular disease similar to that of smoking or hyperlipidemia. It powerfully increases the risk associated with smoking and hypertension. It is time to undertake randomized controlled trials of the effect of vitamins that reduce plasma homocysteine levels on vascular disease risk.

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A L Cousins

Papers

Plasma homocyst(e)ine, folate, and vitamin B-12 concentrations and risk for early-onset coronary artery disease.