İbrahim KEMBER, Gözde GİRGİN, Terken BAYDAR

Neopterin Düzeylerinin ve Kinürenin Yolağının Akut Koroner Sendrom Hastalarında Değerlendirilmesi

Neopterin Düzeylerinin ve Kinürenin Yolağının Akut Koroner Sendrom Hastalarında Değerlendirilmesi Koroner arter hastalığının en önemli nedeni koroner aterosklerozdur. Aterosklerotik plağın yırtılması ile oluşan intrakoroner trombüs ise akut koroner sendomun temel nedenidir. Yırtılmaya hassas plakların daha fazla sayıda maktofaj ve T lenfosit içerdiği çeşitli çalışmalarda gösterilmiştir. Neopterin hücresel immün yanıtın önemli bir biyogöstergesidir. İnflamasyon, çeşitli enfeksiyonlar ve maligniteler de dahil olmak üzere çok çeşitli patolojilerde erken tanı ve prognoz için önemli bir biyomarkör olarak kabul edilir. Hücresel immün aktivasyonda neopterin salınımına ilave olarak triptofan yıkımında hız kısıtlayıcı basamağı katalizleyen indolamin 2,3-dioksijenaz (İDO) enzimi de aynı anda indüklenir. Kinürenin (Kyn) in triptofan (Trp) ’a oranlanmasıyla ifade edilebilien İDO aktivitesinin, immün değişkenlerle desteklenerek hücresel immünitenin düzenlenmesinde önemli bir gösterge olarak kullanılabileceği rapor edilmiştir. Bu derleme makalesinde, anjiyografik olarak ateroskleroz zemininde gelişen akut koroner sendrom (AKS) hastalarında, neopterin, C reaktif protein (CRP), İDO gibi biyokimyasal göstergelerin koroner arter hastalığı (KAH) tanısı, mortalite ve morbidite süreçlerindeki olası değişimlerin değerlendirilmesi hedeflenmiştir. Akut koroner sendrom hastalarında, neopterin düzeyleri ile kinürenin yolağı parametlerinin belirlenmesi ve biyomarkör olarak kullanılmaları anlamlı ve değerlidir.

Anahtar Kelimeler:

Neopterin, İDO, triptofan, kinürenin, koroner arter hastalığı

Evaluation of Neopterin Levels and Kynurenine Pathway in Acute Coronary Syndrome Patients

The leading cause of coronary artery disease is coronary atherosclerosis. Intracoronary thrombus caused by rupture of atherosclerotic plaque is the main cause of acute coronary syndrome. It has been shown in various studies that tear-sensitive plaques contain more macrophages and T lymphocytes. Neopterin is an important biomarker of cellular immune response. It is considered an important biomarker of early diagnosis and prognosis in a wide variety of pathologies, including inflammation, infections and malignancies. In addition to the release of neopterin in cellular immune activation, indolamine 2,3-dioxygenase (IDO), which catalyzes the rate limiting step in tryptophan degradation, is also induced. It has been reported that the IDO activity, shown by kynurenine (Kyn) to tryptophan (Trp) ratio, can be used as an important indicator in the regulation of cellular immunity, supported by immune variables. In this review, it is aimed to evaluate the possible changes in the diagnosis of coronary artery disease (CAD), mortality and morbidity determination of biochemical indicators such as neopterin, C-reactive protein (CRP), IDO in patients with acute coronary syndrome that develop angiographically on the basis of atherosclerosis. Determination and use of neopterin levels and kynurenine pathway parameters as biomarkers in acute coronary syndrome patients are meaningful and valuable.

Keywords:

Neopterin, IDO, kynurenin, coronary artery disease, tryptophan,

PDF

___

1. Sulo G, Vollset SE, Nygard O, Midttun O, Ueland PM, Eussen SJPM, et al. Neopterin and kynurenine-tryptophan ratio as predictors of coronary events in older adults, the Hordaland Health Study. International Journal of Cardiology. 2013, 168:1435-1440. DOI: 10.1016/j.ijcard.2012.12.090
2. Sugioka K, Naruko T, Matsumura Y, Shirai N, Hozumi T, Yoshiyama M, et al. Neopterin and atherosclerotic plaque instability in coronary and carotid arteries. Journal of Atherosclerosis and Thrombosis. 2010, 17(11):1115-1121. DOI: 10.5551/ jat.4606
3. Polyzos KA, Ketelhuth DF. The role of the kynurenine pathway of tryptophan metabolism in cardiovascular disease. An emerging field. Hamostaseologie. 2015, 35:128–136. DOI: 10.5482/HAMO-14-10-0052
4. Hoffmann G, Wirleitner B, Fuchs D. Potential role of immune system activation associated production of neopterin derivatives in humans. Inflammation Research. 2003, 52:313-321. DOI: 10.1007/s00011-003-1181-9
5. Eisenhut M. Neopterin in diagnosis and monitoring of infectious diseases. Journal of Biomarkers. 2013, 2013:196432. DOI: 10.1155/2013/196432
6. Soliman H, Mediavilla-Varela M, Indoleamine 2,3-dioxygenase: is it an immune suppressor? Cancer Journal. 2010, 16:354- 359. DOI: 10.1097/PPO.0b013e3181eb3343
7. Schrocksnadel K, Wirleitner B, Winkler C, Fuchs D. Monitoring tryptophan metabolism in chronic immune activation. Clinica Chimica Acta. 2006, 364:82-90. DOI: 10.1016/j. cca.2005.06.013
8. King NJ, Thomas SR. Molecules in focus: Indoleamine 2,3-dioxygenase. The International Journal Biochemistry and Cell Biolology. 2007, 39:2167–2172. DOI: 10.1016/j.biocel. 2007.01.004
9. Curti A, Trabanelli S, Salvestrini V, Baccarani M, Lemoli RM. The role of indoleamine 2,3-dioxygenase in the induction of immune tolerance: focus on hematology. Blood. 2009, 113:2394-2401. DOI: 10.1182/blood-2008-07-144485
10. Fox KAA, Goodman SG, Klein W, Brieger D, Steg PG, Dabbous O, et al. Management of acute coronary syndromes. Variations in practice and outcome; findings from the Global Registry of Acute Coronary Events (GRACE). European Heart Journal. 2002, 23:1177-1189 DOI: 10.1053/euhj.2001.3081
11. Thygesen K, Alpert JS, Jaffe AS, Simoons ML, Chaitman BR, White HD. Third universal definition of myocardial infarction. Global Heart. 2012, 7(4):275-95. 126:2020-2035. DOI: 10.1016/j.gheart.2012.08.001
12. WHO reveals leading causes of death and disability worldwide: 2000-2019. Erişim Adresi: https://www.who.int/news/ item/09-12-2020-who-reveals-leading-causes-of-death-anddisability- worldwide-2000-2019, Erişim Tarihi: 30.11.2023.
13. Mozaffarian D. Benjamin E. J, Go AS, Arnett DK, Blaha MJ, Cushman M, et al. Heart disease and stroke statistics- 2015 update: a report from the American Heart Association. Circulation. 2015, 131(4):e29-322. DOI: 10.1161/ CIR.0000000000000152
14. Onat A (Editör). TEKHARF 2015 Yetişkinlerimizin Sağlığı ve Kronik Hastalıklara Tıbbın Yaklaşımına Öncülük. Logos Yayıncılık; İstanbul, 2015.
15. Libby P. Current concepts of the pathogenesis of the acute coronary syndromes. Circulation. 2001, 104(3):365-372. DOI: 10.1161/01.cir.104.3.365
16. Libby P. Inflammatory mechanisms : the moleculer basis of inflammation and disease. Nutrition Reviews. 2007, 65(12 Pt2):140-146. DOI: 10.1111/j.1753-4887.2007.tb00352.x
17. Dehnavi RA, de Ross A, Rabelink TJ, van Pelt J, Wensink MJ, Romijn JA, et al. Elevated CRP levels are associated with increased carotid atherosclerosis idependent of visceral obesity. Atherosclerosis. 2008, 200(2):417-423. DOI: 10.1016/j. atherosclerosis.2007.12.050
18. Rizzo M, Corrado E, Coppola G, Muratori I, Novo G, Novo S. Markers of inflammation are strong predictors of subclinical and clinical atherosclerosis in women with hypertension. Coronary Artery Disease. 2009, 20(1):15-20. DOI: 10.1097/ MCA.0b013e3283109065
19. Ross R. The pathogenesis of atherosclerosis an update. The New England Journal of Medicine. 1986, 314(8):488-500. DOI: 10.1056/NEJM198602203140806
20. Moreno PR, Falk E, Palacios IF, Newell JB, Fuster V, Fallon JT. Macrophage infiltration in acute coronary syndromes. Implications for plaque rupture. Circulation. 1994, 90(2):775- 778. DOI: 10.1161/01.cir.90.2.775
21. Celermajer DS. Endothelial dysfunction: Does it matter? Is it reversible? Journal of the American Collage of Cardiology. 1997, 30(2):325-333. DOI: 10.1016/s0735-1097(97)00189-7
22. Hillis GS, Flapan AD. Cell adhesion molecules in cardiovascular disease: a clinical perspective. Heart. 1998, 79:429-431. DOI: 10.1136/hrt.79.5.429
23. Libby P. Molecular bases of the acute coronary syndromes. Circulation. 1995, 91:2844-2850. DOI: 10.1161/01.cir.91.11.2844
24. Kültürsay H. Koroner kalp hastalığında yüksek risk kavramı. The Anatolian Journal of Cardiology. 2002, 2(1): 61-64. https://jag.journalagent.com/anatoljcardiol/pdfs/AnatolJCardiol_ 2_1_61_64.pdf
25. Okamatsu K, Takano M, Sakai S. Ishibashi F, Uemura R, Takano T, et al. Elevated troponin T levels and lesion characteristics in non-ST-elevation acute coronary syndromes. Circulation. 2004, 109 (4): 465-470. DOI: 10.1161/01. CIR.0000109696.92474.92
26. Macrae AR, Kavsak PA, Lustig V, Bhargava R, Vandersluis R, Palomaki GE, et al. Assessing the requirement for the 6-hour interval between specimens in the American Heart Association classification of myocardial infarction in epidemiology and clinical research studies. Clinical Chemistry. 2006, 52(5):812- 818. DOI: 10.1373/clinchem.2005.059550
27. Weber M, Bazzino O, Navarro Estrada JL, de Miguel R, Salzberg S, Fuselli JJ, et al. Improved diagnostic and prognostic performance of a new high-sensitive troponin T assay in patients acute coronary syndrome. American Heart Journal. 2011, 162(1):81-88. DOI: 10.1016/j.ahj.2011.04.007
28. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. European Heart Journal. 2007, 28:2525-2538. DOI: 10.1093/eurheartj/ehm355
29. Murr C, Widner B, Wirleitner B, Fuchs D. Neopterin as a marker for immune system activation. Current Drug Metabolism. 2002, 3(2):175-187.
30. Fuchs D, Weiss G, Reibnegger G, Wachter H. The role of neopterin as amonitor of cellular immune activation in transplantation, inflammatory, infectious and malignant disease. Critical Reviews in Clinical Laboratory Sciences. 1992, 29(3- 4):307-341. DOI: 10.3109/10408369209114604
31. Schumacher M, Halwachs G, Tatzber F, Fruhwald FM, Zweiker R, Watzinger N, et al. Increased neopterin in patients with chronic and akut coronary sendromes, Journal of the American Collage of Cardiology. 1997, 30(3):703-707. DOI: 10.1016/s0735-1097(97)00172-1
32. Pacileo M, Cirillo P, De Rosa S, Ucci G, Petrillo G, D’Amore SM, et al. The role of neopterin in cardiyovascular disease. Monaldi Archives for Chest Disease. 2007, 68(2):68-73. DOI: 10.4081/monaldi.2007.454
33. Berdowska A, Zwirska-Korczala K. Neopterin measurement in clinical diagnosis. Journal of Clinical Pharmacy and Therapeutics. 2001, 26(5):319-329. DOI: 10.1046/j.1365- 2710.2001.00358.x
34. Fuchs D, Hausen A, Reibnegger G. Neopterins in clinical medicine. Lancet 1988; 1:509-511. DOI: 10.1016/s0140- 6736(88)91495-x
35. Duch DS, Bowers SW, Woolf JH, Nichol CA. Biopterin cofactor biosynthesis: GTP cyclohydrolase, neopterin and biopterin in tissues and body fluids of mammalian species. Life Sciences. 1984, 35:1895-1901. DOI: 10.1016/0024-3205(84)90541-1
36. Deliveli S. İnsan Kolostrum Sütünde Neopterin ve Kinürenin Düzeylerinin Araştırılması [Bilim Uzmanlığı]. Ankara: Hacettepe Üniversitesi; 2021 [28.02.2023]. http://www.openaccess. hacettepe.edu.tr:8080/xmlui/handle/11655/25878
37. Özmeriç N, Baydar T, Bodur A, Engin AB, Uraz A, Eren K, et al. Level of neopterin, a marker of immune cell activation in gingival crevicular fluid, saliva, and urine in patients with aggressive periodontitis. Journal of Periodontology. 2002, 73(7):720-725. DOI: 10.1902/jop.2002.73.7.720
38. Baydar T, Kemer Evren Ö, Çakmak A, Kılıçarslan B, Girgin G. Detection of neopterin in tear samples. Pteridines. 2016, 27(1- 2):13-16. DOI: 10.1515/pterid-2015-0020
39. Arat AZ, Şahin G. Neopterinin klinik önemi. Türkiye Klinikleri Tıp Bilimleri Dergisi. 1993, 13(3): 224-30. https://www.turkiyeklinikleri. com/article/tr-neopterin-ve-klinik-onemi-6457. html
40. Richard, DM., Dawes, MA., Mathias, CW., Acheson, A Hill- Kapturczak, N Dougherty, DM. L-Tryptophan: Basic metabolic functions, behavioral research and therapeutic indications. International Journal of Tryptophan Research. 2009, 2:45-60. DOI: 10.4137/ijtr.s2129
41. Chen Y, Gıillemin GJ. Kynurenine pathway in humans: disease and health states. International Journal of Tryptophan Research. 2009, 2:1-19. DOI: 10.4137/ijtr.s2097
42. Mellor AL, Munn DH. Tryptophan catabolism and T-cell tolerance: immunosuppression by starvation? Immunology Today. 1999, 20:469-473. DOI: 10.1016/s0167-5699(99)01520-0
43. Della Chiesa M, Carlomagno S, Frumento G, Balsamo M, Cantoni C, Conte R, et al. The tryptophan catabolite L-kynurenine inhibits the surface expression of NKp46- and NKG2D-activating receptors and regulates NK-cell function. Blood. 2006, 108(13):4118-4125. DOI: 10.1182/blood- 2006-03-006700
44. Kema IP, Vries EGE, Mıskiet FAJ. Clinical chemistry of serotoin and metabolites. Journal of Chromatography. 2000, 747:33-48. DOI: 10.1016/s0378-4347(00)00341-8
45. Yuasa HJ, Takubo M, Takahashi A, Hasegawa T, Noma H, Suzuki T. Evolution of vertebrate indoleamine 2,3-dioxygenases. Journal of Molecular Evolution. 2007, 65:705-714. DOI: 10.1007/s00239-007-9049-1
46. Ball HJ, Sanchez-Perez A, Weiser S, Austin CJD, Astelbauer F, Miu J, et al. Characterization of an indoleamine 2,3-dioxygenase- like protein found in humans and mice. Gene. 2007, 396(1):203-213. DOI: 10.1016/j.gene.2007.04.010
47. Daubener W, MacKenzie CR. IFN-gamma activated indoleamine 2,3-dioxygenase activity in human cells is an antiparasitic and an antibacterial effector mechanism. Advances in Experimental Medicine and Biology. 1999, 467:517–524. DOI: 10.1007/978-1-4615-4709-9_64
48. Munn DH, Sharma MD, Baban B, Harding HP, Zhang Y, Ron D, et al. GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase. Immunity. 2005, 22(5):633– 642. DOI: 10.1016/j.immuni. 2005.03.013
49. Frostegård, Johan. Immunity, atherosclerosis and cardiovascular disease. BMC Medicine. 2013, 11:117. DOI: 10.1186/1741- 7015-11-117
50. Wirleitner B, Rudzite V, Neurauter G, Murr C, Kalnins U, Erglis A, et al. Immune activation and degradation of tryptophan in coronary heart disease. European Journal of Clinical Investigation. 2003, 33:550-554. DOI: 10.1046/j.1365- 2362.2003.01186.x
51. Avanzas P, Kaski JC. Neopterin for risk assessment in angina pectoris. Drug News and Perspectives. 2009, 22(4):215-219. DOI: 10.1358/dnp.2009.22.4.1367710
52. Mangge H, Becker K, Fuchs D, Gostner JM. Antioxidants, inflammation and cardiovascular disease. World Journal of Cardiology. 2014, 6(6):462-477. DOI: 10.4330/wjc.v6.i6.462
53. Gurumurthy P, Borra SK, Yeruva RKR, Babu S, Thomas J, Cherian KM. Estimation of serum neopterin in patients with acute coronary syndrome. Asian Cardiovascular and Thoracic Annals. 2013, 21(4):426-431. DOI: 10.1177/0218492312458511
54. Kember I, Sanajou S, Kilicarslan B, Girgin G, Baydar T. Evaluation of neopterin levels and kynurenine pathway in patients with acute coronary syndrome. Acute Critical Care. 2023, 38(3):325-332. DOI: 10.4266/acc.2023.00024.
55. Geisler S, Mayersbach P, Becker K, Schennach H, Fuchs D, Gostner JM. Serum tryptophan, kynurenine, phenylalanine, tyrosine and neopterin concentrations in 100 healthy blood donors. Pteridines. 2015, 26(1):31-36. DOI: 10.1515/pterid- 2014-0015
56. Firoz CK, Jabir NR, Kamal MA, Alama MN, Damanhouri GA, Khan W, et al. Neopterin: An immune biomarker of coronary artery disease and its association with other CAD markers. IUBMB Life. 2015, 67(6):453-459. DOI: 10.1002/iub.1390
57. Zuo H, Ueland PM, Ulvik A, Eussen SJPM, Vollset SE, Nygard O, et al. Plasma biomarkers of inflammation, the kynurenine pathway, and risks of all-cause, cancer, and cardiovascular disease mortality: The Hordaland Health Study. American Journal of Epidemiology. 2016, 183(4):249-258. DOI: 10.1093/ aje/kwv242
58. Pedersen ER, Svingen GFT, Schartum-Hansen H, Ueland PM, Ebbing M, Nordrehaug JE, et al. Urinary excretion of kynurenine and tryptophan, cardiovascular events, and mortality after elective coronary angiography. European Heart Journal. 2013, 34(34):2689-2696. DOI: 10.1093/eurheartj/eht264
59. Nazer B, Ray KK, Sloan S, Scirica B, Morrow DA, Cannon CP, et al. Prognostic utility of neopterin and risk of heart failure hospitalization after an acute coronary syndrome. European Heart Journal. 2011, 32(11):1390-1397. DOI: 10.1093/eurheartj/ ehr032
60. Ozkan Y, Sukuroglu MK, Tulmac M, Kisa U, Simsek B. Relation of kynurenine/tryptophan with immune and inflammatory markers in coronary artery disease. Clinical Laboratory. 2014, 60(3):391-396. DOI: 10.7754/clin.lab.2013.121204
61. Murr C, Grammer TB, Kleber ME, Meinitzer A, Marz W, Fuchs D. Low serum tryptophan predicts higher mortality in cardiovascular disease. European Journal of Clinical Investigation. 2015, 45(3):247–254. DOI: 10.1111/eci.12402
62. Shirai R, Sato K, Yamashita T, Yamaguchi M, Okano T, Watanabe-Kominato K, et al. Neopterin counters vascular inflammation and atherosclerosis. Journal of the American Heart Association. 2018, 7(3):e007359. DOI: 10.1161/ JAHA.117.007359
63. Baydar T, Palabıyık S, Şahin G. Neopterin: Günümüzün popüler biyogöstergesi mi? Türkiye Klinikleri Tıp Bilimleri Dergisi. 2009, 29(5): 1280-1291. https://www.turkiyeklinikleri. com/article/tr-neopterin-gunumuzun-populer-biyogostergesimi- 56025.html