Koroner arter bypass cerrahisinde ramiprilin miyokardiyal hasar ve inflamatuvar yanıttaki etkisi üzerinde sitokin gen polimorfizmlerinin rolü

Yıl 2017, Cilt: 42 Sayı: 3, 436 - 445, 30.09.2017

Meral Urhan Küçük Kerem Karaca Seyhan Şahan Fırat Özden , Vezir Necmiye Canacankatan Barlas Naim Aytaçoğlu Sema Erden Bahar Tunçtan Nehir Sucu

https://doi.org/10.17826/cutf.323386

Öz

Amaç: Ramipril, inflamatuar miyokardial hasarın tedavisinde TNF-α, IL-6 ve IL-8 gibi sitokin seviyelerini azaltarak etkili olmaktadır. Çalışmamızda, ramipril tedavisinin, koroner arter bypass cerrahisi esnasında oluşan inflamatuar yanıt ve miyokardiyal hasara yönelik etkisi üzerinde, sitokin gen polimorfizmlerinin herhangi bir rolü olup olmadığını araştırdık. 

Gereç ve Yöntem: Çalışmamıza, koroner arter bypass cerrahisi uygulanan hastalardan cerrahi öncesi ramipril alan 51, kontrol grubu olarak ise ramipril almayan  51 olmak üzere toplam 102 hasta dahil edildi. Her iki grupta, anestezi başlamadan hemen önce (t1), kros klemp sonrası 20. dakikada (t2), ameliyatın sonunda  (t3) ve anestezinin başlangıcından 24 saat sonra (t4) alınan kan örneklerinden TNFα, IL-6,  IL-8 ve TnT serum düzeyleri ELISA yöntemi ile, genotipleme ise PCR-RFLP yöntemleri ile belirlendi. 

Bulgular: Her iki grupta TNF-α artışı cerrahi ile başlarken, IL-6 ve IL-8 artışı kardiyopulmoner bypass sırasında kardiyak arrestle başlayıp ameliyat sonuna kadar devam etmiştir. Postoperatif dönemde ise sadece IL-8 kontrol grubunda yüksek kalırken; çalışma grubunda TNF-α, IL-6, IL-8 düşüşe geçmektedir. t3 zaman aralığında IL-6, t4 zamanında TNFα değerlerinde anlamlı azalma gözlenmiştir. 

Sonuç: Ramiprilin kardiyak arrest sonrası sitokin ve TnT düzeylerini azaltarak inflamatuar miyokardiyal hasarı önlemede yeri olabilir. 

Anahtar Kelimeler

ACE inhibitörleri, sitokin, polimorfizm

Role of cytokine gene polymorphisms on ramipril-altered inflammatory response and myocardial injury in patients undergoing coronary artery bypass surgery

Öz

Purpose: Ramipril is effective in treating inflammatory myocardial injury by reducing cytokines such as TNF-α, IL-6, and IL-8. In this study, we investigated the effect of cytokine gene polymorphisms on inflammatory response which might be reduced by ramipril.

Material and Methods: Of 102 patients undergoing on-pump coronary artery bypass grafting surgery, 51 were the treatment group which received ramipril and the remaining 51 were the non-treated  control group. TNF-α, IL-6, and IL-8 were measured with Enzyme-Linked Immuno Sorbent Assay (ELISA), before anesthesia induction (t1), at 20 min following cross clamping (t2), at the end of the operation (t3), and 24 hours after anesthesia (t4). Genotyping was performed with PCR method. 

Results: While TNF-α increase began with surgery, IL-6 and IL-8 increase began with cardiac arrest during cardiopulmonary bypass and continued until the end of the operation. In contrast, only IL-8 remained high in the control group during the postoperative period, while TNF-α, IL-6, and IL-8 began to decrease. The decreases in IL-6 at t3 and in TNF-α at t4 were significant. 

Conclusion: Ramipril might have a role in preventing inflammatory myocardial injury by reducing cytokine and TnT levels after cardiac arrest. 

Anahtar Kelimeler

ACE inhibitors; cytokines, polymorphism

Kaynakça

• 1. Larmann J, Theilmeier G. Inflammatory response to cardiac surgery: cardiopulmonary bypass versus non-cardiopulmonary bypass surgery. Best Pract Res Clin Anaesthesiol. 2004;18:425-38.
• 2. Lazar HL. The use of angiotensin-converting enzyme inhibitors in patients undergoing coronary artery bypass graft surgery. Vascul Pharmacol. 2005;42:119-23.
• 3. Ng CS, Wan S. Limiting inflammatory response to cardiopulmonary bypass: pharmaceutical strategies. Curr Opin Pharmacol. 2012;12:155-9.
• 4. Wan S, LeClerc JL, Vincent JL. Cytokine responses to cardiopulmonary bypass: lessons learned from cardiac transplantation. Ann Thorac Surg. 1997;63:269-76.
• 5. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-8.
• 6. Kumar R, Sharma R, Bairwa K, Roy R K, Kumar A, Baruw A. Modern development in ACE inhibitors. Der Pharmacia Letter. 2010;2:388-419.
• 7. Brull DJ, Montgomery HE, Sanders J, Dhamrait S, Luong L, Rumley A et al. Interleukin-6 Gene 2174G>C and 2572G>C promoter polymorphisms are strong predictors of plasma interleukin-6 levels after coronary artery bypass surgery. Arterioscler Thromb Vasc Biol. 2001;21;1458-63.
• 8. Trevelyan J, Brull DJ, Needham EWA, Montgomery HE, Morris A, Mattu RK. Effect of enapril and losartan on cytokines in patients with stable angina pectoris awaiting coronary artery bypass grafting and their interaction with polymorphisms in the Interleukin-6 gene. Am J Cardiol. 2004;94:564-9.
• 9. Urhan Kucuk M, Sucu N, Sahan Firat S, Aytacoglu BN, Vezir O, Bozali C et al. Role of ACE I/D gene polymorphisms on the effect of ramipril in inflammatory response and myocardial injury in patients undergoing coronary artery bypass grafts. Eur J Clin Pharmacol. 2014;70:1443-51.
• 10. Bittar MN, Carey JA, Barnard JB, Pravica V, Deiraniya AK, Yonan N et al. Tumor necrosis factor alpha influences the inflammatory response after coronary surgery. Ann Thorac Surg. 2006;81:132-7.
• 11. Yoon, SZ, Jang IJ, Yoon JC, Kang MH, Lim HJ, Lim YJ et al. Association between tumor necrosis factor -308G/A polymorphism and increased proinflammatory cytokine release after cardiac surgery with cardiopulmonary bypass in the Korean population. J Cardiothorac Vasc Anesthesia. 2009;23:646-50.
• 12. Boehm J, Hauner K, Grammer J, Dietrich W, Wagenpfeil S, Braun S et al. Tumor necrosis factor-a -863 C/A promoter polymorphism affects the inflammatory response after cardiac surgery. Eur J Cardio-thoracic Surg. 2011;40:e50-4.
• 13. Wang Z, Shao J, Zhou Q, Liu J, Zhu Y, Yang J, Wei M. The -251A>T polymorphism of interleukin-8 is associated with longer mechanical ventilation and hospital staying after coronary surgery. Cytokine. 2010;50:268-72.
• 14. Tekeli A, İsbir CS, Ergen A, Bozkurt N, Görmüs U, Bulgurcuoglu S et al. Interleukin-8 polymorphism has no effect on levels of IL-8 following coronary artery bypass grafting. Adv Mol Med. 2007;3:77-83.
• 15. Schröeder S, Börger N, Wrigge H, Welz A, Putensen C, Hoeft A et al. Tumor necrosis factor gene polymorphism influences the inflammatory response after cardiac operation. Ann Thorac Surg. 2003;75:534-7.
• 16. Elahi MM, Gilmour A, Matata BM, Mastana SS. A Variant of position -308 of tumour necrosis factor alpha gene promoter and the risk of coronary heart disease. Heart Lung Circulation. 2008;17:14-8.
• 17. Reyes-Gibby CC, Spitz M, Wu X, Merriman K, Etzel C, Bruera E et al. Cytokine genes and pain severity in lung cancer: exploring the influence of TNF-a-308 G/A IL6-174G/C and IL8-251T/A. Cancer Epidemiol Biomarkers Prev. 2007;16:2745-51.
• 18. Burlina A, Zaninotto M, Secchiero S, Rubin D, Accorsi F. Troponin T as a marker of ischemic myocardial injury. Clin Biochem. 1994;27:113-21.
• 19. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215.
• 20. Ates I, Suzen HS, Yucesoy B, Tekin IO, Karakaya A. Association of cytokine gene polymorphisms in CWP and its severity in Turkish coal workers. Am J Ind Med. 2008;51:741-7.
• 21. Karahan ZC, Deda G, Sipahi T, Elhan A H, Akar N. TNF-A -308 G/A and IL-6 -174 G/C polymorphisms in the Turkish pediatric stroke patients Thromb Res. 2005;115:393-8.
• 22. Heinzmann A, Ahlert I, Kurz T, Berner, Deichmann KA. Association study suggests opposite effects of polymorphisms within IL8 on bronchial asthma and respiratory syncytial virus bronchiolitis. J Allergy Clin Immunol. 2004;114:671-6.
• 23. Neto AC, Rasmussen LT, Labio RW, Queiroz VF , Smith MAC, Viani GA et al. Gene polymorphism of interleukin 1 and 8 in chronic gastritis patients infected with Helicobacter pylori. J Venom Anim Toxins Incl Trop Dis. 2014;20:17.
• 24. Qing M, Vazquez-Jimenez JF, Klosterhalfen B, Sigler M, Schumacher K, Duchateau J et al. Influence of temperature during cardiopulmonary bypass on leukocyte activation, cytokine balance and postoperative organ damage. Shock. 2001;15:372-7.
• 25. Halter J, Steinberg J, Fink G, Lutz C, Picone A, Maybury R et al. Evidence of systemic cytokine release in patients undergoing cardiopulmonary bypass. J Extra Corpor Technol. 2005;37:272-7.
• 26. Hennein HA, Ebba H, Rodriguez JL, Merrick SH, Keith FM, Bronstein MH et al. Relationship of the proinflammatory cytokines to myocardial ischemia and dysfunction after uncomplicated coronary revascularization. J Thoracic Cardiovasc Surg. 1994;108:626-35.
• 27. Dzau VJ. Tissue renin-angiotensin system in myocardial hypertrophy. Arch Intern Med. 1993;153:937-42.
• 28. Steinberg JB, Kapelanski DP, Olson JD, Weiler JM. Cytokine and complement levels in patients undergoing cardiopulmonary bypass. J Thoracic Cardiovasc Surg. 1993;106:1008-16.
• 29. Wan S, DeSmet JM, Barvais L, Goldstein M, Vincent JL LeClerc JL. Myocardium is a major source of proinflammatory cytokines in patients undergoing cardiopulmonary bypass. J Thorac Cardiovasc Surg. 1996;112:806-11.
• 30. Meldrum DR. Tumor necrosis factor in the heart. Am J Physiol. 1998;274:577-95.
• 31. Torre-Amione G, Kapadia S, Benedict C, Oral H, Young JB, Mann DL. Proinflammatory cytokine levels in patients with depressed left ventricular ejection fraction: a report from the Studies of Left Ventricular Dysfunction (SOLVD). J Am Coll Cardiol. 1996;27:1201-6.
• 32. Lindmark E, Diderholm E, Wallentin L, Siegbahn A. Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease effects of an early invasive or noninvasive strategy. JAMA 2001;286:2107-13.
• 33. Kukielka GL, Smith CW, LaRosa GJ, Manning AM, Mendoza LH, Daly TJ et al. Interleukin-8 gene induction in the myocardium after ischemia and reperfusion in vivo. J Clin Invest. 1995;95:89-103.
• 34. Ivey CL, Williams FM, Collins PD, Jose PJ, Williams TJ. Neutrophil chemoattractants generated in two phases during reperfusion of ischemic myocardium in the rabbit: evidence for a role for C5a and interleukin-8. J Clin Invest. 1995;95:2720-8.
• 35. Atta-ur-Rahman, Harvey K, Siddiqui RA. Interleukin-8: an autocrine inflammatory mediator. Curr Pharm Des 1999;5:241-53.
• 36. Sharma HS, Das DK. Role of cytokines in myocardial ischemia and reperfusion. Mediators Inflamm. 1997;6:175-83.
• 37. The Studies on Left Ventricular Dysfunction (SOLVD) Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302.
• 38. ACE Inhibitor Myocardial Infarction Collaborative Group. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. Circulation. 1998;97:2202-12.
• 39. Galinanes M, James M, Codd V, Baxi A, Hadjinikolaou L. TNF-alpha gene promoter polymorphism at nucleotide -308 and the inflammatory response and oxidative stress induced by cardiac surgery: Role of heart failure and medical treatment. Eur J Cardiothorac Surg. 2008;34:332-7.
• 40. Westerberg M, Bengtsson A, Ricksten A, Jeppsson A. Tumor necrosis factor gene polymorphisms and inflammatory response in coronary artery bypass grafting patients. Scand Cardiovasc J. 2004;38:312-7.
• 41. Burzotta F, Iacoviello L, Di Castelnuovo A, Glieca F, Luciani N, Zamparelli R et al. Relation of the -174 G/C polymorphism of interleukin-6 to interleukin-6 plasma levels and to length of hospitalization after surgical coronary revascularization. Am J Cardiol. 2001;88:1125-8.
• 42. Gaudino M, Andreotti F, Zamparelli R, Di Castelnuovo A, Nasso G, Burzotta F et al. The -174G/C interleukin-6 polymorphism influences postoperative interleukin-6 levels and postoperative atrial fibrillation. Is atrial fibrillation an inflammatory complication? Circulation. 2003;108:II-195–9.