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Indian Journal of Medical Sciences
Medknow Publications on behalf of Indian Journal of Medical Sciences Trust
ISSN: 0019-5359 EISSN: 1998-3654
Vol. 61, Num. 6, 2007, pp. 361-371

Indian Journal of Medical Sciences, Vol. 61, No. 6, June, 2007, pp. 361-371

Practitioners section

Homocysteine in cardiovascular disease: A culprit or an innocent bystander?

Manager Clinical Development, Nicholas Piramal Research Centre, Goregaon (E), Mumbai - 63
Correspondence Address:B-36/A-002, Golkuldham, Goregaon (E), Mumbai - 400 063, kothekarashish@rediffmail.com

Code Number: ms07061

Abstract

Whether hyperhomocysteinemia is a cardiovascular risk factor or is just an epiphenomenon is a subject of debate. More than 20 prospective and 30 retrospective studies on the topic have been published. Despite huge literature available, an unequivocal view has not been firmly established. Medical fraternity is still witnessing differing opinions regarding need to treat hyperhomocysteinemia. A medical practitioner needs to be well informed of developments and current opinion on this subject as it has a strong bearing on a major emerging public health problem of cardiovascular disease (CVD). This review presents the two views - for and against the acceptance of association between hyperhomocysteinemia and cardiovascular disease - and their basis. The two views are examined in the light of clinical, epidemiologic and genetic studies, reviews and meta-analyses available. Following conclusion was drawn from the exercise: The available evidence indicates that homocysteine is not an innocent bystander; it is an independent risk factor for CVD. The need for homocysteine-lowering therapy is however not yet unequivocally established. Physicians need to be vigilant of the updates on this much-debated topic thrusted on them time and again.

Keywords: Bystander, cardiovascular, hyperhomocysteinemia, risk factor, therapy

The hypothesis that hyperhomocysteinemia is a risk factor for cardiovascular disease (CVD) was suggested by the observation that children with homozygous homocysteinuria had a high incidence of premature occlusive vascular disease. The initial epidemiological evidence from retrospective case-control studies came in support of this hypothesis. However, inconsistent results have been reported from prospective observational studies, with some showing highly significant association and some showing none. It has also been postulated that hyperhomocysteinemia is just an epiphenomenon and there is no causal relationship between elevated homocysteine levels and CVD risk. Nevertheless, the debate is ongoing, and both the opinions - one, that homocysteine is a culprit; and the other, that it is an innocent bystander - are prevailing in the scientific community. This article is an attempt to throw light on both the aspects of the hypothesis and to form some opinion in the light of various recently published reports and meta-analyses on the subject.

Biochemistry of Homocysteine

Homocysteine is a sulfur-containing amino acid, produced during the metabolism of methionine. It enters two divergent metabolic pathways [Figure - 1]:
  1. Remethylation: Homocysteine is converted back to methionine.
  2. Trans-sulfuration: Homocysteine is converted to cystathionine and then to cysteine.

Remethylation reaction requires folic acid in the form of methyl tetrahydrofolate for donation of methyl group to homocysteine. This methyl group transfer occurs under the influence of the enzyme methionine synthase, and vitamin B 12 is also required as a cofactor for the reaction. Methylene tetrahydrofolate reductase (MTHFR) is an essential enzyme required for continuous supply of methyl tetrahydrofolate; this enzyme converts methylene tetrahydrofolate to methyl tetrahydrofolate and ensures a constant supply of the methyl donor methyl tetrahydrofolate.

The trans-sulfuration reaction is dependent on cystathionine beta-synthase, which needs vitamin B 6 (pyridoxine) as a cofactor.

Causes of Hyperhomocysteinemia

  1. Cystathionine beta-synthase deficiency
  2. Methylene tetrahydrofolate reductase (MTHFR) deficiency
  3. Methionine synthase deficiency or other rare enzymatic defects
  4. Dietary deficiency-
    · Folate deficiency
    · Vitamin B 12 deficiency
    · Vitamin B 6 deficiency
  5. Other causes-
    · Renal failure
    · Liver disorders
    · Hypothyroidism
    · Malignancy including breast, ovarian or pancreatic cancer in addition to ALL (Acute Lymphocytic Leukemia).
    · Drugs which interfere with metabolic pathway, deteriorate renal function, retard vitamin synthesis or reduce absorption of vitamins - for example, methotrexate, trimethoprim, cholestyramine, colestipole, phenytoin, carbamazepine, niacin, theophylline, cyclosporine and fibric acid derivatives.
Elevated homocysteine levels are common in the general population. Twenty-one percent of elderly participants in the Framingham study had plasma homocysteine levels exceeding 15.8 µmol/L. [1] These can result from heterozygous deficiency of cystathionine beta-synthase or methylene tetrahydrofolate reductase (MTHFR) or from suboptimal intake of nutritional factors (folate, vitamin B 6 , vitamin B 12 ).

Damaging Effects of Homocysteine

[2]Prothrombotic effects
  1. Reduces thrombomodulin levels
  2. Reduces heparin sulfate levels
  3. Decreases protein C activity
  4. Inhibits binding of tissue plasminogen activator (tPA) to endothelial cells
  5. Activates factors V and XII
  6. Increases tissue factor expression
  7. Induces platelet adhesiveness and aggregation
Other damaging effects
  1. Endothelial cell dysfunction - decreases eNO (endothelial nitric oxide) bioavailability
  2. Endothelial cell toxicity - apoptosis
  3. Smooth muscle cell proliferation - myointimal hyperplasia and hypertrophy
  4. Extracellular matrix remodeling activates redox sensitive MMPs (matrix metalloproteinases) and decreases bioavailability of eNO and results in ECM (extracellular matrix) fibrosis.
  5. Promotes vasoconstriction
  6. Promotes LDL cholesterol modification: promotes macrophage - foam cell formation via LDL cholesterol modification
  7. Pro-inflammatory
  8. Pro-oxidant - increases oxidative stress via reactive oxygen species formation

Evidence Base for Damaging Effects of Homocysteine

More than 75 clinical and epidemiologic studies have shown a relation between total homocysteine levels and coronary artery disease, peripheral artery disease, stroke or venous thrombosis. [3] More than 20 prospective and 30 retrospective (cross-sectional and case-control) studies on the topic have been published. Prospective studies showed that an increment of 5 µmol/L in total homocysteine level results in a 20-30% increase in cardiovascular risk. Retrospective studies showed a 60-90% risk enhancement. [4],[5]

To quote one study, [3] Nygard et al. prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. A strong, graded relation was found between plasma homocysteine levels and overall mortality. After 4 years, 3.8% of the patients with homocysteine levels below 9 mmol/L had died, as compared with 24.7% of those with homocysteine levels of 15 mmol/L or higher. In an analysis in which the patients with homocysteine levels below 9 mmol/L were used as the reference group, the mortality ratios were 1.9 for patients with homocysteine levels of 9.0 to 14.9 mmol/L, 2.8 for those with levels of 15.0 to 19.9 mmol/L and 4.5 for those with levels of 20.0 mmol/L or higher [Figure - 2].

Is the risk enhancement real? - Contentions against the association

The very fact that well-defined association between hyperhomocysteinemia and CVD has been observed only in retrospective studies [odds ratio (OR) = 0.67], with a much lower association observed in prospective studies (OR = 0.83), casts doubt on the hypothesis. [5] Some prospective studies actually indicate a weak or no association. Thus the hypothesis is based mainly on results of retrospective studies. Following contentions have been put forth against this association:

  1. Hyperhomocysteinemia is an effect rather than cause of AMI (Acute Myocardial Infarction) and stroke.
  2. The association between hyperhomocysteinemia and cardiovascular disease is not independent; it is confounded by the presence of other traditional risk factors.
  3. If hyperhomocysteinemia is a cause of CVD, genetic deficiency of MTHFR should increase the risk of CVD, which is not the case.

Hyperhomocysteinemia is an effect rather than cause of AMI and Stroke

It has been observed that homocysteine levels increase in convalescent phase of acute cardiac and coronary events. Homocysteine concentrations have been reported to be higher by 4% at 6 weeks, by 19% at 6 months and by 27% at 1.5 years, compared with initial values determined between 24 and 48 h after onset of an acute vascular event. [6],[7],[8]

There is evidence to suggest that homocysteine is released from damaged vascular tissue after myocardial infarction and stroke. It is proposed that during the repair of damaged tissue, there is an increased demand for DNA. These repair processes require the methylation of DNA, RNA and proteins - reactions that lead to the generation of homocysteine as the end point of methylation. [9] Homocysteine levels also increase in numerous inflammatory diseases such as psoriasis, SLE (Systemic Lupus Erythematosus), malignancies, dementia and rheumatoid arthritis. Hyperhomocysteinemia therefore may merely be a biomarker of inflammatory disease processes, including atherosclerosis. Hence rise in homocysteine levels may be an effect rather than a cause of the event.

Retrospective studies cannot resolve this CAUSE or EFFECT relationship because the event has already occurred. Also, the time interval between occurrence of event and sample collection is not consistent in retrospective studies. It cannot be determined whether the elevated homocysteine levels preceded atherosclerosis or were secondary to the disease process. Prospective studies have the major advantage of collecting blood specimens before any relevant clinical events have occurred. The temporal relationship between elevated homocysteine levels and CVD risk is more clearly defined in prospective studies. Given that there is variation in homocysteine levels at baseline and at convalescence and that hyperhomocysteinemia may be an effect rather than cause, prospective studies should be the basis for accepting or refuting the hypothesis.

Confounding Effect of Other Risk Factors

High homocysteine levels are associated with other predictors of CVD, such as high blood pressure, elevated cholesterol levels and cigarette smoking, among others. Hence the CVD risk enhancement seen with hyperhomocysteinemia may be an effect of all the risk factors together rather than the effect of hyperhomocysteinemia per se, unless all the other risk factors are adjusted during the analysis. It has been found that studies that included adjustment for these confounders report lower risk of CVD due to high homocysteine levels. Adjustment for confounders is more accurate in prospective studies than in retrospective ones; because in prospective studies, information regarding presence/absence of these other risk factors can be collected before the occurrence of an event.

Genetic Deficiency of MTHFR Doses not Increase CVD Risk

The enzyme MTHFR catalyzes the irreversible conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which serves as a methyl donor in the reaction converting homocysteine to methionine. C (Cytosine) to T (Thymidine) transition at base pair 677 of the gene coding this enzyme confers thermolability and reduces catalytic activity of the enzyme. Homozygous TT individuals are prone to elevated homocysteine levels under conditions of impaired folate status. In most populations investigated, those bearing the TT genotype have homocysteine concentrations approximately 25% higher than do those with the CC genotype. It has therefore been anticipated that the TT genotype confers increased CVD risk. However, meta-analyses including approximately 6,000 patients showed no or a borderline significant relation between the C677T MTHFR polymorphism and occurrence of coronary heart disease. [4]

Defense of the Contentions

The foregoing discussion is based on certain observations that cast doubt on association between elevated homocysteine levels and increased CVD risk. However, the second school of thought, the one in favor of the association, addresses all these contentions, leading the opinion towards favor of the hypothesis. The defense of contentions is on the following lines:
  1. Studies designed specifically to address the cause-effect relationship have shown that hyperhomocysteinemia is a cause of acute coronary and cerebral events.
  2. Adjustment of confounders reduces but does not nullify the association.
  3. Studies that showed no association between MTHFR TT genotype and CVD were statistically under-powered to show the association. Moreover, MTHFR TT genotype need not necessarily increase the CVD risk.

Addressing the CAUSE or EFFECT contention

The contention that hyperhomocysteinemia is an effect and not cause of cardiovascular events is based largely on the observation that homocysteine levels increase in convalescent phase of acute cardiac and coronary events.It has also been proposed that prospective studies address this issue better than retrospective ones.

Prospective studies designed specifically to address the cause-effect relationship have shown that hyperhomocysteinemia is a cause of acute coronary and cerebral events. A prospective study [10] was conducted to examine variations in plasma homocysteine concentration in patients presenting with acute coronary syndromes. Consecutive patients presenting with acute myocardial infarction and unstable angina pectoris were studied. Plasma samples were obtained on admission (before clinical intervention), on days 2, 7, 28 and again 6 months after admission. Results indicated that homocysteine concentrations in myocardial infarction (median, 25 th to 75 th interquartile range) were 11.9 (10.7 to 12.6), 11.5 (9.1 to 13.4), 12.1 (11.4 to 14.1), 12.4 (11.1 to 14.4) and 12.1 (11.2 to 14.0) µmol/L, for days 1, 2, 7, 28 and 180 respectively (P = 0.02). Significant differences were observed only between day 2 and day 7 (P < 0.05) [Figure - 3]. The final homocysteine measurement was not different from the admission level. Homocysteine concentrations in unstable angina did not differ between admission and convalescence [12.5 (9.1 to 14.5) µmol/L and 12.3 (7.7 to 14.9) µmol/L respectively]. It was concluded that in acute coronary syndrome, there was no difference between plasma homocysteine concentrations on admission and after a long period of convalescence. Results of this study answer a major contention against the retrospective studies and strengthen reliability on the retrospective studies that showed an association between homocysteine and CVD risk.

Addressing the confounding effect of other risk factors

As discussed above, the adjustment of confounding risk factors is more accurate in prospective studies. A meta-analysis published in 2002, i.e., after publication of most of the retrospective and prospective studies addressed this issue. [5] This was a combined analysis of prospective studies. Odds ratios were adjusted for confounding variables - namely, age, sex, smoking, systolic BP and cholesterol level. Unadjusted odds ratio for IHD (Ischemic Heart Disease) associated with a 25% lower homocysteine level was 0.83 in prospective studies; after adjustment for the risk factors mentioned above, the OR was attenuated to 0.89. Thus the OR was slightly attenuated but not negated. The study concluded that a 25% lower-than-usual homocysteine level is associated with about an 11% lower IHD risk and about a 19% lower stroke risk. Thus even after adjustment of confounding risk factors, there still remains some risk of CVD in hyperhomocysteinemia patients, meaning that there is some independent relationship between elevated homocysteine levels and CVD risk.

The Swiss Heart Study [11] was a randomized double-blind placebo-controlled trial to evaluate the effect of homocysteine-lowering therapy (folic acid + vitamin B 12 + vitamin B 6 ) on clinical outcome after percutaneous coronary intervention in 553 patients. It was found that homocysteine-lowering therapy significantly reduced the incidence of major adverse events (significant reduction in composite end point of death, nonfatal myocardial infarction and need for repeat revascularization at 1 year) compared to placebo, and the effect remained unchanged after adjustment for confounders.

Why did MTHFR polymorphism studies show no increase in risk of CVD?

No or borderline significant relation has been found between the C677T MTHFR polymorphism and CVD; this has been thought to be a contention for disproving the hypothesis. However, careful statistical evaluation indicated that the studies addressing correlation between MTHFR polymorphism and CVD risk were inadequately powered due to smaller sample size, and the results are FALSE NEGATIVE. It has been found that the total homocysteine concentration was 2.6 µmol/L higher in those with the TT than in those with the CC genotype. [12] With use of data from prospective studies, a 5-µmol/L total homocysteine increment can be shown to be associated with an OR of 1.20-1.30. For a difference of 2.6 µmol/L, this OR translates to 1.10-1.15. Standard sample size calculations show that to detect a relative risk in the range of 1.10-1.15 with a power of 80% and a significance level of 5%, 7,800-16,300 cases and an equal number of controls are required. This exceeds the sample size in the studies showing no association between MTHFR and CVD. In fact, the relative risk of 1.12 reported in these studies [12] agrees well with the expected relative risk. A statistically powered meta-analysis [13] involving 12,193 cases of ischemic heart disease reported significant difference in IHD risk between TT homozygous allele and the wild type homozygous allele. The odds ratio was 1.21, indicating 21% higher risk in TT homozygotes than in CC homozygotes.

There are two more aspects involved in the interrelationship between MTHFR polymorphism and hyperhomocysteinemia and CVD. MTHFR deficiency causes hyperhomocysteinemia only in patients who are deficient in folic acid; and in the trials that found no association between MTHFR and CVD risk, the patients were well nourished. It has been found that hyperhomocysteinemia and the TT genotype have opposite effects on processes related to vascular occlusive disease; C677T MTHFR transition protects against vascular disease by mechanisms independent of homocysteine. [4] This may partly explain the inconsistent and weak relation of the MTHFR polymorphism with CVD, i.e., MTHFR deficiency despite causing hyperhomocysteinemia need not necessarily increase the risk of CVD.

Current Opinion : Results of Recent Studies

In view of the two schools of thought, it is worthwhile having a look at the current opinion and the most recent evidence generated on the topic. In a prospective study by Matetzky et al., [14] homocysteine levels were determined within 24 h of presentation in 157 patients with AMI. Patients were allocated to two groups: those with homocysteine levels of 20 µmol/L or more and those with levels less than 20 µmol/L. Patients with higher homocysteine levels had a significantly higher incidence of recurrent coronary events and mortality compared with patients with lower homocysteine levels during an average follow-up of 30 months [Figure - 4]. In multivariate analysis, higher homocysteine levels remained independent predictors of recurrent coronary event and/or death.

Bodi et al.[15] measured troponin I, myoglobin, high-sensitivity C-reactive protein, fibrinogen and homocysteine levels in 557 consecutive patients admitted for non-ST elevation acute coronary syndrome. The risk for major events (death or nonfatal myocardial infarction) at first month and at first year follow-up was analyzed. It was found that the variables independently related to major events at 1 year were age, insulin-dependent diabetes, tobacco habit, previous history of ischemic heart disease, Killip class> 1, troponin I> 1 ng/ml, C-reactive protein> 11 mg/L and homocysteine> 12 µmol/L. The study clearly showed that elevated homocysteine was not associated with major events at 1 month but was independently related to 1-year mortality.

The skeptical meta-analysis published in 2001 that raised suspicion about the hypothesis also states that ′homocysteine may be a late-stage predictor of CVD and that homocysteine may increase the risk of clinical disease among those with atherosclerotic disease.′ [16] This is in agreement with the recent findings that indicate an independent association between hyperhomocysteinemia and long-term event rate and mortality.

One more study, for the first time evaluated association between hyperhomocysteinemia and severity of coronary artery disease (CAD) and left ventricular systolic function. [17] One hundred fifty-seven patients with angiographically defined CAD were included. The relationships between hyperhomocysteinemia, severity of CAD and left ventricular systolic function were studied. Left ventricular systolic function was determined primarily by ventriculography. The severity of CAD was determined through coronary angiography using the Gensini score and by determining the number of vessels with stenosis ≥50%. Results indicated that elevated levels of homocysteine correlated significantly with increased severity of CAD both by the Gensini scores (′r′ value = 0.344, P < 0.0005) and the total number of diseased vessels (r = 0.387, P < 0.0005). The patients with hyperhomocysteinemia had significantly reduced left ventricular ejection fraction (r = -0.382, P < 0.0005). A multivariate regression analysis revealed homocysteine level to be an independent predictor of left ventricular systolic function. In addition, adjusted analysis revealed hyperhomocysteinemia to be associated with global left ventricular dysfunction.

Results of recent large-scale trials - the Norwegian Vitamin (NORVIT) trial, [18] the Heart Outcomes Prevention Evaluation (HOPE)-2 trial [19] and the Women′s Antioxidant and Folic Acid Cardiovascular Study (WAFACS) [20] - have posed threat to the homocysteine hypothesis. These randomized controlled trials in a huge number of patients showed no benefit of homocysteine-lowering therapy in reducing cardiovascular events. These studies have however been challenged on several grounds. First, these studies were statistically underpowered. [21] Second, folic acid fortification in the study population was a confounding factor in the WAFACS and HOPE-2 trials. [21] Third, the treatment duration was inadequate. [22] Fourth, there was a significant (24%) reduction in risk of stroke in the intervention group in the HOPE-2 trial (RR = 0.75; 95% confidence interval = 0.59-0.97; P = 0.03), which the authors underplayed in the report. [23] Fifth, negative results from these studies might be due to much higher doses of folic acid (2 to 6 times the RDA (Recommended Dietary Allowance)), vitamin B 12 (166 to 416 times the RDA) and vitamin B 6 (12 to 25 times the RDA). Use of high doses, especially of vitamin B6, as discussed in the HOPE-2 report itself, may adversely affect vascular remodeling and myocardial repair, leading to increased rates of complications and death among patients with cardiovascular disease. [24],[19] Sixth, the baseline homocysteine levels in these studies were less than 15 µmol/L, whereas earlier studies that support the hypothesis showed increased risk at concentrations more than 15 µmol/L. A similar large-scale trial, the VISP (The Vitamin Intervention for Stroke Prevention) trial, [25] that showed no benefit of homocysteine lowering in reducing major events in patients surviving stroke, however, observed that there was a persistent, significant and graded association between baseline total homocysteine level and the outcomes, i.e., recurrent cerebral infarction, coronary heart disease (CHD) events and death. Hence it appears that homocysteine-lowering therapy benefits patients who are really hyperhomocysteinemic.

A recent meta-analysis by Bazzano et al.[26] that included NORVIT and HOPE-2 studies also, expectedly, has gone against the homocysteine hypothesis; it was found that folic acid supplementation does not reduce risk of cardiovascular diseases or all-cause mortality among participants with prior history of vascular disease. This same year, an analysis by Wald et al.[27] of various studies published on the subject, however, concluded differently - that the evidence is now sufficient to justify action on lowering homocysteine concentrations. The authors at the same time had kept a provision to review the decision if needed at a later stage by saying, ′. . . although the position should be reviewed as evidence from ongoing clinical trials emerges.′

In view of the intriguing evidence, it can be concluded that homocysteine is definitely associated with CVD risk. Regarding the benefit of homocysteine-lowering therapy, accumulation of more data from ongoing trials is required so that a statistically valid comment can be made from results of the pooled data. Studies in special populations like the Indian and other Asian populations, known to have higher homocysteine levels, and studies in renal transplant recipients who are not affected by folic acid content of fortified foods are especially warranted. Till then, balanced diet would be the best preventive approach to deal with this novel risk factor. Homocysteine-lowering therapy may be considered when hyperhomocysteinemia is present in addition to other CVD risk factors, as the presence of other CVD risk factors increases the overall risk. At the same time, it is imperative upon the physicians to keep themselves well informed of the upcoming results of the ongoing clinical trials and meta-analyses on the topic so as to be able to revise their decisions if needed.

Conclusion

That homocysteine is a culprit and not an innocent bystander is apparent from various epidemiologic and genetic studies; however, intriguingly, the need of homocysteine-lowering therapy still remains a subject of debate. Till unequivocal evidence on benefit of vitamin supplementation is apparent, balanced diet appears to be the best strategy for reducing CVD risk associated with hyperhomocysteinemia. As various studies are ongoing and as this is a topic currently in debate worldwide, physicians need to keep themselves updated of the upcoming views on the topic and accordingly revise their decisions.

References

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2.Hayden MR, Tyagi SC. Homocysteine and reactive oxygen species in metabolic syndrome, type 2 diabetes mellitus and atheroscleropathy: The pleiotropic effects of folate supplementation. Nutr J 2004;3:4.  Back to cited text no. 2  [PUBMED]  [FULLTEXT]
3.Nygard O, Nordrehaug JE, Refsum H, Ueland PM, Farstad M, Vollset SE. Plasma homocysteine levels and mortality in patients with coronary artery disease. N Engl J Med 1997;337:230-6.  Back to cited text no. 3    
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7.Landgren F, Israelsson B, Lindgren A, Hultberg B, Andersson A, Brattstrom L. Plasma homocysteine in acute myocardial infarction: Homocysteine-lowering effect of folic acid. J Intern Med 1995;237:381-8.  Back to cited text no. 7    
8.Lindgren A, Brattstrom L, Norrving B, Hultberg B, Andersson A, Johansson BB. Plasma homocysteine in the acute and convalescent phases after stroke. Stroke 1995;26:795-800.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Moat SJ, Doshi SN, Lang D, McDowell IF, Lewis MJ, Goodfellow J. Treatment of coronary heart disease with folic acid: Is there a future? Am J Physiol Heart Circ Physiol 2004;287:H1-7.  Back to cited text no. 9  [PUBMED]  [FULLTEXT]
10.Al-Obaidi MK, Stubbs PJ, Amersey R, Noble MI. Acute and convalescent changes in plasma homocysteine concentrations in acute coronary syndromes. Heart 2001;85:380-4.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]
11.Schnyder G, Roffi M, Flammer Y, Pin R, Hess OM. Effect of homocysteine-lowering therapy with folic acid, vitamin B 12 and vitamin B 6 on clinical outcome after percutaneous coronary intervention: The Swiss Heart study: A randomized controlled trial. JAMA 2002;288:973-9.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]
12.Brattstrom L, Wilcken DE, Ohrvik J, Brudin L. Common methylenetetrahydrofolate reductase gene mutation leads to hyperhomocysteinemia but not to vascular disease: The result of a meta-analysis. Circulation 1998;98:2520-6.  Back to cited text no. 12    
13.Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: Evidence on causality from a meta-analysis. BMJ 2002;325:1202-6.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]
14.Matetzky S, Freimark D, Ben-Ami S, Goldenberg I, Leor J, Doolman R, et al. Association of elevated homocysteine levels with a higher risk of recurrent coronary events and mortality in patients with acute myocardial infarction. Arch Intern Med 2003;163:1933-7.  Back to cited text no. 14  [PUBMED]  [FULLTEXT]
15.Bodi V, Sanchis J, Llacer A, Facila L, Nunez J, Pellicer M, et al. Multimarker risk strategy for predicting 1-month and 1-year major events in non-ST-elevation acute coronary syndromes. Am Heart J 2005;149:268-74.   Back to cited text no. 15  [PUBMED]  [FULLTEXT]
16.Christen WG, Ajani UA, Glynn RJ, Hennekens CH. Blood levels of homocysteine and increased risks of cardiovascular disease: Causal or casual? Arch Intern Med 2000;160:422-34.  Back to cited text no. 16  [PUBMED]  [FULLTEXT]
17.Bokhari SW, Bokhari ZW, Zell JA, Lee DW, Faxon DP. Plasma homocysteine levels and the left ventricular systolic function in coronary artery disease patients. Coronary Artery Dis 2005;16:153-61.  Back to cited text no. 17    
18.Bonaa KH, Njolstad I, Ueland PM, Schirmer H, Tverdal A, Steigen T, et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006;354:1578-88.  Back to cited text no. 18    
19.Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006;354:1567-77.  Back to cited text no. 19  [PUBMED]  [FULLTEXT]
20.Women's Antioxidant and Folic Acid Cardiovascular Study (WAFACS- Presented at AHA 2006). Presented by Dr. Christine Albert at the American Heart Association Annual Scientific Sessions: Chicago, IL; November 2006, Available from: http://www.medscape.com/viewarticle/548663.   Back to cited text no. 20    
21.Bostom AG, Selhub J, Jacques PF, Rosenberg IH. Power Shortage: Clinical trials testing the "homocysteine hypothesis" against a background of folic acid-fortified cereal grain flour. Ann Intern Med 2001;135:133-7.  Back to cited text no. 21  [PUBMED]  [FULLTEXT]
22.Quinlivan EP, Gregory JF 3 rd . Homocysteine, B vitamins and cardiovascular disease. N Engl J Med 2006;355:207-9.  Back to cited text no. 22    
23.Refsum H, Smith AD. Homocysteine, B vitamins and cardiovascular disease. N Engl J Med 2006;355:207.  Back to cited text no. 23  [PUBMED]  
24.Tomlinson DR, Lang D, Lewis MJ. Homocysteine, B vitamins and cardiovascular disease. N Engl J Med 2006;355:209.  Back to cited text no. 24  [PUBMED]  
25.Toole JF, Malinow MR, Chambless LE, Spence JD, Pettigrew LC, Howard VJ, et al. Lowering homocysteine in patients with ischemic stroke to prevent recurrent stroke, myocardial infarction and death: The Vitamin Intervention for Stroke Prevention (VISP) randomized controlled trial. JAMA 2004;291:565-75.  Back to cited text no. 25  [PUBMED]  [FULLTEXT]
26.Bazzano LA, Reynolds K, Holder KN, He J. Effect of folic acid supplementation on risk of cardiovascular diseases: A meta-analysis of randomized controlled trials. JAMA 2006;296:2720-6.   Back to cited text no. 26  [PUBMED]  [FULLTEXT]
27.Wald DS, Wald, NJ, Morris JK, Law M. Folic acid, homocysteine and cardiovascular disease: Judging causality in the face of inconclusive trial evidence. BMJ 2006;333:1114-7.  Back to cited text no. 27    

Copyright 2007 - Indian Journal of Medical Sciences


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