Histologic Changes of the Immunologically Untreated Xenogenic Valved Conduit

면역학적 처리 없는 이종 심장 판막 도관의 조직학적 변화에 관한 연구

  • Sung, Ki-Ick (Department of Thoracic and Cardiovascular Surgery, Samsung Medical Center, College of Medicine, Sungkyunkwan University) ;
  • Seo, Jeong-Wook (Department of Pathology, Seoul National University College of Medicine) ;
  • Kim, Won-Gon (Department of Thoracic and Cardiovascular Surgery, Seoul National University Hospital)
  • 성기익 (성균관대학교 의과대학 삼성서울병원 흉부외과) ;
  • 서정욱 (서울대학교 의과대학 병리학교실) ;
  • 김원곤 (서울대학교병원 흉부외과)
  • Published : 2007.01.05

Abstract

Backgound: It has been shown that the endothelium of cardiac valves and adjacent great vessels have a reduced immune reaction compared to other vessels. We investigated the clinical feasibility of using immunologically untreated xenogenic valves, in a pig-to-goat pulmonary valve conduit implantation model. Material and Method: Porcine pulmonary valve conduits were prepared without specific immunologic treatment and implanted into the right ventricular outflow tract of goats while undergoing cardiopulmonary bypass. Two goats each were assigned to the following observation time intervals: one day, one week, three months, six months and twelve months. Echo-cardiographic examinations were performed prior to sacrifice of the goat to evaluate pulmonary valve function. After the xenograft specimens were retrieved, histological changes were evaluated microscopically. Result: Ten of the twelve animals survived the predetermined observation time intervals. Aneurysmal dilatations, of the anterior wall of the implanted pulmonary artery, were observed at each of three and twelve month-survival animals. A variable degree of pulmonary valve regurgitation was observed on echocardiography. However, valve stenosis, thrombotic occlusion and vegetation were not seen. Microscopically, the nuclei of the donor tissue disappeared as a result of pyknosis and karyolysis; however the three components of the implanted xenografts (the pulmonary artery, the valve and the infundibulum) were gradually replaced by host cells over time, while maintaining their structural integrity. Conclusion: Immunologically untreated xenogenic pulmonary valve conduits were replaced by host cells with few observed clinical problems in a pig to goat pulmonary valve implantation model. Therefore, they might be an alternative bioprosthesis option.

배경: 심장판막 및 그 주변의 큰 혈관들의 내피세포는 다른 부위와 달리 훨씬 완화된 면역 반응을 보이는 것에 착안하여, 고정액이나 면역학적 처치를 거치지 않은 이종 판막의 대동맥 판막의 임상적 유용성을 돼지-염소 간 이종 폐동맥 판막도관 이식 실험을 통해 알아보고자 하였다. 대상 및 방법: 돼지 폐동맥 판막도관은 특별한 면역학적 처치를 거치지 않은 채 준비하여 인공심폐기 가동 하에 염소의 우심실 유출로에 이식하였다. 염소들은 군당 2마리씩 배정하여 이식 후 하루, 1주, 3개월, 6개월, 12개월 동안 각각 관찰하였다. 실험동물을 희생하기 전 심초음파검사를 시행하여 판막의 움직임을 관찰하였고, 이종 장기를 적출한 후 판막도관의 조직학적 변화를 관찰하였다. 결과: 총 12마리 중 10마리에서 정해진 기간 동안 생존하였다. 이식된 폐동맥의 전벽의 동맥류가 12개월과 3개월 관찰한 각각 한 마리의 염소에서 발견되었다. 심초음파 검사에서는 다양한 정도의 폐동맥 판막 폐쇄부전의 소견을 보였으나 판막의 협착이나 혈전형성, 증식증은 관찰되지 않았다. 조직학적 관찰에서 이식 세포의 핵은 핵농축 및 핵융해를 통해 없어졌지만, 이식된 이종 판막도관의 세 구역(폐동맥, 폐동맥 판막, 누두부)은 구조가 보존되면서 점차적으로 시간에 따라 숙주 세포로 대체되었다. 결론: 면역학적 처리를 거치지 않은 이종 폐동맥 판막도관이 돼지-염소 간 이종 이식실험에서 다소의 문제점이 발견되기는 하였지만 성공적으로 숙주 세포로 대체되어 기존의 조직판막의 대안이 될 가능성을 제시하였다.

Keywords

References

  1. Eyble E, Griesmacher A, Grimm M, Wolner E. Toxic effects of aldehydes release from fixed pericardium on bovine aortic endothelial cell. J Biomed Mater Res 1989;23:1355-65 https://doi.org/10.1002/jbm.820231111
  2. Wiebe D, Megerman J, L'Italien GJ, Abbott WA. Glutaraldehyde release from vascular prosthesis of biologic origin. Surg 1988;104:26-33
  3. Carpentier A, Nashef A, Carpentier S, Ahmed A, Goussef N. Techniques for preservation of calcification of vascular bioprostheses. Circulation 1984;70:I165-8 https://doi.org/10.1161/01.CIR.70.2.165
  4. Grimm M, Eybl E, Granbenwoger M, et al. Biocompatibility of aldehyde-fixed bovine pericardium. J Thorac Cardiovasc Surg 1991;102:195-201
  5. Levy RJ, Hawley MA, Schoen FJ, Lund SA, Liu PY. Inhibition by diphosphonate compounds of calcification of porcine bioprosthetic heart valve cusp implanted subcutaneously in rats. Circulation 1985;71:349-56 https://doi.org/10.1161/01.CIR.71.2.349
  6. Cebotari S, Mertsching H, Kallenbach K. Construction of autologous human heart valves based on acellular allograft matrix. Circulation 2002;106(suppl I):63-8 https://doi.org/10.1161/01.CIR.0000020014.14176.6D
  7. Steinhoff G, Stock U, Karim N, et al. Tissue engineering of pulmonary heart valves on allogenic acellular matrix conduits: in vivo restoration of valve tissue. Circulation 2000; 102(suppl III):50-5 https://doi.org/10.1161/01.CIR.102.8.e50
  8. Goldstein S, Clarke DR, Walsh SP, Black KS, O'Brien MF. Transpecies heart valve replacement: advanced studies of a bioengineered xeno-autograft. Ann Thorac Surg 2000;70: 1962-9 https://doi.org/10.1016/S0003-4975(00)01812-9
  9. Leyh RG, Wilhelmi M, Rebe P, et al. In vivo repopularization of xenogenic and allogenic acellular valve matrix conduits in the pulmonary circulation. Ann Thorac Surg 2003;75:1457-63 https://doi.org/10.1016/S0003-4975(02)04845-2
  10. Kim WG, Huh JH. Time related histopathologic changes of acellularized xenogenic pulmonary valved conduits. ASAIO J 2004;50:601-5 https://doi.org/10.1097/01.MAT.0000142873.72813.C5
  11. Carins T, Lee J, Goldberg L, et al. Inhibition of the pig to human xenograft reaction using soluble Gal alpha 1-3Gal and Gal alpha 1-3Gal beta 1-4GlcNAc. Transplantation 1995; 60:1202-7 https://doi.org/10.1097/00007890-199512150-00004
  12. Galli U, Shohet SB, Kobrin E, Stults CL, Macher BA. Man, apes and old world monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. J Bio Chem 1988;263:17755-62
  13. Lavecchio JA, Dunne AD, Edge AS. Enzymatic removal of alpha-galactosyl epitopes from porcine endothelial cells diminishes the cytotoxic effect of natural antibodies. Transplantation 1995;60:841-7 https://doi.org/10.1097/00007890-199510270-00014
  14. Chen RH, Mitchell RN, Kadner A, Adams DH. Differential galactose alpha (1,3) galactose expression by porcine cardiac vascular endothelium. Xenotransplantation 1996;6:169-72 https://doi.org/10.1034/j.1399-3089.1999.00024.x
  15. Chen RH, Kadner A, Mitchell RN, Adams DH. Fresh porcine cardiac valves are not rejected in primates. J Thorac Cardiovasc Surg 2000;119:1216-20 https://doi.org/10.1067/mtc.2000.106526
  16. Simon P, Kasimir MT, Seebacher G, et al. Early failure of the tissue engineered porcine heart valve $SYNERGRAFT^{TM}$ in pediatric patients. Eur J Cardiothorac Surg 2003;23:1002-6 https://doi.org/10.1016/S1010-7940(03)00094-0
  17. Macchiarini P, Oriol R, Azimzadeh A, Wolf P, Dartevelle P. Characterization of a pig-to-goat orthotopic lung transplantation model to study beyond hyperacute rejection. J Thorac Cardiovasc Surg 1999;118:805-14 https://doi.org/10.1016/S0022-5223(99)70049-8
  18. Enzan K, Wang Y, Schultz E, et al. Pulmonary hemodynamic reaction to foreign blood in goats and rabbits. J Appl Physiolo 1991;71:2231-7 https://doi.org/10.1152/jappl.1991.71.6.2231