Startseite Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality
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Elevated levels of asymmetric dimethylarginine (ADMA) as a marker of cardiovascular disease and mortality

  • Rainer H. Böger , Renke Maas , Friedrich Schulze und Edzard Schwedhelm
Veröffentlicht/Copyright: 21. September 2011
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Abstract

The endothelium plays a crucial role in the maintenance of vascular tone and structure by releasing the endothelium-derived vasoactive mediator, nitric oxide (NO). NO is formed in healthy vascular endothelium from the amino acid precursor L-arginine. Endothelial dysfunction is caused by various cardiovascular risk factors, metabolic diseases, and systemic or local inflammation. One mechanism that explains the occurrence of endothelial dysfunction is the presence of elevated blood levels of asymmetric dimethylarginine (ADMA) – an L-arginine analogue that inhibits NO formation and thereby can impair vascular function. Accumulating evidence from prospective clinical studies suggests that elevated plasma or serum levels of ADMA are associated with an increased risk of major adverse cardiovascular events. This article gives an updated overview of the currently available literature on ADMA and cardiovascular disease from prospective clinical trials. Recently, advances have been made in the development of analytical methods that are reliable and fast enough to allow determination of ADMA in clinical routine.


Corresponding author: Prof. Dr. med. Rainer H. Böger, Arbeitsgruppe Klinische Pharmakologie, Institut für Experimentelle und Klinische Pharmakologie und Toxikologie, Universitätsklinikum Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany Phone: +40-42803-9759, Fax: +40-42803-9757,

References

1. Kakimoto Y, Akazawa S. Isolation and identification of NG,NG- and NG,N′G-dimethyl-arginine, N-epsilon-mono-, di-, and trimethyllysine, and glucosylgalactosyl- and galactosyl-delta-hydroxylysine from human urine. J Biol Chem 1970; 245:5751–8.10.1016/S0021-9258(18)62716-4Suche in Google Scholar

2. McDermott JR. Studies on the catabolism of NG-methylarginine, NG,NG-dimethylarginine and NG,N′G-dimethyl-arginine in the rabbit. Biochem J 1976; 154:179–84.10.1042/bj1540179Suche in Google Scholar

3. Böger RH, Sydow K, Borlak J, Thum T, Lenzen H, Schubert B, et al. LDL cholesterol upregulates synthesis of asymmetric dimethylarginine (ADMA) in human endothelial cells. Involvement of S-adenosylmethionine-dependent methyltransferases. Circ Res 2000; 87:99–105.Suche in Google Scholar

4. Böger RH. Association of asymmetric dimethylarginine and endothelial dysfunction. Clin Chem Lab Med 2003; 41:1467–72.10.1515/CCLM.2003.225Suche in Google Scholar

5. Panza JA, Quyyumi AA, Brush JE Jr, Epstein SE. Abnormal endothelium-dependent vascular relaxation in patients with essential hypertension. N Engl J Med 1990; 323:22–7.10.1056/NEJM199007053230105Suche in Google Scholar

6. Celermajer DS, Sorensen KE, Georgakopoulos D, Bull C, Thomas O, Robinson J, et al. Cigarette smoking is associated with dose-related and potentially reversible impairment of endothelium-dependent dilation in healthy young adults. Circulation 1993; 88:2149–55.10.1161/01.CIR.88.5.2149Suche in Google Scholar

7. Johnstone MT, Creager SJ, Scales KM, Cusco JA, Lee BK, Creager MA. Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus. Circulation 1993; 88:2510–6.10.1161/01.CIR.88.6.2510Suche in Google Scholar

8. Tawakol A, Omland T, Gerhard M, Wu JT, Creager MA. Hyperhomocyst(e)inemia is associated with impaired endothelium-dependent vasodilation in humans. Circulation 1997; 95:1119–21.10.1161/01.CIR.95.5.1119Suche in Google Scholar

9. Böger RH, Bode-Böger SM, Szuba A, Tangphao O, Tsao PS, Chan JR, et al. Asymmetric dimethylarginine (ADMA): a novel risk factor for endothelial dysfunction: its role in hypercholesterolemia. Circulation 1998; 98:1842–7.10.1161/01.CIR.98.18.1842Suche in Google Scholar

10. Hingorani AD, Cross J, Kharbanda RK, Mullen MJ, Bhagat K, Taylor M, et al. Acute systemic inflammation impairs endothelium-dependent dilatation in humans. Circulation 2000; 102:994–9.10.1161/01.CIR.102.9.994Suche in Google Scholar

11. Böger RH, Bode-Böger SM, Frölich JC. The L-arginine-nitric oxide pathway: role in atherosclerosis and therapeutic implications. Atherosclerosis 1996; 127:1–11.10.1016/S0021-9150(96)05953-9Suche in Google Scholar

12. Cooke JP. Asymmetrical dimethylarginine: the Über marker? Circulation 2004; 109:1813–8.10.1161/01.CIR.0000126823.07732.D5Suche in Google Scholar

13. Böger RH. The emerging role of ADMA as a novel cardiovascular risk factor. Cardiovasc Res 2003; 59:824–33.10.1016/S0008-6363(03)00500-5Suche in Google Scholar

14. Ogawa T, Kimoto M, Sasaoka K. Occurrence of a new enzyme catalysing the direct conversion of NG,NG-dimethyl-L-arginine to L-citrulline in rats. Biochem Biophys Res Commun 1987; 148:671–7.10.1016/0006-291X(87)90929-6Suche in Google Scholar

15. Dayoub H, Achan V, Adimoolam S, Jacobi J, Stühlinger MC, Wang BY, et al. Dimethylarginine dimethylaminohydrolase regulates nitric oxide synthesis: genetic and physiological evidence. Circulation 2003; 108:3042–7.10.1161/01.CIR.0000101924.04515.2ESuche in Google Scholar

16. MacAllister RJ, Parry H, Kimoto M, Ogawa T, Russell RJ, Hodson H, et al. Regulation of nitric oxide synthesis by dimethylarginine dimethylaminohydrolase. Br J Pharmacol 1996; 119:1533–40.10.1111/j.1476-5381.1996.tb16069.xSuche in Google Scholar

17. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of NO synthesis in chronic renal failure. Lancet 1992; 339:572–5.10.1016/0140-6736(92)90865-ZSuche in Google Scholar

18. Calver A, Collier J, Leone A, Moncada S, Vallance P. Effect of local intra-arterial asymmetric dimethylarginine (ADMA) on the forearm arteriolar bed of healthy volunteers. J Hum Hypertens 1993; 7:193–4.Suche in Google Scholar

19. Chan JR, Böger RH, Bode-Böger SM, Tangphao O, Tsao PS, Blaschke TF, et al. Asymmetric dimethylarginine increases mononuclear cell adhesiveness in hypercholesterolemic humans. Arterioscler Thromb Vasc Biol 2000; 20:1040–6.10.1161/01.ATV.20.4.1040Suche in Google Scholar PubMed

20. Achan V, Broadhead M, Malaki M, Whitley G, Leiper J, MacAllister R, et al. Asymmetric dimethylarginine causes hypertension and cardiac dysfunction in humans and is actively metabolised by dimethylarginine dimethylaminohydolase. Arterioscler Thromb Vasc Biol 2003; 23:1455–9.10.1161/01.ATV.0000081742.92006.59Suche in Google Scholar PubMed

21. Kielstein JT, Impraim B, Simmel S, Bode-Böger SM, Tsikas D, Frölich JC, et al. Cardiovascular effects of systemic nitric oxide synthase inhibition with asymmetrical dimethylarginine in humans. Circulation 2004; 109:172–7.10.1161/01.CIR.0000105764.22626.B1Suche in Google Scholar PubMed

22. Böger RH, Lentz SR, Bode-Böger SM, Knapp HR, Haynes WG. Elevation of asymmetrical dimethylarginine may mediate endothelial dysfunction during experimental hyperhomocyst(e)inaemia in humans. Clin Sci 2001; 100:161–7.10.1042/cs1000161Suche in Google Scholar

23. Sydow K, Schwedhelm E, Arakawa N, Bode-Böger SM, Tsikas D, Hornig B, et al. ADMA and oxidative stress are responsible for endothelial dysfunction in hyperhomocyst(e)inemia. Effects of L-arginine and B vitamins. Cardiovasc Res 2003; 57:244–52.10.1016/S0008-6363(02)00617-XSuche in Google Scholar

24. Sydow K, Hornig B, Arakawa N, Bode-Böger SM, Tsikas D, Münzel T, et al. Endothelial dysfunction in patients with peripheral arterial disease and chronic hyperhomocysteinemia: potential role of ADMA. Vasc Med 2004; 9:1377–83.10.1191/1358863x04vm538oaSuche in Google Scholar

25. Böger RH, Bode-Böger SM, Sydow K, Heistad DD, Lentz SR. Plasma concentration of asymmetric dimethylarginine, an endogenous inhibitor of nitric oxide synthase, is elevated in monkeys with hyperhomocyst(e)inemia. Arterioscler Thromb Vasc Biol 2000; 20:1557–64.10.1161/01.ATV.20.6.1557Suche in Google Scholar

26. Stühlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway. Role of asymmetric dimethylarginine. Circulation 2001; 104:2569–75.10.1161/hc4601.098514Suche in Google Scholar

27. Böger RH, Bode-Böger SM, Thiele W, Junker W, Alexander K, Frölich JC. Biochemical evidence for impaired nitric oxide synthesis in patients with peripheral arterial occlusive disease. Circulation 1997, 95:2068–74.10.1161/01.CIR.95.8.2068Suche in Google Scholar

28. Surdacki A, Nowicki M, Sandmann J, Tsikas D, Böger RH, Bode-Böger SM, et al. Reduced urinary excretion of nitric oxide metabolites and increased plasma levels of asymmetrical dimethylarginine in men with essential hypertension. J Cardiovasc Pharmacol 1999; 33:652–8.10.1097/00005344-199904000-00020Suche in Google Scholar

29. Kielstein JT, Böger RH, Bode-Böger SM, Schäffer J, Barbey M, Koch KM, et al. Asymmetric dimethylarginine plasma concentrations differ in patients with end-stage renal disease: relationship to treatment method and atherosclerotic disease. J Am Soc Nephrol 1999; 10:594–600.10.1681/ASN.V103594Suche in Google Scholar

30. Miyazaki H, Matsuoka H, Cooke JP. Endogenous nitric oxide synthase inhibitor. A novel marker of atherosclerosis. Circulation 1999; 99:1141–6.10.1161/01.CIR.99.9.1141Suche in Google Scholar

31. Zoccali C, Benedetto FA, Maas R, Mallamaci F, Tripepi G, Malatino L, et al. Asymmetric dimethylarginine (ADMA), C-reactive protein, and carotid intima media-thickness in end-stage renal disease. J Am Soc Nephrol 2002; 13:490–6.10.1681/ASN.V132490Suche in Google Scholar

32. Valkonen VP, Päivä H, Salonen JT, Lakka TA, Lehtimaki T, Laakso J, et al. Risk of acute coronary events and serum concentration of asymmetrical dimethylarginine. Lancet 2001; 358:2127–8.10.1016/S0140-6736(01)07184-7Suche in Google Scholar

33. Zoccali C, Bode-Böger SM, Mallamaci F, Benedetto FA, Tripepi G, Malatino L, et al. Asymmetric dimethylarginine (ADMA): an endogenous inhibitor of nitric oxide synthase predicts mortality in end-stage renal disease (ESRD). Lancet 2001; 358:2113–7.10.1016/S0140-6736(01)07217-8Suche in Google Scholar

34. Nijveldt RJ, Teerlink T, van der Hoven B, Siroen MP, Kuik DJ, Rauwerda JA, et al. Asymmetrical dimethylarginine (ADMA) in critically ill patients: high plasma ADMA concentration is an independent risk factor of ICU mortality. Clin Nutr 2003; 22:23–30.10.1054/clnu.2002.0613Suche in Google Scholar

35. Lu TM, Ding YA, Lin SJ, Lee WS, Tai HC. Plasma levels of asymmetrical dimethylarginine and adverse cardiovascular events after percutaneous coronary intervention. Eur Heart J 2003; 24:1912–9.10.1016/j.ehj.2003.08.013Suche in Google Scholar

36. Krempl TK, Maas R, Sydow K, Meinertz T, Böger RH,Kähler J. Elevation of asymmetric dimethylarginine in patients with unstable angina and recurrent cardiovascular events. Eur Heart J 2005;28. In press.10.1093/eurheartj/ehi287Suche in Google Scholar

37. Bae SW, Stühlinger MC, Yoo HS, Yu KH, Park HK, Choi BY, et al. Plasma asymmetric dimethylarginine concentrations in newly diagnosed patients with acute myocardial infarction or unstable angina pectoris during two weeks of medical treatment. Am J Cardiol 2005; 95:729–33.10.1016/j.amjcard.2004.11.023Suche in Google Scholar

38. Kielstein JT, Bode-Böger SM, Hesse G, Martens-Lobenhöffer J, Takacs A, Fliser D, et al. Asymmetrical dimethylarginine in idiopathic pulmonary arterial hypertension. Arterioscler Thromb Vasc Biol 2005; 25:1414–8.10.1161/01.ATV.0000168414.06853.f0Suche in Google Scholar

39. Vallance P, Leiper J. Cardiovascular biology of the asymmetric dimethylarginine:dimethylarginine dimethylaminohydrolase pathway. Arterioscler Thromb Vasc Biol 2004; 24:1023–30.10.1161/01.ATV.0000128897.54893.26Suche in Google Scholar

40. Böger RH, Zoccali C. ADMA: a novel risk factor that explains excess cardiovascular event rate in patients with end-stage renal disease. Atherosclerosis Suppl 2003; 4:23–8.10.1016/S1567-5688(03)00030-8Suche in Google Scholar

41. Kielstein JT, Böger RH, Bode-Böger SM, Martens-Lobenhöffer J, Lonnemann G, Frölich JC, et al. Low dialysance of asymmetric dimethylarginine (ADMA) – in vivo and in vitro evidence of significant protein binding. Clin Nephrol 2004; 62:295–300.10.5414/CNP62295Suche in Google Scholar

42. Schwedhelm E. Quantification of ADMA: analytical approaches. Vasc Med 2005. In press.10.1177/1358836X0501000113Suche in Google Scholar PubMed

43. Albsmeier J, Schwedhelm E, Schulze F, Kastner M, Böger RH. Determination of NG,NG-dimethyl-L-arginine, an endogenous NO synthase inhibitor, by gas chromatography-mass spectrometry. J Chromatogr B 2004; 809:59–65.10.1016/j.jchromb.2004.06.008Suche in Google Scholar PubMed

44. Schwedhelm E, Tan-Andresen J, Maas R, Riederer U, Schulze F, Böger RH. Liquid chromatography-tandem MS method for the analysis of asymmetric dimethylarginine in human plasma. Clin Chem 2005; 51:1268–71.10.1373/clinchem.2004.046037Suche in Google Scholar PubMed

45. Schulze F, Wesemann R, Schwedhelm E, Sydow K, Albsmeier J, Cooke JP, et al. Determination of ADMA using a novel ELISA assay. Clin Chem Lab Med 2004; 42:1377–83.10.1515/CCLM.2004.257Suche in Google Scholar PubMed

46. Böger RH. All about ADMA. www.allaboutadma.com (accessed May 09, 2005).Suche in Google Scholar

47. Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1:307–10.Suche in Google Scholar

48. NHLBI Framingham Heart Study. Estimating coronary heart disease (CHD) risk using Framingham Heart Study prediction score sheets, December 2002. http://www.nhlbi.nih.gov/about/framingham/riskabs.htm (accessed May 04, 2005).Suche in Google Scholar

49. International Task Force for Prevention of Coronary Heart Disease. PROCAM risk calculator, 2004. http://www.chd-taskforce.de/calculator/calculator.htm (accessed May 04, 2005).Suche in Google Scholar

50. European Society of Cardiology. CVD prevention score risk charts, 2004. http://www.escardio.org/initiatives/prevention/SCORE+Risk+Charts.htm (accessed May 04, 2005).Suche in Google Scholar

51. Lee DS, Vasan RS. Novel markers for heart failure diagnosis and prognosis. Curr Opin Cardiol 2005; 20:201–10.10.1097/01.hco.0000161832.04952.6aSuche in Google Scholar PubMed

Published Online: 2011-9-21
Published in Print: 2005-10-1

©2005 by Walter de Gruyter Berlin New York

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