Vol 28, No 4 (2021)
Original Article
Published online: 2020-12-01

open access

Page views 1339
Article views/downloads 1006
Get Citation

Connect on Social Media

Connect on Social Media

Homocysteine and long-term recurrent infarction following an acute coronary syndrome

Gema Miñana12, Carolina Gil-Cayuela23, Lorenzo Fácila4, Vicent Bodi12, Ernesto Valero12, Anna Mollar1, Maria Marco1, Teresa García-Ballester1, Begoña Zorio1, Jorge Martí-Cervera5, Eduardo Núñez1, Francisco J. Chorro12, Juan Sanchis12, Julio Núñez12
Pubmed: 33346372
Cardiol J 2021;28(4):598-606.


Background: There are no well-established predictors of recurrent ischemic coronary events after an acute coronary syndrome (ACS). Higher levels of homocysteine have been reported to be associated with an increased atherosclerotic burden. The primary endpoint was to assess the relationship between homocysteine at discharge and very long-term recurrent myocardial infarction (MI).
Methods: 1306 consecutive patients with ACS were evaluated (862 with non-ST-segment elevation ACS [NSTEACS] and 444 with ST-segment elevation myocardial infarction [STEMI]) discharged from October 2000 to June 2003 in a single teaching-center. The relationship between homocysteine at discharge and recurrent MI was evaluated through bivariate negative binomial regression accounting for mortality as a competitive event.
Results: The mean age was 66.8 ± 12.4 years, 69.1% were men, and 32.2% showed prior diabetes mellitus. Most of the patients were admitted for an NSTEACS (66.0%). The median (interquartile range) GRACE risk score, Charlson comorbidity index, and homocysteine were 144 (122–175) points, 1 (1–2) points, and 11.9 (9.3–15.6) μmol/L, respectively. In-hospital revascularization was performed in 26.3% of patients. At a median follow-up of 9.7 (4.5–15.1) years, 709 (54.3%) deaths were registered and 779 recurrent MI in 478 (36.6%) patients. The rates of recurrent MI were higher in patients in the upper homocysteine quartiles (p < 0.001). After a multivariate adjustment, homocysteine along its continuum remained almost linearly associated with a higher risk of recurrent MI (p = 0.001) and all-cause mortality (p < 0.001).
Conclusions: In patients with ACS, higher homocysteine levels identified those at a higher risk of recurrent MI at very long-term follow-up.

Article available in PDF format

View PDF Download PDF file


  1. Benjamin EJ, Muntner P, Alonso A, et al. American Heart Association Council on E, Prevention Statistics C, Stroke Statistics S. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019; 139: e56–e528.
  2. Selhub J. The many facets of hyperhomocysteinemia: studies from the Framingham cohorts. J Nutr. 2006; 136(6 Suppl): 1726S–1730S.
  3. Fácila L, Nuñez JE, G VB, et al. Early determination of homocysteine levels in acute coronary syndromes, is it an independent prognostic factor? Int J Cardiol. 2005; 100(2): 275–279.
  4. Bostom AG, Rosenberg IH, Silbershatz H, et al. Nonfasting plasma total homocysteine levels and stroke incidence in elderly persons: the Framingham Study. Ann Intern Med. 1999; 131(5): 352–355.
  5. Anderson JL, Muhlestein JB, Horne BD, et al. Plasma homocysteine predicts mortality independently of traditional risk factors and C-reactive protein in patients with angiographically defined coronary artery disease. Circulation. 2000; 102(11): 1227–1232.
  6. Holvoet P, Collen D. Oxidized lipoproteins in atherosclerosis and thrombosis. FASEB J. 1994; 8(15): 1279–1284.
  7. McCully KS. Macromolecular basis for homocystein-induced changes in proteoglycan structure in growth and arteriosclerosis. Am J Pathol. 1972; 66(1): 83–96.
  8. Thambyrajah J, Townend JN. Homocysteine and atherothrombosis--mechanisms for injury. Eur Heart J. 2000; 21(12): 967–974.
  9. Tofler GH, D'Agostino RB, Jacques PF, et al. Association between increased homocysteine levels and impaired fibrinolytic potential: potential mechanism for cardiovascular risk. Thromb Haemost. 2002; 88(5): 799–804.
  10. Folsom AR, Nieto FJ, McGovern PG, et al. Prospective study of coronary heart disease incidence in relation to fasting total homocysteine, related genetic polymorphisms, and B vitamins: the Atherosclerosis Risk in Communities (ARIC) study. Circulation. 1998; 98(3): 204–210.
  11. Ubbink JB, Fehily AM, Pickering J, et al. Homocysteine and ischaemic heart disease in the Caerphilly cohort. Atherosclerosis. 1998; 140(2): 349–356.
  12. Myocardial infarction redefined: a consensus document of The Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. Eur Heart J. 2000; 21(18): 1502–1513.
  13. Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). J Am Coll Cardiol. 1999; 34: 890–911.
  14. Ryan T, Anderson J, Antman E, et al. ACC/AHA guidelines for the management of patients with acute myocardial infarction. J Am Coll Cardiol. 1996; 28(5): 1328–1419.
  15. Tang EW, Wong CK, Herbison P. Global Registry of Acute Coronary Events (GRACE) hospital discharge risk score accurately predicts long-term mortality post acute coronary syndrome. Am Heart J. 2007; 153(1): 29–35.
  16. Charlson ME, Pompei P, Ales KL, et al. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987; 40(5): 373–383.
  17. Xu X, Hardin J. Regression models for bivariate count outcomes. Stata J. 2018; 16(2): 301–315.
  18. Royston P, Sauerbrei W. Multivariable Model‐Building: A Pragmatic Approach to Regression Analysis Based on Fractional Polynomials for Modelling Continuous Variables. Wiley, Chichester, UK 2008.
  19. McCully KS. Vascular pathology of homocysteinemia: implications for the pathogenesis of arteriosclerosis. Am J Pathol. 1969; 56(1): 111–128.
  20. Ueland PM, Refsum H. Plasma homocysteine, a risk factor for vascular disease: plasma levels in health, disease, and drug therapy. J Lab Clin Med. 1989; 114(5): 473–501.
  21. Berman RS, Martin W. Arterial endothelial barrier dysfunction: actions of homocysteine and the hypoxanthine-xanthine oxidase free radical generating system. Br J Pharmacol. 1993; 108(4): 920–926.
  22. Heinecke JW, Rosen H, Suzuki LA, et al. The role of sulfur-containing amino acids in superoxide production and modification of low density lipoprotein by arterial smooth muscle cells. J Biol Chem. 1987; 262(21): 10098–10103.
  23. Naruszewicz M, Mirkiewicz E, Kłosiewicz-Latoszek L. Modification of low density lipoproteins from hypertriglyceridemic patients by macrophages in vitro and the effect of bezafibrate treatment. Atherosclerosis. 1989; 79(2-3): 261–265.
  24. Parthasarathy S. Oxidation of low-density lipoprotein by thiol compounds leads to its recognition by the acetyl LDL receptor. Biochim Biophys Acta. 1987; 917(2): 337–340.
  25. Dudman NP, Temple SE, Guo XW, et al. Homocysteine enhances neutrophil-endothelial interactions in both cultured human cells and rats In vivo. Circ Res. 1999; 84(4): 409–416.
  26. Speidl WS, Nikfardjam M, Niessner A, et al. Mild hyperhomocysteinemia is associated with a decreased fibrinolytic activity in patients after ST-elevation myocardial infarction. Thromb Res. 2007; 119(3): 331–336.
  27. McDonald L, Bray C, Field C, et al. Homocystinuria, thrombosis, and the blood-platelets. Lancet. 1964; 1(7336): 745–746.
  28. Fan Y, Wang J, Zhang S, et al. Homocysteine enhances the predictive value of the GRACE risk score in patients with ST-elevation myocardial infarction. Anatol J Cardiol. 2017; 18(3): 182–193.
  29. Acevedo M, Pearce GL, Jacobsen DW, et al. Serum homocysteine levels and mortality in outpatients with or without coronary artery disease: an observational study. Am J Med. 2003; 114(8): 685–688.
  30. Boushey CJ, Beresford SA, Omenn GS, et al. A quantitative assessment of plasma homocysteine as a risk factor for vascular disease. Probable benefits of increasing folic acid intakes. JAMA. 1995; 274(13): 1049–1057.
  31. Study of the Effectiveness of Additional Reductions in C, Homocysteine Collaborative G, Armitage JM, Bowman L, Clarke RJ, Effects of homocysteine-lowering with folic acid plus vitamin B12 vs placebo on mortality and major morbidity in myocardial infarction survivors: a randomized trial. JAMA. 2010; 303: 2486–2494.
  32. Albert CM, Cook NR, Gaziano JM, et al. Effect of folic acid and B vitamins on risk of cardiovascular events and total mortality among women at high risk for cardiovascular disease: a randomized trial. JAMA. 2008; 299(17): 2027–2036.
  33. Toole JF, Malinow MR, Chambless LE, 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(5): 565–575.
  34. Hultdin J, Thøgersen AM, Jansson JH, et al. Elevated plasma homocysteine: cause or consequence of myocardial infarction? J Intern Med. 2004; 256(6): 491–498.
  35. Nevado JB, Imasa MS. Homocysteine predicts adverse clinical outcomes in unstable angina and non-ST elevation myocardial infarction: implications from the folate intervention in non-ST elevation myocardial infarction and unstable angina study. Coron Artery Dis. 2008; 19(3): 153–161.
  36. Ma Yi, Li Li, Geng XB, et al. Correlation between hyperhomocysteinemia and outcomes of patients with acute myocardial infarction. Am J Ther. 2016; 23(6): e1464–e1468.