Many studies have found an association between high homocysteine, impaired cognitive performance and dementia development and progress. Elevated level of plasma homocysteine has been demonstrated to be an independent risk factor of coronary artery disease.

Clarke et al. [1] conducted study in 1991 and found that Hyperhomocysteinemia 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. They studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency.

They first established a diagnostic criterion for hyperhomocysteinemia 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 umol 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. They concluded that Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease and in most instances is probably due to deficiency of cystathionine beta- synthase.

Harker et al. conducted study in 1976, three groups of baboons were studied: 

• 8 control animals

• 15 animals after 3 month of continuous homocystinemia

• 11

Animals after 3 months of combined homocystinemia and oral treatment with dipyridamole. Experimental homocystinemia caused patch endothelial desquamation comprising about 10% of the aortic surface despite a 25-fold increase in endothelial cell regeneration. They found that homocysteine-induced vascular deendothelialization produced a threefold increase in platelet consumption that was interrupted by dipyridamole inhibition of platelet function. The effect of plasa homocysteine has been demonstrated due to its highly atherogenic and prothrombotic property. They concluded that the homocysteine-induced endothelial cell injury resulted in arteriosclerosis through platelet-mediated intimal proliferation of smooth muscle cells that can be prevented by drug-induced platelet dysfunction [2].

Nygård O. et al. conducted study in 1997 that elevated plasma homocysteine levels was a risk factor for coronary heart disease, but the prognostic value of homocysteine levels in patients with established coronary artery disease has not been defined. They prospectively investigated the relation between plasma total homocysteine levels and mortality among 587 patients with angiographically confirmed coronary artery disease. At the time of angiography in 1991 or 1992, risk factors for coronary disease, including homocysteine levels, were evaluated. The majority of the patients subsequently underwent coronary-artery bypass grafting (318 patients) or percutaneous transluminal coronary angioplasty (120 patients); the remaining 149 were treated medically. It has been shown by the this study that patients who have angiographically determined by CAD have an increase in the risk of death with increasing homocysteine concentration [3]. 

John et al. conducted a study in 2000. In this study, they have investigated the extent to which the Methylenetetrahydrofolate Reductase (MTHFR) 677 C3T mutation accounts for elevated plasma homocysteine and increased CHD risk in Indian Asians compared with European whites. They investigated 454 male cases (with myocardial infarction or angiographically proven CHD: 224 Indian Asians, 230 European whites) and 805 healthy male controls (381 Indian Asians, 424 European whites). Fasting homocysteine concentrations, MTHFR 677 C3T genotype and conventional CHD risk factors were measured. Elevated homocysteine in Indian Asian compared with European white controls was accounted for by their reduced levels of B vitamins but not by the MTHFR 677T genotype. 

They concluded that novel genetic defects and/or environmental factors influence homocysteine metabolism in Indian Asians residing in the United Kingdom and showed the association between homocysteine concentrations and plasma markers of thrombosis activation in patients admitted for acute coronary syndrome in UK Indian Asian and European Men [4].

Welch et al. conducted study in 1997. In this study two large, prospective studies have assessed the risk of coronary artery disease in patients with hyperhomocysteinemia. In the Physicians’ Health Study, 14, 916 male physicians without known atherosclerosis had an initial homocysteine measurement and were prospectively followed for an average of five years. Men with plasma homocysteine concentrations that were 12 percent above the upper limit of normal had approximately a threefold increase in the risk of myocardial infarction, as compared with those with lower levels, even after correction for other risk factors. The authors estimated that 7 percent of the 271 observed myocardial infarctions could be attributed to hyperhomocysteinemia. They concluded that homocysteine concentrations lead to myocardial injury in acute coronary syndrome and thus lead to worse prognosis of ACS [5].

Al-Obaidi et al. conducted study in 2000 and suggested relationship between homocysteine, factor V11a and thrombin generations in ACS. In this study, Patients with ACS (n = 117) presenting with confirmed acute Myocardial Infarction (MI) (n = 57) or Unstable Angina Pectoris (UAP) (n = 60) were consecutively recruited together with patients (n = 18) in whom the presenting chest pain was not of cardiac, included as controls. Plasma samples were collected on admission and before clinical intervention. Homocysteine was assayed by high performance liquid chromatography and both Factor VIIa and prothrombin fragment F1+2 were analyzed by ELISA. There were significant elevations in F1+2 in MI (p<0.001) and UAP (p = 0.003) and modest elevations in FactorVIIa in UAP (p<0.05) compared with Not of Cardiac Origin (NCP) but no differences in homocysteine levels among those group. They concluded that. Elevated plasma homocysteine is associated with and may cause elevated Factor VIIa and thrombin generation in patients presenting with ACS. These findings suggest an explanation for the prothrombotic effect of homocysteine in ACS [6].

Stampfer et al. conducted study in 2000 and suggested the plasma homocysteine and risk of MI in US physicians. They took 14,916 male physicians aged 40 to 80 years, with no prior 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 homocysteine levels together with paired controls, matched by age and smoking. They concluded that moderately high level of plasma homocysteine was associated with subsequent risk of MI independent of other risk factors because high levels can be easily treated with vitamin supplements, homocysteine may be an independent, modifiable risk factor [7].

Perry et al. [8] conducted study in 1999 and studied total serum homocysteine concentration and risk of stroke in middle aged British man. They examined the association between serum total homocysteine concentration and stroke in nested case - control studies within the British Regional Heart study cohort. They found that that total homocysteine is a strong and independent risk factor for stroke [8].

Giles et al. conducted study in 2000 and suggested association between total homocysteine and liklihood for a history of acute MI by race and ethnicity. They found almost a 2 -fold increased likelihood of MI among persons with the total homocysteine concentration>/=15umol/ltr was noted in this nationally representative survey. The magnitude of the association did not differ by race or ethnicity [9]. 

Schwartz et al. studied MI in young women in relation to plasma total homocysteine, folate and the common variant in the methylenetetrahydrofolate reductase gene. They found that elevated plasma total homocysteine and low plasma folate are risk factor for MI among women although homozygosity for MTHER T677 is related to increased plasma total homocysteine and low plasma folate are risk factors for MI in this population [10].

AL-Obaidi et al. studied that elevated homocysteine level is associated with increases ischemic myocardial injury in ACS. They studied consecutive patients presenting with acute MI (n = 205) and unstable angina (n = 185). Plasma sample were collected on admission and prior to intervention and were assayed for Homocysteine by High Performance Liquid Chromatography (HPLC). Myocardial necrosis was assessed by measurements of cardiac Troponin T(cTnT) on admission and 12 hr after admission (peak cTnT). They found that elevated HCY levels are associated with higher risk of ischemic Myocardial injury in patients presenting with ACS [11].

Matetzky, studied association of elevated homocysteine level with higher risk of recurrent coronary events and mortality in patients with acute MI. Homocysteine levels were determined in 24 hours of presentation in 157 constitutive patients with acute MI. They found that elevated homocysteine levels are associated with higher risk of recurrent coronary events and death, independent others risk factors and the extent of coronary artery disease [12].

Soinio et al. studied total homocysteine level is an independent predictor of coronary heart disease events in patients with type 2 diabetes mellitus. Participants with homocysteine levels of 15 umol/l or more at baseline had a higher risk for CHD death than those with plasma levels less than 15umol/l (26.1% and 13.5%, respectively, p=0.005). They concluded in this cohort of patients with type 2 diabetes, plasma homocysteine was strong and independent risk factor CHD events [13].

In a recent study, homocysteine was demonstrated to contribute to the initiation and progression of vascular disease by activating monocytes, resulting in the secretion of cytokines that amplify the inflammatory response. The demonstration of a relationship among homocysteine, inflammation and autoimmunity intriguingly expands the spectrum of the possible pathogenetic implications for homocysteine in the course of arterial disease [14]. 

Several epidemiological studies have identified moderately elevated concentrations of homocysteine was a potentially modifiable risk factor for coronary artery disease, which may contribute to the development of atherosclerosis. One of the major causes of hyperhomocysteinemia is a deficiency in vitamin B12 and folates–important cofactors in homocysteine metabolism. The possible mechanism by which homocysteine promotes atherosclerosis is unclear; however, inflammatory markers have been recently implicated.

1. Clarke, R. Forn et al. "Hyperhomocysteinemia: An Independent Risk Factor for Vascular Disease." New England Journal of Medicine, vol. 324, no. 17, 1991, pp. 1149-1155.

2. Harker, L.A. Forn et al. "Homocystine-Induced Arteriosclerosis: The Role of Endothelial Cell Injury and Platelet Response in Its Genesis." The Journal of Clinical Investigation, vol. 58, no. 3, 1976, pp. 731-741.

3. Nygard, O. Forn et al. "Department of Public Health and Primary Health Care, University of Bergen, Haukeland University Hospital, Norway." New England Journal of Medicine, vol. 337, no. 4, 1997, pp. 230-236.

4. Chambers, J.C. Forn et al. "Plasma Homocysteine Concentrations and Risk of Coronary Heart Disease in UK Indian Asian and European Men." The Lancet, vol. 355, no. 9203, 2000, pp. 523-527.

5. Welh, G.N. and J. Loscalzo. "Whitaler Cardiovascular Institute and Evans Department of Medicine, Boston University School of Medicine." New England Journal of Medicine, vol. 338, no. 15, 1998, pp. 1042-1050.

6. Al-Obaidi, M.K. Forn et al. "Relationships Between Homocysteine, Factor VIIa and Thrombin Generation in Acute Coronary Syndromes." Circulation, vol. 101, no. 4, 2000, pp. 372-377.

7. Stampfer, M.J. Forn et al. "Southern Oregon JAM MED ASSOC." Journal of the American Medical Association, vol. 268, no. 7, 1992, pp. 877.

8. Perry, I.J. Forn et al. "Prospective Study of Serum Total Homocysteine Concentration and Risk of Stroke in Middle-Aged British Men." The Lancet, vol. 346, no. 8987, 1995, pp. 1395-1398.

9. Giles, W.H. Forn et al. "Association Between Total Homocyst(e)ine and the Likelihood for a History of Acute Myocardial Infarction by Race and Ethnicity: Results from the Third National Health and Nutrition Examination Survey." American Heart Journal, vol. 139, no. 3, 2000, pp. 446-53.

10. Schwartz, S.M. Forn et al. "Myocardial Infarction in Young Women in Relation to Plasma Total Homocysteine, Folate and a Common Variant in the Methylenetetrahydrofolate Reductase Gene." Circulation, vol. 96, no. 2, 1997, pp. 412-417.

11. Al-Obaidi, M.K. Forn et al. "Elevated Homocysteine Levels Are Associated with Increased Ischemic Myocardial Injury in Acute Coronary Syndromes." Journal of the American College of Cardiology, vol. 36, no. 4, 2000, pp. 1217-1222.

12. Matetzky, S. Forn et al. "Southern Oregon Arch. Intern. Med." Archives of Internal Medicine, vol. 16, no. 16, 2003, pp. 1933.

13. Soinio, M. Forn et al. "Elevated Plasma Homocysteine Level Is an Independent Predictor of Coronary Heart Disease Events in Patients with Type 2 Diabetes Mellitus." Annals of Internal Medicine, vol. 140, no. 2, 2004, pp. 94-100.

14. Oudi, M.E. Forn et al. "Homocysteine and Markers of Inflammation in Acute Coronary Syndrome." Experimental and Clinical Cardiology, vol. 15, no. 2, 2010, pp. e25-28.