Homocysteine, vitamins, and coronary artery disease. Comprehensive review of the literature.

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Homocysteine, vitamins, and coronary artery disease

Comprehensive review of the literature

Brian V. Taylor, MD, MSC Gavin Y. Oudit, MD, MSC Michael Evans, MD, CCFP

OBJECTIVETo summarize results of clinical trials investigating the role of homocysteine (tHcy) as a risk factor for coronary artery disease (CAD) and the role of vitamin therapy (folic acid and vitamins B6and B12) in primary and secondary prevention of CAD.

QUALITY OF EVIDENCEMEDLINE was searched from January 1976 to January 1999 to locate cross-sectional, retrospective and prospective cohort studies and meta-analyses on CAD using the MeSH words homocysteine, folic acid, vitamins B6and B12, and coronary artery or heart disease.

MAIN MESSAGEElevated tHcy levels are prevalent; most retrospective and cross-sectional studies show an association with increased risk of CAD. Results from recent prospective studies are less consistent. Folic acid, alone or with vitamins B6and B12, reduces tHcy concentrations in the blood.

Results from ongoing randomized controlled trials could determine the effect of vitamins B6and B12and folic acid supplementation on CAD-related morbidity and mortality and could indicate whether routine supplementation with these vitamins should be advocated. Before mass screening for tHcy can be done, the tHcy assay must be standardized.

CONCLUSION The role of homocysteine and vitamins B6 and B12in managing CAD is unclear.

Routine screening is not recommended.

OBJECTIFFaire la synthèse des résultats d’essais cliniques analysant le rôle de l’homocystéine à titre de facteur de risque de coronaropathies et le rôle d’une thérapie à base de vitamines (acide folique et vitamines B6et B12) dans la prévention primaire et secondaire des coronaropathies.

Q U A L I T É D E S D O N N É E S Une recension a été ef fectuée dans MEDLINE de janvier 1976 à janvier1999 pour trouver des études transversales, de cohortes rétrospectives et prospectives ainsi que des méta-analyses sur les coronaropathies à l’aide des termes MeSH en anglais pour homocystéine, acide folique, vitamines B6et B12, cardiopathies ou coronaropathies.

P R I N C I P A L M E S S A G EDes taux élevés d’homocystéine sont fréquents; la plupart des études rétrospectives et transversales démontrent un lien entre ces derniers et un risque accru de coronaropathies. Les résultats d’études prospectives récentes sont moins cohérents à ce chapitre.

L’acide folique, seule ou combinée à des vitamines B6 et B12, réduit les concentrations d’homocystéine dans le sang. Les résultats d’essais aléatoires contrôlés présentement en progression pourraient déterminer l’effet d’un supplément de vitamines B6et B12ainsi que d’acide folique sur la morbidité et la mortalité associées aux coronaropathies. Ils pourraient aussi indiquer s’il faudrait préconiser systématiquement l’administration d’un tel supplément vitaminique. Avant de pouvoir procéder à un dépistage généralisé de l’homocystéine, il faudrait en normaliser les épreuves.

CONCLUSIONLe rôle de l’homocystéine et de la vitamine B6et B12dans la prise en charge de la coronaropathie reste imprécis. Le dépistage systématique n’est pas recommandé.

This article has been peer reviewed.

Cet article a fait l’objet d’une évaluation externe.

Can Fam Physician 2000;2236-2245.

résumé abstract

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onventional risk factors for coronary artery disease (CAD) include smoking, hyperten- sion, hyperlipidemia, diabetes, and a family history. Family physicians should be aware of the discovery of new, potentially reversible, risk factors for CAD. Elevated serum levels of the amino acid homocysteine (tHcy) is one such factor.

Because this is a topic of increasing discussion in our medical community, this paper will review the medical literature to determine criteria for and prevalence of hyperhomocysteinemia in the general population; how tHcy serum levels are measured in the laboratory; how tHcy is metabolized, causes for elevated levels, and putative atherogenic role; results from retrospective and case-control studies and prospective cohort studies that do or do not support tHcy as an independent risk factor for CAD; the association between dietary intake and serum levels of folic acid, vitamin B6and B12, and risk of CAD; and whether good evidence supports use of vitamin supplementation for primary or secondary prevention of CAD.

Quality of evidence

A MEDLINE search of English-language literature from January 1976 to January 1999 revealed 17 retrospective (case-control, cross-sectional) studies,^1-17one meta-analysis (based on studies completed before 1995),¹⁸and eight prospective studies suppor ting tHcy as a risk factor for CAD.^19-26One of the support- ive prospective studies, when extended by 2.5 years, however, no longer showed a statistically significant association between tHcy and incidence of CAD.²⁷ More recently, results from four large prospective cohort studies also did not demonstrate a significant association between tHcy concentration and increased risk of CAD.^28-31Plasma vitamins B6and B12and folic acid are strong correlates of tHcy;12,16,18,32-34

the literature is not entirely consistent, but does suggest that folic acid and vitamin B6 and B12 concentrations in blood are associated positively with CAD occur- rence.12,18,27,32-44

Results from five prospective epidemiologic studies showed low dietar y folic acid and vitamin B6and B12or low serum folic acid to be associated with increased incidence of CAD.^27-31 Twelve inter vention studies showed notable decreases in tHcy levels after administration of folic acid with or

without vitamins B6 and B12.^9,45-55Several prospective, double-blinded studies examining the effect of vitamin supplementation on morbidity and mor tality of patients with CAD are currently under way.⁵⁶

Main findings

Prevalence of hyperhomocysteinemia. Normal tHcy levels range from 5 to 15 µmol/L in fasting patients.^40,43Hyperhomocysteinemia is defined as any value above the 95th percentile or more than two standard deviations above the mean values obtained from healthy, fasting control subjects. Elevated tHcy levels are classified as moderate (15 to 30 µmol/L), interme- diate (> 30 to 100 µmol/L), or severe (> 100 µmol/L) based on fasting blood samples. Using this definition of hyperhomocysteinemia, its prevalence in the general population is 5%.⁵⁷Between 13% and 47% of people with symptomatic atherosclerotic disease, however, have been reported to have hyperhomocysteinemia.⁵⁵

Measurement of plasma tHcy levels. About 80%

of total tHcy in blood is protein bound by disulfide linkage.⁵⁸ Free tHcy is variable, but tHcy frozen immediately or centrifuged within 2 hours of collec- tion (tHcy levels may increase secondar y to the export of homocysteine from red and white blood cells) remains constant.⁵⁹Studies have not definitive- ly established tHcy reference standards by age and sex, although these variables are known to influence tHcy levels, with higher tHcy concentrations in men and older people.⁶⁰

Among patients with vitamin B12deficiency, tHcy levels are generally higher than 23 µmol/L; confir- mation might require ser um methylmalonic acid assay.⁶¹A single measurement of tHcy after fasting appears to be the most cost-effective method and has recently been offered in Canada at a cost of about

$35 per assay. Testing for tHCy should always be done after fasting; efforts are under way to standard- ize testing methods.

How homocysteine works. Homocysteine is an amino acid formed as a result of metabolism of sul- furous methionine supplied from dietar y proteins (eg, yellow and green leafy vegetables, grains, poul- try, and meats). A simplification of tHcy metabolism⁶² is summarized in Figure 1. Several disease states and medications have been shown to elevate tHcy levels, and this elevation could lead to CAD if unde- tected (Table 1).

Nutrition: Researchers have suggested that up to two thirds of all hyperhomocysteinemia is attributable to

C

Dr Taylor is a resident and Dr Evans teaches in the Department of Family and Community Medicine, and Dr Oudit is a resident in the Department of Medicine, in the University Health Network at the University of Toronto in Ontario.

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deficiencies of one or more B vitamins.³⁶Homocysteine levels can be markedly elevated with deficiencies of the essential cofactor vitamin B12or the cosubstrate folic acid.^28,63,64An inverse relationship has been found to exist with plasma vitamins B6and B12 and folic acid in relation to plasma tHcy levels in normal subjects.³⁶

Disease states: Markedly elevated tHcy levels have been reported in association with acute lymphoblastic leukemia; they decrease dramatically after chemother- apy.^65,66Moderately elevated tHcy levels have been found in patients with breast, ovarian, and pancreatic cancer.⁶⁵In patients with chronic renal failure, plasma tHcy levels can be two to four times normal, but they decrease with dialysis.^8,20A positive correlation exists between fasting tHcy and serum creatinine levels.

Increases in tHcy levels during chronic renal failure might be due to impaired metabolism rather than excretion.²⁰The observed acceleration of atherosclerosis during end-stage renal disease could be due to elevated tHcy concentrations.

Hyperhomocysteinemia has been found in hypothyroid patients, suggesting an explanation for the obser ved higher incidence of vascular disease in hypothyroid patients. Hyperhomocysteinemia has also been reported in patients with pernicious anemia.

Elevations in plasma tHcy levels are useful in diagnos- ing this disorder.⁶¹

Drugs: Several drugs increase plasma tHcy levels:

methotrexate, phenytoin, carbamazepine, and nitrous oxide. Methotrexate depletes folic acid, the cosubstrate for methionine synthase, and causes an increase in tHcy levels.^67,68Both phenytoin and carbamazepine interfere with folic acid metabolism, causing mild hyperhomocysteinemia.^67,68Nitrous oxide inactivates vitamin B12- dependent methionine synthase and is known to elevate tHcy levels.⁶⁸Smoking is associated with a proportional increase in plasma tHcy levels, particularly in older men who smoke 20 or more cigarettes a day.⁶⁹

Genetic causes:Cystathionine β-synthase deficiency is the most common genetic cause of hyperhomcys- teinemia. Heterozygotes for this disorder have tHcy levels in the range of 20 to 40µmol/L. Congenital hyperhomocystinuria, the homozygous form of the disease, can be associated with fasting levels of tHcy of up to 400 µmol/L,⁷⁰but this form of cystathionine β-synthase deficiency is rare (one in 200000 births).⁷¹About 50% of patients with untreated hyperhomocystinuria will have a thromboembolic event before age 30.⁷⁰ A thermolabile variant of 5, 10-methylenetetrahydrofolate reductase, caused by a point mutation (C677T) in the coding region for the folate binding site, has been found in 38% of French Canadians and 5% to 15% of the general Canadian population. This variant of the 5, 10-methylenetetrahydrofolate reductase gene is not a significant independent risk factor for CAD.^72-74 Those who are homozygous for this mutation, however, might be at increased risk of vascular disease.⁷⁵

Toxicity theory: It has been postulated that tHcy increases risk of CAD through direct toxicity to endothelial cells, increased coagulability, elevated triglyceride levels, and oxygen free radical produc- tion, which leads to lower endothelial reactivity with stimulation of smooth muscle cell proliferation (Figure 1).58,68,76-78

Cross-sectional and retrospective case-control studies.Some evidence indicates tHcy is an independent risk factor for CAD. A meta-analysis based on 27 observational studies from 1976 to 1995 estimated that 10% of the United States population’s CAD risk could be attributed to elevated tHcy levels.¹⁸The Table 1. Causes of hyperhomocysteinemia

NUTRITION

Deficiencies in folic acid, vitamin B₆, and vitamin B₁₂ DISEASE STATES

Chronic renal failure Hypothyroidism

Malignancies (all, especially breast, ovarian, pancreatic) Pernicious anemia

Systemic lupus erythematosus DRUGS

Cigarettes

Antimetabolites (eg, methotrexate)

Anticonvulsants (eg, phenytoin, carbamazepine) Cholestyramine

Nicotinic acid Nitrous oxide Thiazide diuretics GENETIC DEFICIENCIES

Cystathionine β-synthase Methionine synthase

Methylenetetrahydrofolate reductase

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odds ratio (OR) for CAD of a 5-µmol/L tHcy incre- ment was 1.6 (95% confidence interval [CI] 1.4 to 1.7) for men and 1.8 (95% CI 1.3 to 1.9) for women. The authors concluded that a 5-µmol/L increase in tHcy raised CAD risk by as much as a 0.5-µmol/L increase in cholesterol.¹⁸The summary estimate for homocysteine as a risk factor for CAD was determined in this meta-analysis to be 1.7 (95% CI 1.5 to 1.9).¹⁸Since this meta-analysis, three more retrospective studies have provided evidence to support elevated tHcy levels increasing risk of CAD^15-17(Table 2^1-18).

Other evidence suggests tHcy is not an indepen- dent risk factor. Two smaller studies (one cross- sectional, one case-control)^79,80 did not show increased risk of CAD with elevated tHcy levels.

These results were later dismissed due to inade- quate sample size and erroneous methods of mea- suring tHcy levels.

Prospective studies.Some evidence indicates tHcy is an independent risk factor for CAD. Eight prospective cohort studies have reported statistically significant positive associations between elevated tHcy levels and risk of CAD.^19-26One study reported a relative risk of 1.41 (95% CI 1.16 to 1.71) for every 4-µmol/L increase in serum tHcy.²⁰The study by Nygard et al²³used patients with angiographically proven heart disease who were followed for a median of 4.6 years. This cohort showed a strong, graded association between tHcy concentration and overall mortality.²³This association was strongest for tHcy levels above 15 µmol/L, with an adjusted mortality OR of 1.6 for patients with

tHcy concentrations of 15 µmol/L compared with patients with levels of 10 µmol/L. After 4 years, only 3.8% of patients with tHcy < 9 µmol/L had died compared with 24.7% of those with tHcy >15 µmol/L (mortality OR 4.5; 95% CI 1.22 to 16.6) for patients with the highest tHcy levels compared with the lowest. Similarly, after 5 years of follow up the Physician’s Health Study reported an adjusted relative risk of fatal or non-fatal MI of 3.4 (CI 1.3 to 8.8; P=.01)¹⁹(Table 3^19-26,28).

Other evidence suggests tHcy is not an indepen- dent risk factor. In contrast to the results discussed above, recent studies have failed to demonstrate a significant association between tHcy concentration and incidence of CAD^27-31(Table 4^27-31). Five reports of four large cohorts followed prospectively do not support a cause-and-effect association between elevated tHcy levels and risk of CAD.^27-31 In particular, when the Physician’s Health Study was extended by 2.5 years, results no longer showed a statistically significant association between tHcy levels and incidence of CAD.²⁷

Similarly, the Multiple Risk Factor Inter vention Trial²⁹and the Atherosclerosis Risk in Communities (ARIC) Study³⁰did not find a significant association between elevated tHcy levels and fatal or non-fatal CAD. Three of the five studies showed a trend toward increased risk of CAD with elevations in tHcy.^27,28,30A significant association might not have been reached because the three studies did not compare events (ie, fatal or non-fatal myocardial infarctions [MIs]) in people at extreme ends of tHcy plasma concentration as the studies that supported tHcy as a risk factor for CAD did. One of these studies suggests, however, that tHcy is a consequence, not a cause, of CAD.²⁸ Among patients with CAD, elevated tHcy levels strongly predict poor outcome,⁷⁷suggesting that tHcy reflects the severity of CAD and perhaps the risk of thrombosis. Among smokers, using an adjusted dose- response relationship, elevated levels of tHcy are not associated with increased mortality.⁶⁹

Dietary intake and serum levels of folic acid and vitamins B₆ and B₁₂. Although not entirely consistent, most retrospective cross-sectional and prospective cohor t studies show a positive and dose- dependent association between ser um levels or dietary intake of folic acid and vitamins B6and B12and risk of CAD.12,18,27,32-34,36-44

Changes in tHcy levels might simply be an epiphenomenon and might, in fact, have no direct effect on risk of developing CAD. A recent prospective epidemiologic study among 80 082 women enrolled in the Nurse’s Health Study followed for F i g u re 1. Homocysteine metabolism and

putative atherogenic mechanism

Methionine Folic acid Vitamin B₁₂

Homocysteine Vitamin B₆ Cystathionine Auto-oxidation

• Low-density lipoprotein oxidation

• Smooth muscle cell proliferation

• Elevated triglyceride levels

• Increased coagulability

Development of coronary artery disease?

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STUDY CASES/CONTROLS SEX* AGE (Y)^† DESIGN

MEAN TOTAL HOMOCYSTEINE LEVELS (µMOL/L)

CASES/CONTROLS

(PFOR DIFFERENCE) MAIN FINDINGS Wilcken and

Wilcken¹

25/22 Men < 50 Cross-sectional NA/NA

Murphy-Chutorian et al²

99/39 Men 21-65 Cross-sectional 0.7/0.6

Kang et al³ 241/202 < 69 Cross-sectional 5.5/4.3 (< .001)

Israelsson et al⁴ 21/36 Men 48-58 Population

case control 16.4/13.5 Malinow et al⁵ 64/92

35/167 99/259

Men Women

65/60 70/62

Cross-sectional 13.1/11.3 (<.05) 12.9/10.2 (<.05) NA

Genest et al⁶ 170/255 Men < 60 Case control 13.7/10.9 (<.001)

Ubbink et al⁷ 163/195 Men 55 Case control 16.2/13.4

Clarke et al⁸ 60/27 < 55 Case control 18.7/13.4

Dudman et al⁹ 14/36 48/20 62/56

Women Men

< 52 Case control NA NA NA Pancharuniti

et al¹⁰

101/108 Men 30-50 Population

case contol

13.5/11.9 (< .001)

Wu et al¹¹ 170/168 < 55 (men)

< 65 (women)

Population case control

13.4/10.1 (< .001) Von Eckardstein

et al¹⁴

199/156 Men 36-65 Case control 8.9/7.8 (< .001)

Hopkins et al¹⁵ 304/231 62 Case control 13.1/10.1 Men: OR

13.8 (CI 3.5-55) Women: OR 12.8 (CI 2.0-82)^‡

Dalery et al¹⁶ 420/521 25-64 Case control 11.8 (< .001)/

8.6 (< .01)

Men: P < .001 Women: P < .01

Robinson et al¹⁷ 162/155 38-68 Case control 14.6/10.6 (< .01) Men: OR 0.29

(CI 1.7-4.7) Women: OR 3.5 (CI 1.4-8.5)

Malinow et al¹³ 150/584 20-59 Case control 16.7/12.9

15.5/14.7

Irish arm: OR 3.4 (CI 1.6-7.2) French arm: OR 5.18

(CI 2.9-9.3)

Graham et al¹² 750/800 48 Case control 11.3/9.7 RR 2.2 (CI 1.6-2.9)

Table 2.Retrospective studies supporting homocysteine as a risk factor for coronar y arter y disease (CAD): Summary risk estimate for CAD in references 1 to 17 is 1.7 (95% CI, 1.5 to 1.9) as deter- mined by Boushey et al¹⁸

CI—confidence interval; NA—not available; OR—odds ratio; RR—relative risk.

*Unless otherwise designated, includes both men and women.

†Unless otherwise specified, mean age of participants.

‡For tHcy levels >19 µmol/L vs < 9 µmol/L.

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STUDY CASES/CONTROLS SEX* AGE (Y)^† MAIN OUTCOMES

MEAN TOTAL HOMOCYSTEINE LEVELS (µMOL/L)

CASES/CONTROLS RR OR OR (95% CI) Stampfer et al^{19 ‡} 271/271 Men 40-84 Fatal/non-fatal MI 11.1/10.5 (P < .05) 3.4 (1.3-8.8)

Arnesen et al²⁰ 122/478 53 Fatal/non-fatal CAD 12.7/11.3 1.41 (1.16-1.71)

Perry et al²² 107/118 Men 12-61 Fatal/non-fatal stroke 13.7/11.9 2.8 (1.3-5.9)

Petri et al²⁵ 60 35 Arterial thrombosis NA/NA 3.49 (0.97-12.54)

Nygard et al²³ 478 109

Men Women

62 62

Fatal CAD 11.4/NA

10.5/NA

4.5 (1.22-16.6)

Wald et al²¹ 229/126 Men 35-64 Fatal CAD > 15.2/<10.3 2.9 (2.04-4.1)

Stehouwer et al²⁴ 878/162 Men 64-84 MI NA/NA 1.81 (1.07-3.08)

Bots et al²⁶ 224/553 > 55 MI 17.3/NA 2.43 (1.11-5.35)

CI—confidence interval; MI—myocardial infarction; NA—not available; OR—odds ratio; RR—relative risk.

†Unless otherwise specified, mean age of participants.

‡Results no longer showed significant association of total homocysteine with incidence of CAD when was study extended by 2.5 years.²⁸

Table 3.Prospective studies supporting homocysteine as a risk factor for coronar y arter y disease (CAD)

STUDY CASES/CONTROLS SEX* AGE (Y) MAIN OUTCOMES

MEAN TOTAL HOMOCYSTEINE LEVELS (µMOL/L) CASES/CONTROLS

RR OR OR (95% CI) Alfthan et al²⁸ 92/141

99/128

Men Women

40-64 Fatal/non-fatal MI 9.8/9.8 9.4/9.3

1.05 (0.56-0.95) 1.22 (0.66-0.78) Chasan-Taber

et al²⁷

333/333 Men 40-84 Fatal/non-fatal MI 5.0/5.2 1.7 (0.9-3.3)

Evans et al²⁹ 93^†/186 147^‡/286

Men 35-57 Non-fatal MI, CAD,

death

12.6/13.1 12.8/12.7

0.82 (0.55-1.54)

Folsom et al³⁰ 232^§/537 45-64 All CAD events 8.86/8.53 1.28 (0.5-3.2)

Verhoef et al³¹ 109/427 Men 40-84 New angina/CABG 10.9/10.4 1.0 (0.4-2.4)

CABG—coronary artery bypass grafting; CI—confidence interval; MI—myocardial infarction; OR—odds ratio; RR—relative risk.

†Non-fatal MI cases.

‡Deaths from coronary heart disease (CHD).

§Composed of 146 definite or probable MIs, 19 silent MIs, 30 definite fatal CHDs, and 37 revascularization procedures.

Table 4.Prospective studies not supporting homocysteine as a risk factor for coronar y arter y disease (CAD)

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14 years examined the relation between intake of folic acid and vitamin B6and risk of CAD.⁸¹A large portion of this study group had insufficient intake of vitamin B6and folic acid to prevent CAD, in agreement with the Framingham Heart Study.⁴¹ Women with the lowest intake of folic acid and vitamin B6had the greatest risk of mortality and MI.⁸¹

In the large prospective ARIC study, only plasma vitamin B6was associated with incidence of CAD after accounting for other risk factors.³⁰The relative risk (RR) for highest versus lowest quintile of vitamin B6was 0.28 (95% CI 0.1 to 0.7).³⁰Interestingly, arterial lesions have been seen in animals raised on vitamin B6–deficient diets.^82,83A summary of the main prospective studies supporting the role of folic acid and vitamins B6and B12in risk of CAD44,63,81,84

are shown in Table 5.44,63,81,84,85

Vitamin supplementation for preventing CAD.

Several studies have shown substantial decreases in tHcy levels when patients add folic acid, with or without vitamins B6and B12,to their diets.^9,45-53According to the Nurse’s Health Study, risk of CAD was reduced

among women who regularly used multiple vitamins (RR 0.76; 95% CI 0.65 to 0.90).⁸¹Maximum benefit was found among women in the highest quintile of both folic acid and vitamin B6intake (RR 0.57; 95% CI 0.40 to 0.82). This finding is consistent with the independent effects of these vitamins in lowering tHcy levels, suggesting that maximum benefit can be obtained with optimal levels of both vitamins.

The association between dietary folic acid intake and tHcy levels appears to reach a plateau beyond which tHcy levels remain stable. Existence of a plateau is supported by studies showing that tHcy levels did not decrease any more after 6 weeks of treatment with 1000 µg of folic acid, 0.4 mg of vitamin B12, and 12.2 mg of vitamin B6 when twice these amounts were given.⁸¹The minimum daily dose of folic acid that has maximal ef ficacy in decreasing plasma tHcy levels is about 0.4 mg.^55,86,87A recent meta-analysis summarizing the ef fects of vitamin therapy on tHcy levels showed that folic acid alone at 0.5 to 5.0 mg/d was accompanied by a 25% reduction in tHcy levels (CI 23% to 28%).⁸⁷

STUDY AGE (Y) PARTICIPANTS DESIGN MEAN FOLLOW UP (Y) MAIN RESULTS

de Bree et al⁸⁴ 35-79 165 men and women who died of CAD

Prospective cohort nested case-control

15 RR 1.69 for lowest vs highest quarters of folate level Verhoef et al⁶³ 40-84 333 men after MI Prospective cohort

nested case-control

7.5 RR 1.4 (CI 0.9-2.3) for lowest vs highest fifths of folate level; RR 1.5 (CI 1.0-2.2) for lowest vs highest fifths of vitamin B₆level

Morrison et al⁴⁴ 45-64 232 men and women with fatal and non-fatal CAD

3.3 RR 0.66 (CI 0.3-1.5) for highest vs lowest fifths of folate level;

RR 0.28 (CI 0.1-0.7) for highest vs lowest fifths of vitamin B₆ level; RR 0.81 (CI 0.4-1.8) for highest vs lowest fifths of B₁₂ level

Giles et al⁸⁵ 35-74 98 men and women with ischemic stroke

13 RR 1.37 (CI 0.82-2.29) for serum folate level <9.2µmol/L vs >9.2 µmol/L

Rimm et al⁸¹ 30-55 658 women with non-fatal MI and CAD death

14 RR 0.69 (CI 0.55-0.87) for highest vs lowest fifths of folate level; RR 0.67 (CI 0.53-0.85) for highest vs lowest fifths of vitamin B₆level

Table 5.Prospective studies of folate, vitamins B₆and B₁₂, and cardiovascular risk

CAD—coronary artery disease; CI—confidence interval; MI—myocardial infarction; RR—relative risk.

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Normalization of plasma tHcy levels occurred 2 to 6 weeks after initiation of folic acid therapy regard- less of the reason for the elevated tHcy. Addition of 0.5 mg/d of vitamin B12to folic acid was associated with an additional 7% drop in tHcy levels,⁸⁷but addition of 16.5 mg/d of vitamin B6did not further lower them. The authors acknowledge, however, that these results might be due to their exclusion of studies using one version of the tHcy assay, the results of which might depend more on vitamin B6.⁸⁷

Canada has recently followed the lead of the United States Food and Drug Administration and has begun supplementing cereal and flour products with 140 µg of folic acid per 100 g of flour. It remains to be seen whether fortifying cereal or flour products with folic acid has any effect on tHcy levels and ultimately CAD risk in the general population.

A rare but potentially serious side effect of folic acid supplementation is subacute combined degenera- tion of the spinal cord in people with subclinical vitamin B12 deficiency. To avoid this complication, physicians should rule out vitamin B12deficiency before therapy; 400 to 1000 µg/d of vitamin B12is suggested. The doses of vitamin B6used to treat mildly or moderately elevated total plasma tHcy levels are too low (25 to 50 mg/d) to induce sensory neuropathy.

Before vitamin therapy can be approved for prima- r y and secondar y prevention of CAD, results from ongoing randomized clinical trials evaluating the effect of vitamin therapy on patient morbidity and mortality must be analyzed. The trials looking specifi- cally at MI as an end point include the Cambridge Heart Antioxidant Study (CHAOS-2), the Norwegian Study of Homocysteine Lowering with B-Vitamins in Myocardial Infarction (NORVIT), and the Study of the Ef fectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH).⁵⁶

Conclusion

Most retrospective studies support an association between elevated tHcy levels and increased risk of CAD, but data from prospective studies are less consistent. Results from large randomized controlled trials are needed to better clarify the relationships among tHcy, folic acid, B vitamins, and risk of CAD.

Adding 0.5 mg/d of folic acid alone can reduce basal tHcy levels by about 25%; adding 0.5 mg/d of vitamin B12to the folic acid further reduces levels by 7%.

Most of the literature supports combining vitamin B6, about 25 to 50 mg/d, with folic acid and vitamin B12. A large randomized controlled trial with clear end points in terms of reducing CAD morbidity and mortality

with vitamin therapy would provide the best evidence on which to base our preventive interventions. Until we know the effect of vitamin supplementation on primary and secondary prevention of CAD, we have no evidence upon which to recommend testing any patient’s tHcy levels. Also, before routine testing can be advocated, the assay must be standardized.

Finally, the effect of vitamin therapy on clinical outcome must be of proven clinical benefit. In the meantime, family physicians are urged to continue to

Key points

• Elevated homocysteine levels appear to be more common in people with symptomatic atherosclerotic disease.

• Homocysteine levels have an inverse relationship with plasma vitamins B₆and B₁₂and folic acid.

• Evidence exists both for and against homocysteine as an independent risk factor for CAD. More recent evidence is less compelling.

• Several studies show that supplementation with folic acid and vitamins B₆and B₁₂reduces serum homocysteine levels; many randomized controlled trials are currently studying their effect on morbidity and mortality.

• Until better evidence is available, mass screening for elevated homocysteine levels and recommending vitamin supplements is still experimental.

Points de repère

• Des taux élevés d’homocystéine semblent plus fréquents chez les personnes atteintes d’athérosclérose symptomatique.

• Des taux élevés d’homocystéine ont un rappor t inversement proportionnel aux taux de vitamines B₆et B₁₂et d’acide folique dans le plasma.

• Il existe à la fois des données favorables et défavor- ables au fait de considérer l’homocystéine comme un facteur de risque indépendant de souffrir de coronaropathies. Les plus récentes données probantes sont moins convaincantes.

• Quelques études font valoir qu’un supplément d’acide folique et de vitamines B₆et B₁₂réduit les taux sériques d’homocystéine; plusieurs essais aléatoires contrôlés étudient présentement l’effet de ce supplément sur la morbidité et la mortalité.

• Avant d’avoir en main de meilleures données probantes, le dépistage systématique des taux élevés d’homocystéine et la recommandation d’ad- ministrer des suppléments vitaminiques n’en sont encore qu’au stade expérimental.

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detect and actively manage traditional risk factors for CAD, including promotion of a well-balanced and nutritious diet.

Correspondence to: Dr Michael Evans, Depar tment of Family and Community Medicine, University of Toronto, 750 Dundas St W, Toronto, ON M6J 3S3; tele- phone (416) 603-5061; fax (416) 603-5821; e-mail michael.evans@utoronto.ca

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