Total homocysteine in patients with angiographic coronary artery disease correlates with inflammation markers

Summary

Moderate hyperhomocysteinaemia is considered as an independent risk marker for cardiovascular disease and stroke. Earlier, increased homocysteine production was detected in stimulated immunocompetent cells in vitro, and several markers of inflammation like neopterin or C-reactive protein (CRP) were demonstrated as significant indicators of cardiovascular risk. The relationship between coronary artery disease (CAD), homocysteine metabolism and markers of immune activation and inflammation was investigated in a population of 1717 patients undergoing coronary angiography, recruited as participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. 1325 patients (77.2%) suffered from coronary artery disease (CAD), which was was defined as the occurrence of a visible luminal narrowing (≥20% stenosis) in at least 1 of 15 coronary segments according to the classification of the American Heart Association, the remaining 392 individuals of the study population served as controls. Significant differences regarding systolic blood pressure, homocysteine, neopterin and folic acid concentrations were observed between patients and controls. Older age, decreased creatinine-clearance and higher concentrations of homocysteine and CRP were indicative for CAD. Low B-vitamin availability, therapy and the extent of immune activation strongly influenced homocysteine concentrations. Homocysteine concentrations were correlated with neopterin levels (r_s =0.325, p<0.001), and hyperhomocysteinaemic patients also presented with significantly higher CRP concentrations. Homocysteine accumulation coincided with impaired renal and heart function (as reflected by ProBNP[Brain natriuretic peptide]-concentrations). We conclude that homocysteine accumulation could result from B-vitamin deficiency which is related to chronic immune activation.

Keywords

Homocysteine - coronary artery disease - inflammation - neopterin - CRP

• References

• 1 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. J Am Med Assoc 1995; 274: 1049-1057.
• 2 McCully KS. Homocysteine and vascular disease. Nat Med 1996; 02: 386-389.
• 3 Hankey GJ, Eikelboom JW. Homocysteine and vascular disease. Lancet 1999; 354: 407-413.
• 4 Harker LA, Slichter SJ, Scott CR. et al. Homocystinemia. Vascular injury and arterial thrombosis. N Engl J Med 1974; 291: 537-543.
• 5 Lentz SR. Mechanisms of homocysteine-induced atherothrombosis. J Thromb Haemost 2005; 03: 1646-1654.
• 6 Libby P. Inflammation in atherosclerosis. Nature 2002; 420: 868-874.
• 7 Frangogiannis NG, Smith CW, Entman ML. The inflammatory response in myocardial infarction. Cardiovasc Res 2002; 53: 31-47.
• 8 Falk E. Morphological features of unstable atherothrombotic plaques underlying acute coronary syndromes. Am J Cardiol 1989; 63: 114E-120E.
• 9 Nathan CF, Murray HW, Wiebe ME. et al. Identification of interferon-gamma as the lymphokine that activates human macrophage oxidative metabolism and antimicrobial activity. J Exp Med 1983; 158: 670-689.
• 10 Fuchs D, Weiss G, Reibnegger G. et al. The role of neopterin as a monitor of cellular immune activation in transplantation, inflammatory, infectious and malignant diseases. Crit Rev Clin Lab Sci 1992; 29: 307-341.
• 11 Garcia-Moll X, Coccolo F, Cole D. et al. Serum neopterin and complex stenosis morphology in patients with unstable angina. J Am Coll Cardiol 2000; 35: 956-962.
• 12 Auer J, Berent R, Labetanig E. et al. Serum neopterin and activity of coronary artery disease. Heart Dis 2001; 03: 297-301.
• 13 Adachi T, Naruko T, Itoh A. et al. Neopterin is associated with plaque inflammation and destabilisation in human coronary atherosclerotic lesions. Heart 2007; 93: 1537-1541.
• 14 Ray KK, Morrow DA, Sabatine MS. et al. Long-term prognostic value of neopterin: a novel marker of monocyte activation in patients with acute coronary syndrome. Circulation 2007; 115: 3071-3078.
• 15 Avanzas P, Arroyo-Espliguero R, Quiles J. et al. Elevated serum neopterin predicts future adverse cardiac events in patients with chronic stable angina pectoris. Eur Heart J 2005; 26: 457-463.
• 16 Konstantino Y, Wolk R, Terra SG. et al. Non-traditional biomarkers of atherosclerosis in stable and unstable coronary artery disease, do they differ?. Acute Card Care 2007; 09: 197-206.
• 17 van Haelst PL, Liem A, van Boven AJ. et al. Usefulness of elevated neopterin and C-reactive protein levels in predicting cardiovascular events in patients with nonQ-wave myocardial infarction. Am J Cardiol 2003; 92: 1201-1203.
• 18 Zouridakis E, Avanzas P, Arroyo-Espliguero R. et al. Markers of inflammation and rapid coronary artery disease progression in patients with stable angina pectoris. Circulation 2004; 110: 1747-1753.
• 19 Shah SH, Newby LK. C-reactive protein: a novel marker of cardiovascular risk. Cardiol Rev 2003; 11: 169-179.
• 20 Zakai NA, Katz R, Jenny NS. et al. Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. J Thromb Haemost 2007; 05: 1128-1135.
• 21 Grammer TB, Fuchs D, Böhm BO. et al. Neopterin as a predictor of total and cardiovascular mortality in individuals undergoing angiography (The Ludwigshafen Risk and Cardiovascular Health Study). Clin Chem 2009; 55: 115-146.
• 22 Schroecksnadel K, Frick B, Kaser S. et al. Moderate hyperhomocysteinaemia and immune activation in patients with rheumatoid arthritis. Clin Chim Acta 2003; 338: 157-164.
• 23 Schroecksnadel K, Leblhuber F, Frick B. et al. Association of hyperhomocysteinemia in Alzheimer disease with elevated neopterin levels. Alzheimer Dis Assoc Disord 2004; 18: 129-133.
• 24 Frick B, Rudzite V, Schroecksnadel K. et al. Homocysteine, B vitamins and immune activation in coronary heart disease. Pteridines 2003; 14: 82-87.
• 25 Schroecksnadel K, Frick B, Wirleitner B. et al. Homocysteine accumulates in supernatants of stimulated human peripheral blood mononuclear cells. Clin Exp Immunol 2003; 134: 53-56.
• 26 Winkelmann BR, Maerz W, Boehm BO. et al. Rationale and design of the LURIC study – a resource for functional genomics, pharmacogenomics and long-term prognosis of cardiovascular disease. Pharmacogenomics 2001; 02: S1-73.
• 27 Austen WG, Edwards JE, Frye RL. et al. A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975; 51: 5-40.
• 28 Selhub J, Jacques PF, Rosenberg IH. et al. Serum total homocysteine concentrations in the third National Health and Nutrition Examination Survey (1991–1994): population reference ranges and contribution of vitamin status to high serum concentrations. Ann Intern Med 1999; 131: 331-339.
• 29 Brattstrom L, Wilcken DE. Homocysteine and cardiovascular disease: cause or effect?. Am J Clin Nutr 2000; 72: 315-323.
• 30 Lonn E, Yusuf S, Arnold MJ. et al. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 2006; 354: 1567-1577.
• 31 Bonaa KH, Njolstad I, Ueland PM. et al. Homocysteine lowering and cardiovascular events after acute myocardial infarction. N Engl J Med 2006; 354: 1578-1588.
• 32 Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost 2009; 07 (Suppl. 01) 332-339.
• 33 Fuchs D, Jaeger M, Widner B. et al. Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake?. Clin Chem Lab Med 2001; 39: 691-694.
• 34 Murr C, Fuith LC, Widner B. et al. Increased neopterin concentrations in patients with cancer: indicator of oxidative stress?. Anticancer Res 1999; 19: 1721-1728.
• 35 Solichova D, Melichar B, Svobodova I. et al. Fluorescence analysis of antioxidant vitamins and neopterin in nonagenarians. Biomed Chromatogr 1999; 13: 117-118.
• 36 Murr C, Schroecksnadel K, Winklhofer-Roob BM. et al. Inverse association between serum concentrations of neopterin and antioxidants in patients with and without angiographic coronary artery disease. Atherosclerosis 2009; 202: 543-549.
• 37 Cirillo P, Pacileo M, De Rosa S. et al. Neopterin induces pro-atherothrombotic phenotype in human coronary endothelial cells. J Thromb Haemost 2006; 04: 2248-2255.
• 38 Voutilainen S, Virtanen JK, Rissanen TH. et al. Serum folate and homocysteine and the incidence of acute coronary events: the Kuopio Ischaemic Heart Disease Risk Factor Study. Am J Clin Nutr 2004; 80: 317-323.
• 39 Bleie O, Semb AG, Grundt H. et al. Homocysteine-lowering therapy does not affect inflammatory markers of atherosclerosis in patients with stable coronary artery disease. J Intern Med 2007; 262: 244-253.
• 40 Frick B, Gruber B, Schroecksnadel K. et al. Homocysteine but not neopterin declines in demented patients on B vitamins. J Neural Transm 2006; 113: 1815-1819.
• 41 Nygard O, Vollset SE, Refsum H. et al. Total plasma homocysteine and cardiovascular risk profile. The Hordaland Homocysteine Study. J Am Med Assoc 1995; 274: 1526-1533.
• 42 de Bree A, Verschuren WM, Kromhout D. et al. Homocysteine determinants and the evidence to what extent homocysteine determines the risk of coronary heart disease. Pharmacol Rev 2002; 54: 599-618.
• 43 Ohsawa M, Okayama A, Nakamura M. et al. CRP levels are elevated in smokers but unrelated to the number of cigarettes and are decreased by long-term smoking cessation in male smokers. Prev Med 2005; 41: 651-656.
• 44 O’Callaghan P, Meleady R, Fitzgerald T. et al. Smoking and plasma homocysteine. Eur Heart J 2002; 23: 1580-1586.
• 45 Diamondstone LS, Tollerud DJ, Fuchs D. et al. Factors influencing serum neopterin and beta 2-microglobulin levels in a healthy diverse population. J Clin Immunol 1994; 14: 368-374.
• 46 Schennach H, Murr C, Larcher C. et al. Neopterin concentrations in cord blood: a single-cohort study of paired samples from 541 pregnant women and their newborns. Clin Chem 2002; 48: 2059-2061.
• 47 Otterbein LE, Bach FH, Alam J. et al. Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway. Nat Med 2000; 06: 422-428.
• 48 Gueant-Rodriguez RM, Juilliere Y, Nippert M. et al. Left ventricular systolic dys-function is an independent predictor of homocysteine in angiographically documented patients with or without coronary artery lesions. J Thromb Haemost 2007; 05: 1209-1216.