The value of peripheral blood eosinophil count in predicting in-stent restenosis in patients with stable angina pectoris undergoing drug eluting stenting

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Introduction. In-stent restenosis (ISR) remains a major limitation of percutaneous coronary intervention (PCI). A role for peripheral blood cells as major regulators of immune and inflammatory systems has been proposed. We aim to evaluate the relationship between eosinophil count and development of restenosis after drug-eluting stent (DES) implantation.

Methods. In this prospective study, all consecutive patients undergoing elective DES implantation for chronic stable angina (CSA) in a university-affiliated heart center within a 6-month period were enrolled and followed for another 6 months. Complete blood count with differentiation was performed 6 weeks after the index procedure. During the follow-up period, the cohort of patients who developed ISR was compared to the cohort of patients without ISR, descriptively and the total number of eosinophilic white cells was used to predict the occurrence of ISR.

Results. 153 men and 48 women with CSA underwent PCI with DES implantation, from which, 26 patients needed repeat coronary angiography for recurrent symptoms. There was an established ISR in 17 (8.5%) patients. The total number of eosinophils in their peripheral blood was 267 ± 132 cells/μL in patients with ISR, significantly higher than the number of eosinophils in those without ISR 174 ± 133 cells/μL (P-value < 0.010). Eosinophil count remained an independent predictor of ISR in multivariate analysis as the eosinophil count value over 242 cells/μL had sensitivity of 66.7% and specificity of 84.5% for the presence of ISR.

Conclusion. The total number of eosinophils, counted 6 weeks after DES implantation, prevails as the sole predictor of ISR occurrence in our study. This suggests an association between immune sensitivity reaction to DES material and development of ISR in patients after PCI.

1. KOLH P, WINDECKER S, ALFONSO F, COLLET J-P, CREMER J, FALK V et al. 2014 ESC/EACTS guidelines on myocardial revascularization. The task force on myocardial revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS) developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). European journal of cardio-thoracic surgery 2014, 46 (4):517-592.

2. MACK MJ, BROWN PP, KUGELMASS AD, BATTAGLIA SL, TARKINGTON LG, SIMON AW et al. Current status and outcomes of coronary revascularization 1999 to 2002: 148,396 surgical and percutaneous procedures. The Annals of thoracic surgery 2004, 77 (3):761-766; discussion 766-768.

3. MINTZ GS, HOFFMANN R, MEHRAN R, PICHARD AD, KENT KM, SATLER LF et al. In-stent restenosis: the Washington Hospital Center experience. The American journal of cardiology 1998, 81 (7a):7e-13e.

4. MORRIS RE. Mechanisms of action of new immunosuppressive drugs. Therapeutic drug monitoring 1995, 17 (6):564-569.

5. MARX SO, MARKS AR. Bench to bedside: the development of rapamycin and its application to stent restenosis. Circulation 2001, 104 (8):852-855.

6. STONE GW, ELLIS SG, CANNON L, MANN JT, GREENBERG JD, SPRIGGS D et al. Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial. JAMA 2005, 294 (10):1215-1223.

7. KASTRATI A, MEHILLI J, VON BECKERATH N, DIBRA A, HAUSLEITER J, PACHE J et al. Sirolimus-eluting stent or paclitaxel-eluting stent vs balloon angioplasty for prevention of recurrences in patients with coronary in-stent restenosis: a randomized controlled trial. JAMA 2005, 293 (2):165-171.

8. COSTA MA, SIMON DI. Molecular basis of restenosis and drug-eluting stents. Circulation 2005, 111 (17):2257-2273.

9. KORNOWSKI R, HONG MK, TIO FO, BRAMWELL O, WU H, LEON MB. In-stent restenosis: contributions of inflammatory responses and arterial injury to neointimal hyperplasia. J Am Coll Cardiol 1998, 31 (1):224-230.

10. HOFFMANN R, MINTZ GS, DUSSAILLANT GR, POPMA JJ, PICHARD AD, SATLER LF et al. Patterns and mechanisms of in-stent restenosis. A serial intravascular ultrasound study. Circulation 1996, 94 (6):1247-1254.

11. SERRUYS PW, KAY IP, DISCO C, DESHPANDE NV, DE FEYTER PJ. Periprocedural quantitative coronary angiography after Palmaz-Schatz stent implantation predicts the restenosis rate at six months: results of a meta-analysis of the BElgian NEtherlands Stent study (BENESTENT) I, BENESTENT II Pilot, BENESTENT II and MUSIC trials. Multicenter Ultrasound Stent In Coronaries. J Am Coll Cardiol 1999, 34 (4):1067-1074.

12. WELT FG, EDELMAN ER, SIMON DI, ROGERS C. Neutrophil, not macrophage, infiltration precedes neointimal thickening in balloon-injured arteries. Arteriosclerosis, thrombosis, and vascular biology 2000, 20 (12):2553-2558.

13. HORVATH C, WELT FG, NEDELMAN M, RAO P, ROGERS C. Targeting CCR2 or CD18 inhibits experimental in-stent restenosis in primates: inhibitory potential depends on type of injury and leukocytes targeted. Circulation research 2002, 90 (4):488-494.

14. KAWAMOTO R, YAMASHITA A, NISHIHIRA K, FURUKOJI E, HATAKEYAMA K, ISHIKAWA T et al. Different inflammatory response and oxidative stress in neointimal hyperplasia after balloon angioplasty and stent implantation in cholesterol-fed rabbits. Pathology, research and practice 2006, 202 (6):447-456.

15. VIRMANI R, GUAGLIUMI G, FARB A, MUSUMECI G, GRIECO N, MOTTA T et al. Localized hypersensitivity and late coronary thrombosis secondary to a sirolimus-eluting stent: should we be cautious? Circulation 2004, 109 (6):701-705.

16. NEBEKER JR, VIRMANI R, BENNETT CL, HOFFMAN JM, SAMORE MH, ALVAREZ J et al. Hypersensitivity cases associated with drug-eluting coronary stents: a review of available cases from the Research on Adverse Drug Events and Reports (RADAR) project. J Am Coll Cardiol 2006, 47 (1):175-181.

17. GABBASOV ZA, KOZLOV SG, LYAKISHEV AA, SABUROVA OS, SMIRNOV VA, SMIRNOV VN. Polymorphonuclear blood leukocytes and restenosis after intracoronary implantation of drug-eluting stents. Canadian journal of physiology and pharmacology 2009, 87 (2):130-136.

18. MELO RC, SPENCER LA, DVORAK AM, WELLER PF. Mechanisms of eosinophil secretion: large vesiculotubular carriers mediate transport and release of granule-derived cytokines and other proteins. Journal of leukocyte biology 2008, 83 (2):229-236.

19. VENGE P, BYSTROM J, CARLSON M, HAKANSSON L, KARAWACJZYK M, PETERSON C et al. Eosinophil cationic protein (ECP): molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease. Clinical and experimental allergy: Journal of the British Society for Allergy and Clinical Immunology 1999, 29 (9):1172-1186.

20. MEMON S, CHHABRA L, MASRUR S, PARKER MW. Allergic acute coronary syndrome (Kounis syndrome). Proceedings (Baylor University Medical Center) 2015, 28 (3):358-362.

21. KOUNIS NG. Kounis syndrome (allergic angina and allergic myocardial infarction): a natural paradigm? Int J Cardiol 2006, 110 (1):7-14.

22. CRANS YOON AM, CHIU V, RANA JS, SHEIKH J. Association of allergic rhinitis, coronary heart disease, cerebrovascular disease, and all-cause mortality. Annals of allergy, asthma & immunology: official publication of the American College of Allergy, Asthma, & Immunology 2016, 117 (4):359-364. e351.

23. KOSTER R, VIELUF D, KIEHN M, SOMMERAUER M, KAHLER J, BALDUS S et al. Nickel and molybdenum contact allergies in patients with coronary in-stent restenosis. Lancet 2000, 356 (9245):1895-1897.

24. EL-MAWARDY R, FUAD H, ABDEL-SALAM Z, GHAZY M, NAMMAS W. Does nickel allergy play a role in the development of in-stent restenosis? European review for medical and pharmacological sciences 2011, 15 (11):1235-1240.

25. HILLEN U, HAUDE M, ERBEL R, GOOS M. Evaluation of metal allergies in patients with coronary stents. Contact dermatitis 2002, 47 (6):353-356.

26. NORGAZ T, HOBIKOGLU G, SERDAR ZA, AKSU H, ALPER AT, OZER O et al. Is there a link between nickel allergy and coronary stent restenosis? The Tohoku journal of experimental medicine 2005, 206 (3):243-246.

27. OTSUKA Y, NAKAMURA M, KOKUBU N, TONOOKA A, INOUE K, HIGAMI T. Diffuse in-stent restenosis of CYPHER(R) stent due to hypersensitivity reaction confirmed by pathohistological findings. Heart and vessels 2012, 27 (1):110-113.

28. YAGI H, AMIYA E, ANDO J, WATANABE M, YANABA K, IKEMURA M et al. In-Stent Restenosis Exacerbated by Drug-Induced Severe Eosinophilia after Second-Generation Drug-Eluting Stent Implantation. The American Journal of Case Reports 2014, 15:397-400.

29. GREWE PH, DENEKE T, MACHRAOUI A, BARMEYER J, MULLER KM. Acute and chronic tissue response to coronary stent implantation: pathologic findings in human specimen. J Am Coll Cardiol 2000, 35 (1):157-163.

30. RITTERSMA SZ, MEUWISSEN M, VAN DER LOOS CM, KOCH KT, DE WINTER RJ, PIEK JJ et al. Eosinophilic infiltration in restenotic tissue following coronary stent implantation. Atherosclerosis 2006, 184 (1):157-162.

31. TAKASHIMA A, SHIMABUKURO M, TABATA M, FUKUDA D, UEMATSU E, ISHIBASHI-UEDA H et al. Histopathological heterogeneity of in-stent restenosis in four coronary endarterectomy specimens. Cardiovascular pathology: the official journal of the Society for Cardiovascular Pathology 2015, 24 (3):194-197.

32. GABBASOV ZA, KOZLOV SG, SABUROVA OS, TITIOV VN, LIAKISHEV AA. [Stromal progenitor cells and blood leukocytes after implantation of drug-eluting stents]. Kardiologiia 2010, 50 (1):36-41.

33. GABBASOV ZA, KOZLOV SG, IMAEVA AE, SABUROVA OS, ZYKOV KA, MASENKO VP et al. In-stent restenosis after revascularization of myocardium with drug-eluting stents is accompanied by elevated level of blood plasma eosinophil cationic protein. Canadian journal of physiology and pharmacology 2011, 89 (6):413-418.

34. MEHILLI J, KASTRATI A, BOLLWEIN H, DIBRA A, SCHUHLEN H, DIRSCHINGER J et al. Gender and restenosis after coronary artery stenting. Eur Heart J 2003, 24 (16):1523-1530.

35. CHEN SJ, LI H, DURAND J, OPARIL S, CHEN YF. Estrogen reduces myointimal proliferation after balloon injury of rat carotid artery. Circulation 1996, 93 (3):577-584.

36. GRUNERT G, PORCIA M, TCHERNITCHIN AN. Differential potency of oestradiol-17 beta and diethylstilboestrol on separate groups of responses in the rat uterus. The Journal of Endocrinology 1986, 110 (1):103-114.

37. SCHWINGSHACKL A, DUSZYK M, BROWN N, MOQBEL R. Human eosinophils release matrix metalloproteinase-9 on stimulation with TNF-alpha. The Journal of allergy and clinical immunology 1999, 104 (5):983-989.

38. KATSAROS KM, KASTL SP, ZORN G, MAURER G, WOJTA J, HUBER K et al. Increased restenosis rate after implantation of drug-eluting stents in patients with elevated serum activity of matrix metalloproteinase-2 and-9. JACC: Cardiovascular Interventions 2010, 3 (1):90-97.

39. FUKUI M, TANAKA M, HAMAGUCHI M, SENMARU T, SAKABE K, SHIRAISHI E et al. Eosinophil Count Is Positively Correlated with Albumin Excretion Rate in Men with Type 2 Diabetes. Clinical Journal of the American Society of Nephrology: CJASN 2009, 4 (11):1761-1765.

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