Bilirubin coating attenuates the inflammatory response to everolimus-coated stents
In-Ho Bae
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorDae Sung Park
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorSo-Youn Lee
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorEun-Jae Jang
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorJae-Won Shim
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorKyung-Seob Lim
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Search for more papers by this authorJun-Kyu Park
Department of Polymer Science and Engineering, Sunchon National University, Suncheon, 540-950 Republic of Korea
Search for more papers by this authorJu Han Kim
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Department of Cardiology, Chonnam National University Hospital, Gwangju, 501-757 Republic of Korea
Search for more papers by this authorDoo Sun Sim
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Department of Cardiology, Chonnam National University Hospital, Gwangju, 501-757 Republic of Korea
Search for more papers by this authorCorresponding Author
Myung Ho Jeong
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Department of Cardiology, Chonnam National University Hospital, Gwangju, 501-757 Republic of Korea
Correspondence to: M. Ho Jeong; e-mail: [email protected]Search for more papers by this authorIn-Ho Bae
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorDae Sung Park
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorSo-Youn Lee
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorEun-Jae Jang
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorJae-Won Shim
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Search for more papers by this authorKyung-Seob Lim
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Search for more papers by this authorJun-Kyu Park
Department of Polymer Science and Engineering, Sunchon National University, Suncheon, 540-950 Republic of Korea
Search for more papers by this authorJu Han Kim
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Department of Cardiology, Chonnam National University Hospital, Gwangju, 501-757 Republic of Korea
Search for more papers by this authorDoo Sun Sim
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Department of Cardiology, Chonnam National University Hospital, Gwangju, 501-757 Republic of Korea
Search for more papers by this authorCorresponding Author
Myung Ho Jeong
The Cardiovascular Convergence Research Center of Chonnam National University Hospital Designated by Korea wMinistry of Health and Welfare, Gwangju, 501-757 Republic of Korea
Korea Cardiovascular Stent Research Institute, Jangsung, 501-893 Republic of Korea
Department of Cardiology, Chonnam National University Hospital, Gwangju, 501-757 Republic of Korea
Correspondence to: M. Ho Jeong; e-mail: [email protected]Search for more papers by this authorAbstract
The aim of this study was to evaluate the effects of bilirubin- and/or everolimus (EVL)-coated stents to prevent arterial neointimal hyperplasia and inflammation in vitro and in vivo. The stents were prepared by spray coating bare metal stents (BMS) with bilirubin and/or EVL. Study groups were divided into (1) BMS, (2) bilirubin-coated stents (BES), (3) commercialized stents (Synergy™; EES), and (4) bilirubin/EVL-coated stents (B-EES). The coating thickness and drug release rates were comparable to previous reports (i.e., <4 µm thickness and 50% drug release in 7 days). Smooth muscle cell migration was inhibited in both EVL-containing groups (20.5 ± 3.80% in EES and 18.4 ± 2.55% in B-EES) compared to the non-EVL-containing groups (78.0 ± 6.41% in BMS and 76.1 ± 4.88% in BES) (n = 10, p < 0.05). Stents were randomly implanted to 40 coronary arteries in 20 pigs and subjected to various analyses after 4 weeks of implantation. As results, the inflammation score was dramatically increased in the EES group (2.1 ± 0.42) compared to that of the other groups (1.5 ± 0.55, 1.3 ± 0.23, and 1.5 ± 0.27 for BMS, BES, and B-EES, respectively, n = 10, p < 0.05). Immunofluorescence analysis revealed that inflammation was prevented in the bilirubin-containing groups (BES and B-EES). However, the percent area of restenosis was decreased in the EVL-containing groups (20.5 ± 4.11% for EES and 18.4 ± 3.61% for B-EES) compared to the non-EVL-containing groups (32.3 ± 6.41% for BMS and 29.6 ± 5.95% for BES, n = 10, p < 0.05). The percent areas of restenosis determined by histopathology, optical coherence tomography, and micro-computed tomography were consistent. In addition, the stent was barely covered in the EES and B-EES groups at 4 weeks postimplantation. These dual drug-coated stents may be especially beneficial to patients who have an increased risk of inflammation. These stents have great potential for use in cardiovascular applications. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 1486–1495, 2018.
REFERENCES
- 1Dibra A, Kastrati A, Alfonso F, Seyfarth M, Perez-Vizcayno MJ, Mehilli J, Schomig A. Effectiveness of drug-eluting stents in patients with bare-metal in-stent restenosis: Meta-analysis of randomized trials. J Am Coll Cardiol 2007; 49: 616–623.
- 2Scott NA. Restenosis following implantation of bare metal coronary stents: Pathophysiology and pathways involved in the vascular response to injury. Adv Drug Deliv Rev 2006; 58: 358–376.
- 3Tung R, Kaul S, Diamond GA, Shah PK. Narrative review: Drug-eluting stents for the management of restenosis: A critical appraisal of the evidence. Ann Intern Med 2006; 144: 913–919.
- 4Abizaid AC, de Ribamar Costa Junior J, Whitbourn RJ, Chang JC. The CardioMind coronary stent delivery system: Stent delivery on a .014″ guidewire platform. EuroIntervention 2007; 3: 154–157.
- 5Ahmed TA, Bergheanu SC, Stijnen T, Plevier JW, Quax PH, Jukema JW. Clinical performance of drug-eluting stents with biodegradable polymeric coating: A meta-analysis and systematic review. EuroIntervention 2001; 7: 505–516.
- 6Klauss V, Serruys PW, Pilgrim T, Buszman P, Linke A, Ischinger T, Eberli F, Corti R, Wijns W, Morice MC, di Mario C, van Geuns RJ, van Es GA, Kalesan B, Wenaweser P, Juni P, Windecker S. 2-year clinical follow-up from the randomized comparison of biolimus-eluting stents with biodegradable polymer and sirolimus-eluting stents with durable polymer in routine clinical practice. JACC Cardiovasc Interv 2001; 4: 887–895.
- 7Zamiri P, Kuang Y, Sharma U, Ng TF, Busold RH, Rago AP, Core LA, Palasis M. The biocompatibility of rapidly degrading polymeric stents in porcine carotid arteries. Biomaterials 2010; 31: 7847–7855.
- 8Peng HY, Chen M, Zheng B, Wang XG, Huo Y. Long-term effects of novel biodegradable, polymer-coated, sirolimus-eluting stents on neointimal formation in a porcine coronary model. Int Heart J 2009; 50: 811–822.
- 9Joner M, Finn AV, Farb A, Mont EK, Kolodgie FD, Ladich E, Kutys R, Skorija K, Gold HK, Virmani R. Pathology of drug-eluting stents in humans: Delayed healing and late thrombotic risk. J Am Coll Cardiol 2006; 48: 193–202.
- 10Farb A, Weber DK, Kolodgie FD, Burke AP, Virmani R. Morphological predictors of restenosis after coronary stenting in humans. Circulation 2002; 105: 2974–2980.
- 11Moreno PR, Bernardi VH, Lopez-Cuellar J, Newell JB, McMellon C, Gold HK, Palacios IF, Fuster V, Fallon JT. Macrophage infiltration predicts restenosis after coronary intervention in patients with unstable angina. Circulation 1996; 94: 3098–3102.
- 12Abizaid A, Costa JR, Jr, Banning A, Bartorelli AL, Dzavik V, Ellis S, Gao R, Holmes DR, Jr, Jeong MH, Legrand V, Neumann FJ, Nyakern M, Orlick A, Spaulding C, Worthley S, Urban PM. The sirolimus-eluting Cypher Select coronary stent for the treatment of bare-metal and drug-eluting stent restenosis: Insights from the e-SELECT (Multicenter Post-Market Surveillance) registry. JACC Cardiovasc Interv 2012; 5: 64–71.
- 13Windecker S, Haude M, Neumann FJ, Stangl K, Witzenbichler B, Slagboom T, Sabate M, Goicolea J, Barragan P, Cook S, Piot C, Richardt G, Merkely B, Schneider H, Bilger J, Eme P, Waksman R, Zaugg S, Juni P, Lefevre T. Comparison of a novel biodegradable polymer sirolimus-eluting stent with a durable polymer everolimus-eluting stent: Results of the randomized BIOFLOW-II trial. Circ Cardiovasc Interv 2015; 8: e001441.
- 14Blazek S, Rossbach C, Borger MA, Fuernau G, Desch S, Eitel I, Stiermaier T, Lurz P, Holzhey D, Schuler G, Mohr FW, Thiele H. Comparison of sirolimus-eluting stenting with minimally invasive bypass surgery for stenosis of the left anterior descending coronary artery: 7-year follow-up of a randomized trial. JACC Cardiovasc Interv 2015; 8: 30–38.
- 15Stefanini GG, Taniwaki M, Windecker S. Coronary stents: Novel developments. Heart 2014; 100: 1051–1061.
- 16Meredith IT, Verheye S, Dubois CL, Dens J, Fajadet J, Carrie D, Walsh S, Oldroyd KG, Varenne O, El-Jack S, Moreno R, Joshi AA, Allocco DJ, Dawkins KD. Primary endpoint results of the EVOLVE trial: A randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent. J Am Coll Cardiol 2012; 59: 1362–1370.
- 17Kereiakes DJ, Meredith IT, Windecker S, Lee Jobe R, Mehta SR, Sarembock IJ, Feldman RL, Stein B, Dubois C, Grady T, Saito S, Kimura T, Christen T, Allocco DJ, Dawkins KD. Efficacy and safety of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent: The EVOLVE II Randomized Trial. Circ Cardiovasc Interv 2015; 8.
- 18Tardif JC, Cote G, Lesperance J, Bourassa M, Lambert J, Doucet S, Bilodeau L, Nattel S, de Guise P. Probucol and multivitamins in the prevention of restenosis after coronary angioplasty. Multivitamins and Probucol Study Group. The N Engl J Med 1997; 337: 365–372.
- 19Yokoi H, Daida H, Kuwabara Y, Nishikawa H, Takatsu F, Tomihara H, Nakata Y, Kutsumi Y, Ohshima S, Nishiyama S, Seki A, Kato K, Nishimura S, Kanoh T, Yamaguchi H. Effectiveness of an antioxidant in preventing restenosis after percutaneous transluminal coronary angioplasty: The Probucol Angioplasty Restenosis Trial. J Am Coll Cardiol 1997; 30: 855–862.
- 20Take S, Matsutani M, Ueda H, Hamaguchi H, Konishi H, Baba Y, Kawaratani H, Sugiura T, Iwasaka T, Inada M. Effect of cilostazol in preventing restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol 1997; 79: 1097–1099.
- 21Kim MH, Cha KS, Han JY, Kim HJ, Kim JS. Effect of antioxidant probucol for preventing stent restenosis. Catheter Cardiovasc Interv 2002; 57: 424–428.
- 22Kim W, Jeong MH, Cha KS, Hyun DW, Hur SH, Kim KB, Hong YJ, Park HW, Kim JH, Ahn YK, Kim MH, Cho JG, Park JT, Park JC, Kang JC. Effect of anti-oxidant (carvedilol and probucol) loaded stents in a porcine coronary restenosis model. Circ J 2005; 69: 101–106.
10.1253/circj.69.101 Google Scholar
- 23Sekiya M, Funada J, Watanabe K, Miyagawa M, Akutsu H. Effects of probucol and cilostazol alone and in combination on frequency of poststenting restenosis. Am J Cardiol 1998; 82: 144–147.
- 24Tenhunen R, Marver HS, Schmid R. The enzymatic conversion of heme to bilirubin by microsomal heme oxygenase. Proc Natl Acad Sci USA 1968; 61: 748–755.
- 25Stocker R, Yamamoto Y, McDonagh AF, Glazer AN, Ames BN. Bilirubin is an antioxidant of possible physiological importance. Science 1987; 235: 1043–1046.
- 26Vitek L, Novotny L, Sperl M, Holaj R, Spacil J. The inverse association of elevated serum bilirubin levels with subclinical carotid atherosclerosis. Cerebrovas Dis 2006; 21: 408–414.
- 27Wiedemann M, Kontush A, Finckh B, Hellwege HH, Kohlschutter A. Neonatal blood plasma is less susceptible to oxidation than adult plasma owing to its higher content of bilirubin and lower content of oxidizable fatty acids. Pediatr Res 2003; 53: 843–849.
- 28Sedlak TW, Snyder SH. Bilirubin benefits: Cellular protection by a biliverdin reductase antioxidant cycle. Pediatrics 2004; 113: 1776–1782.
- 29Lin JP, O'Donnell CJ, Schwaiger JP, Cupples LA, Lingenhel A, Hunt SC, Yang S, Kronenberg F. Association between the UGT1A1*28 allele, bilirubin levels, and coronary heart disease in the Framingham Heart Study. Circulation 2006; 114: 1476–1481.
- 30Fondevila C, Shen XD, Tsuchiyashi S, Yamashita K, Csizmadia E, Lassman C, Busuttil RW, Kupiec-Weglinski JW, Bach FH. Biliverdin therapy protects rat livers from ischemia and reperfusion injury. Hepatology 2004; 40: 1333–1341.
- 31Wang WW, Smith DL, Zucker SD. Bilirubin inhibits iNOS expression and NO production in response to endotoxin in rats. Hepatology 2004; 40: 424–433.
- 32Keshavan P, Deem TL, Schwemberger SJ, Babcock GF, Cook-Mills JM, Zucker SD. Unconjugated bilirubin inhibits VCAM-1-mediated transendothelial leukocyte migration. J Immunol 2005; 174: 3709–3718.
- 33Lanone S, Bloc S, Foresti R, Almolki A, Taille C, Callebert J, Conti M, Goven D, Aubier M, Dureuil B, El-Benna J, Motterlini R, Boczkowsk J. Bilirubin decreases nos2 expression via inhibition of NAD(P)H oxidase: Implications for protection against endotoxic shock in rats. FASEB J 2005; 19: 1890–1892.
- 34Nakao A, Neto JS, Kanno S, Stolz DB, Kimizuka K, Liu F, Bach FH, Billiar TR, Choi AM, Otterbein LE, Murase N. Protection against ischemia/reperfusion injury in cardiac and renal transplantation with carbon monoxide, biliverdin and both. Am J Transplant 2005; 5: 282–291.
- 35Overhaus M, Moore BA, Barbato JE, Behrendt FF, Doering JG, Bauer AJ. Biliverdin protects against polymicrobial sepsis by modulating inflammatory mediators. Am J Physiol Gastrointest Liver Physiol 2006; 290: G695–G703.
- 36Kadl A, Pontiller J, Exner M, Leitinger N. Single bolus injection of bilirubin improves the clinical outcome in a mouse model of endotoxemia. Shock 2007; 28: 582–588.
- 37Buszman P, Trznadel S, Zurakowski A, Milewski K, Kinasz L, Krol M, Kondys M. Prospective registry evaluating safety and efficacy of cobalt-chromium stent implantation in patients with de novo coronary lesions. Kardiol Pol 2007; 65: 1041–1046; discussion 1047–1048.
- 38Bae IH, Lim KS, Park JK, Lee SY, Jang EJ, Ji MS, Sim DS, Hong YJ, Ahn YK, Park JC, Cho JG, Kang JC, Kim IS, Nah JW, Jeong MH. Mechanical behavior and in vivo properties of newly designed bare metal stent for enhanced flexibility. J Ind Eng Chem 2015; 21: 1295–1300.
- 39Ma X, Oyamada S, Gao F, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Gu Z, Bianchi CF, Sellke FW, Laham R. Paclitaxel/sirolimus combination coated drug-eluting stent: In vitro and in vivo drug release studies. J Pharm Biomed Anal 2011; 54: 807–811.
- 40Liang CC, Park AY, Guan JL. In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2007; 2: 329–333.
- 41Schwartz RS, Edelman E, Virmani R, Carter A, Granada JF, Kaluza GL, Chronos NA, Robinson KA, Waksman R, Weinberger J, Wilson GJ, Wilensky RL. Drug-eluting stents in preclinical studies: Updated consensus recommendations for preclinical evaluation. Circ Cardiovasc Interv 2008; 1: 143–153.
- 42Goto K, Takebayashi H, Kihara Y, Hagikura A, Fujiwara Y, Kikuta Y, Sato K, Kodama S, Taniguchi M, Hiramatsu S, Haruta S. Appearance of neointima according to stent type and restenotic phase: Analysis by optical coherence tomography. EuroIntervention 2013; 9: 601–607.
- 43Qian Z, Haessler M, Lemos JA, Arsenault JR, Aguirre JE, Gilbert JR, Bowler RP, Park F. Targeting vascular injury using Hantavirus-pseudotyped lentiviral vectors. Mol Ther 2006; 13: 694–704.
- 44Neamtu I, Chiriac AP, Diaconu A, Nita LE, Balan V, Nistor MT. Current concepts on cardiovascular stent devices. Mini Rev Med Chem 2014; 14: 505–536.
- 45Vetrovec GW, Rizik D, Williard C, Snead D, Piotrovski V, Kopia G. Sirolimus PK trial: A pharmacokinetic study of the sirolimus-eluting Bx velocity stent in patients with de novo coronary lesions. Catheter Cardiovasc Interv 2006; 67: 32–37.
- 46Engelhardt EM, Micol LA, Houis S, Wurm FM, Hilborn J, Hubbell JA, Frey P. A collagen-poly(lactic acid-co-varepsilon-caprolactone) hybrid scaffold for bladder tissue regeneration. Biomaterials 2001; 32: 3969–3976.
- 47Garratt KN. Duration of dual anti-platelet therapy post-percutaneous intervention: Is there a correct amount of time? Prog Cardiovasc Dis 2015; 58: 285–298.
10.1016/j.pcad.2015.09.001 Google Scholar
- 48Helft G. The saga of the duration of dual antiplatelet therapy after drug-eluting stent placement. Arch Cardiovasc Dis 2015; 108: 469–471.
10.1016/j.acvd.2015.09.001 Google Scholar
- 49Palmerini T, Stone GW. Optimal duration of dual antiplatelet therapy after drug-eluting stent implantation: Conceptual evolution based on emerging evidence, Eur Heart J 2016; 37: 353–364.
- 50Horsfall LJ, Hardy R, Wong A, Kuh D, Swallow DM. Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert's syndrome) and respiratory health in the 1946 British birth cohort. J Hepatol 2014; 61: 1344–1351.
10.1016/j.jhep.2014.07.028 Google Scholar
- 51de Vries HS, Te Morsche RH, Jenniskens K, Peters WH, de Jong DJ. A functional polymorphism in UGT1A1 related to hyperbilirubinemia is associated with a decreased risk for Crohn's disease. J Crohns Colitis 2012; 6: 597–602.
- 52Baranano DE, Rao M, Ferris CD, Snyder SH. Biliverdin reductase: A major physiologic cytoprotectant. Proc Natl Acad Sci USA 2002; 99: 16093–16098.
- 53Cook-Mills JM, Marchese ME, Abdala-Valencia H. Vascular cell adhesion molecule-1 expression and signaling during disease: Regulation by reactive oxygen species and antioxidants. Antioxid Redox Signal 2011; 15: 1607–1638.
- 54Meng S, Liu Z, Shen L, Guo Z, Chou LL, Zhong W, Du Q, Ge J. The effect of a layer-by-layer chitosan-heparin coating on the endothelialization and coagulation properties of a coronary stent system. Biomaterials 2009; 30: 2276–2283.
