vtioВестник трансплантологии и искусственных органовRussian Journal of Transplantology and Artificial Organs1995-1191Academician V.I.Shumakov National Medical Research Center of Transplantology and Artificial Organs", Ministry of Health of the Russian Federation10.15825/1995-1191-2026-1-255-262vtio-2014Research ArticleИмплантаты и искусственные органыImplants and Artificial OrgansОсобенности отложения антител класса IgG в биологическом компоненте эпоксиобработанных ксеногенных биопротезов клапанов сердцаFeatures of IgG subclass deposition in the biological component of epoxy-treated xenogenic bioprosthetic heart valveshttps://orcid.org/0000-0001-6099-0315КостюнинА. Е.KostyuninA. E.

Костюнин Александр Евгеньевич

650002, Кемерово, бульвар Академика Л.С. Барбараша, д. 6.

Тел. (900) 108-10-97

Alexander Kostyunin

Akademika Barbarasha bul’var, Kemerovo, 650002

Phone: (900) 108-10-97

Rhabdophis_tigrina@mail.ruhttps://orcid.org/0000-0003-4890-0393ГлушковаТ. В.GlushkovaT. V.

Кемерово

Kemerovo

bio.tvg@mail.ruhttps://orcid.org/0009-0008-8957-5041КлюеваА. А.KlyuevaA. A.

Кемерово

Kemerovo

kaiketsu@mail.ruhttps://orcid.org/0000-0002-0033-9376АкентьеваТ. Н.AkentyevaT. N.

Кемерово

Kemerovo

t.akentyeva@mail.ruhttps://orcid.org/0000-0003-4124-2316БогдановЛ. А.BogdanovL. A.

Кемерово

Kemerovo

bogdanovleone@gmail.comhttps://orcid.org/0000-0002-5558-3229МухамадияровР. А.MukhamadiyarovR. A.

Кемерово

Kemerovo

rem57@rambler.ruhttps://orcid.org/0000-0003-3211-1250КлышниковК. Ю.KlyshnikovK. Yu.

Кемерово

Kemerovo

klyshnikovk@gmail.comhttps://orcid.org/0000-0003-2404-2873ОнищенкоП. С.OnishchenkoP. S.

Кемерово

Kemerovo

onis.pavel@gmail.comhttps://orcid.org/0000-0001-7477-3979ОвчаренкоЕ. А.OvcharenkoE. А.

Кемерово

Kemerovo

ov.eugene@gmail.comФГБНУ «Научно-исследовательский институт комплексных проблем сердечно-сосудистых заболеваний»РоссияResearch Institute for Complex Issues of Cardiovascular DiseasesRussian Federation202631032026281255262Copyright © Костюнин А.Е., Глушкова Т.В., Клюева А.А., Акентьева Т.Н., Богданов Л.А., Мухамадияров Р.А., Клышников К.Ю., Онищенко П.С., Овчаренко Е.А., 20262026Костюнин А.Е., Глушкова Т.В., Клюева А.А., Акентьева Т.Н., Богданов Л.А., Мухамадияров Р.А., Клышников К.Ю., Онищенко П.С., Овчаренко Е.А.Kostyunin A.E., Glushkova T.V., Klyueva A.A., Akentyeva T.N., Bogdanov L.A., Mukhamadiyarov R.A., Klyshnikov K.Y., Onishchenko P.S., Ovcharenko E.А.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.transpl.ru/vtio/article/view/2014Цель

Цель: оценить изменение иммуногенности эпоксиобработанных ксенобиопротезов клапанов серд ца (БП) при их функционировании в организме реципиентов посредством детекции человеческих антител класса IgG в биоматериале эксплантированных образцов.

Материалы и методы

Материалы и методы. Изучено 14 БП, удаленных в ходе репротезирования клапанов. Из них 3 клапана иссечены через 1, 20 и 42 дня после имплантации, тогда как 11 БП функционировали от 3 до 25 лет. Из створчатого аппарата исследуемых БП подготовлены гистологические срезы, которые окрашивали иммуногистохимически с помощью антитела к человеческому IgG и пентахромом по Расселу–Мовату. Часть фрагментов створок изучена методом сканирующей электронной микроскопии.

Результаты

Результаты. Удаленные по причине ранних дисфункций БП, функционировавшие 1, 20 и 42 дня, не имели дегенеративных изменений в биоматериале, однако на поверхности их створок присутствовали незначительные тромбы. В свою очередь, клапаны, функционировавшие от 3 до 25 лет, развили признаки структурной дегенерации биологической ткани, включающие наличие в створках разрывов и крупных кальцификатов. Также эти БП характеризовались умеренной макрофагальной инфильтрацией и незначительным нарастанием паннуса на поверхности створчатого аппарата. Иммуногистохимическое окрашивание гистологических срезов на иммуноглобулин IgG человека продемонстрировало интенсивное отложение антител в биоматериале всех исследуемых БП вне зависимости от времени их функционирования. Положительное окрашивание на IgG человека отмечено вдоль волокон ксеногенной ткани, но отсутствовало в тканях реципиента (в тромбах и паннусе).

Заключение

Заключение. Биологический элемент БП не теряет иммуногенных свойств даже при длительном (до 25 лет) функционировании в организме реципиента.

Objective

Objective: to evaluate changes in the immunogenicity of epoxy-treated xenogeneic bioprosthetic heart valves (BHVs) during in vivo function by detecting human IgG antibodies in the biomaterial of explanted samples.

Materials and methods

Materials and methods. Fourteen BHVs explanted during repeat valve replacement were examined. Of these, three valves were removed at 1, 20, and 42 days after implantation, while 11 valves had functioned for periods ranging from 3 to 25 years. Histological sections were prepared from the valve leaflets and analyzed by immunohistochemistry using antibodies against human immunoglobulin G (IgG), as well as Russell–Movat pentachrome staining. Selected leaflet fragments were additionally examined by scanning electron microscopy.

Results

Results. BHVs removed due to early dysfunction after 1, 20, and 42 days of implantation showed no signs of biomaterial degeneration; however, small thrombi were detected on their leaflet surfaces. In contrast, valves that had functioned for 3 to 25 years exhibited clear features of structural degeneration of the biological tissue, including leaflet tears and extensive calcification. These BHVs were also characterized by moderate macrophage infiltration and a slight increase in pannus on the valve surface. Immunohistochemical staining of histological sections for human IgG revealed intense antibody deposition within the biomaterial of all examined BHVs, irrespective of implantation duration. Positive IgG staining was localized along the fibers of the xenogeneic tissue and was absent in recipient tissues, including thrombi and pannus.

Conclusion

Conclusion. The biological component of BHVs retains its immunogenic properties even after long-term (up to 25 years) function in the recipient’s body.

Биопротезы клапанов сердцаструктурная дегенерация клапанаантитела класса IgGиммунный ответиммуногистохимияBioprosthetic heart valvesstructural valve degenerationIgGimmune responseimmunohistochemistryРабота подготовлена в рамках комплексной программы фундаментальных научных исследований СО РАН по фундаментальной теме НИИ КПССЗ № 0419-2022-0001 «Молекулярные, клеточные и биомеханические механизмы патогенеза сердечно-сосудистых заболеваний в разработке новых методов лечения заболеваний сердечно-сосудистой системы на основе персонифицированной фармакотерапии, внедрения малоинвазивных медицинских изделий, биоматериалов и тканеинженерных имплантатов».The research was funded by the Complex Program of Basic Research under the Siberian Branch of the Russian Academy of Sciences within the Basic Research Topic of Research Institute for Complex Issues of Cardiovascular Diseases No. 0419-2022-0001 “Discovering molecular, cellular and biomechanical mechanisms of cardiovascular diseases to develop novel approaches for their treatment, including personalized pharmacotherapy, minimally invasive surgery, composite biomaterials, and tissue-engineered cardiovascular implants”.ReferencesOtto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP, Gentile F et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology / American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2021; 143 (5): e72–e227. doi: 10.1161/CIR.0000000000000923.Otto CM, Nishimura RA, Bonow RO, Carabello BA, Erwin JP, Gentile F et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: a report of the American College of Cardiology / American Heart Association Joint Committee on clinical practice guidelines. Circulation. 2021; 143 (5): e72–e227. doi: 10.1161/CIR.0000000000000923.Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022; 43 (7): 561–632. doi: 10.1093/eurheartj/ehab395.Vahanian A, Beyersdorf F, Praz F, Milojevic M, Baldus S, Bauersachs J et al. 2021 ESC/EACTS Guidelines for the management of valvular heart disease. Eur Heart J. 2022; 43 (7): 561–632. doi: 10.1093/eurheartj/ehab395.Барбараш ЛС, Журавлева ИЮ. Эволюция биопротезов клапанов сердц а: достижения и проблемы двух десятилетий. Комплексные проблемы сердечно-сосудистых заболеваний. 2012; 1: 4–11. doi: 10.17802/2306-1278-2012-1-4-11.Barbarash LS, Zhuravleva IYu. Bioprosthetic heart valve evolution: two decades of advances and challenges. Complex Issues of Cardiovascular Diseases. 2012; 1: 4–11. (in Russ.). doi: 10.17802/2306-1278-2012-1-4-11.Velho TR, Pereira RM, Fernandes F, Guerra NC, Ferreira R, Nobre Â. Bioprosthetic aortic valve degeneration: a review from a basic science perspective. Braz J Cardiovasc Surg. 2022; 37 (2): 239–250. doi: 10.21470/16789741-2020-0635.Velho TR, Pereira RM, Fernandes F, Guerra NC, Ferreira R, Nobre Â. Bioprosthetic aortic valve degeneration: a review from a basic science perspective. Braz J Cardiovasc Surg. 2022; 37 (2): 239–250. doi: 10.21470/16789741-2020-0635.Wen S, Zhou Y, Yim WY, Wang S, Xu L, Shi J et al. Mechanisms and drug therapies of bioprosthetic heart valve calcification. Front Pharmacol. 2022; 13: 909801. doi: 10.3389/fphar.2022.909801.Wen S, Zhou Y, Yim WY, Wang S, Xu L, Shi J et al. Mechanisms and drug therapies of bioprosthetic heart valve calcification. Front Pharmacol. 2022; 13: 909801. doi: 10.3389/fphar.2022.909801.Capodanno D, Petronio AS, Prendergast B, Eltchaninoff H, Vahanian A, Modine T et al. Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017; 38 (45): 3382–3390. doi: 10.1093/eurheartj/ehx303.Capodanno D, Petronio AS, Prendergast B, Eltchaninoff H, Vahanian A, Modine T et al. Standardized definitions of structural deterioration and valve failure in assessing long-term durability of transcatheter and surgical aortic bioprosthetic valves: a consensus statement from the European Association of Percutaneous Cardiovascular Interventions (EAPCI) endorsed by the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2017; 38 (45): 3382–3390. doi: 10.1093/eurheartj/ehx303.Dvir D, Bourguignon T, Otto CM, Hahn RT, Rosenhek R, Webb JG et al. Standardized definition of structural valve degeneration for surgical and transcatheter bioprosthetic aortic valves. Circulation. 2018; 137 (4): 388–399. doi: 10.1161/CIRCULATIONAHA.117.030729.Dvir D, Bourguignon T, Otto CM, Hahn RT, Rosenhek R, Webb JG et al. Standardized definition of structural valve degeneration for surgical and transcatheter bioprosthetic aortic valves. Circulation. 2018; 137 (4): 388–399. doi: 10.1161/CIRCULATIONAHA.117.030729.Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009; 119 (7): 1034–1048. doi: 10.1161/CIRCULATIONAHA.108.778886.Pibarot P, Dumesnil JG. Prosthetic heart valves: selection of the optimal prosthesis and long-term management. Circulation. 2009; 119 (7): 1034–1048. doi: 10.1161/CIRCULATIONAHA.108.778886.Cote N, Pibarot P, Clavel MA. Incidence, risk factors, clinical impact, and management of bioprosthesis structural valve degeneration. Curr Opin Cardiol. 2017; 32 (2): 123–129. doi: 10.1097/HCO.0000000000000372.Cote N, Pibarot P, Clavel MA. Incidence, risk factors, clinical impact, and management of bioprosthesis structural valve degeneration. Curr Opin Cardiol. 2017; 32 (2): 123–129. doi: 10.1097/HCO.0000000000000372.Kostyunin AE, Yuzhalin AE, Rezvova MA, Ovcharenko EA, Glushkova TV, Kutikhin AG. Degeneration of bioprosthetic heart valves: update 2020. J Am Heart Assoc. 2020; 9 (19): e018506. doi: 10.1161/JAHA.120.018506.Kostyunin AE, Yuzhalin AE, Rezvova MA, Ovcharenko EA, Glushkova TV, Kutikhin AG. Degeneration of bioprosthetic heart valves: update 2020. J Am Heart Assoc. 2020; 9 (19): e018506. doi: 10.1161/JAHA.120.018506.Мухамадияров РА, Рутковская НВ, Сидорова ОД, Барбараш ЛС. Исследование клеточного состава кальцинированных биопротезов клапанов серд ца. Вестник РАМН. 2015; 70 (6): 662–668. doi: 10.15690/vramn560.Mukhamadiyarov RA, Rutkovskaya NV, Sidorova OD, Barbarash LS. Cellular composition of calcified bioprosthetic heart valves. Annals of the Russian Academy of Medical Sciences. 2015; 70 (6): 662–668. (In Russ.). doi: 10.15690/vramn560.Shetty R, Pibarot P, Audet A, Janvier R, Dagenais F, Perron J et al. Lipid-mediated inflammation and degeneration of bioprosthetic heart valves. Eur J Clin Invest. 2009; 39 (6): 471–480. doi: 10.1111/j.13652362.2009.02132.x.Shetty R, Pibarot P, Audet A, Janvier R, Dagenais F, Perron J et al. Lipid-mediated inflammation and degeneration of bioprosthetic heart valves. Eur J Clin Invest. 2009; 39 (6): 471–480. doi: 10.1111/j.13652362.2009.02132.x.Sakaue T, Koyama T, Nakamura Y, Okamoto K, Kawashima T, Umeno T et al. Bioprosthetic valve deterioration: accumulation of circulating proteins and macrophages in the valve interstitium. JACC Basic Transl Sci. 2023; 8 (7): 862–880. doi: 10.1016/j.jacbts.2023.01.003.Sakaue T, Koyama T, Nakamura Y, Okamoto K, Kawashima T, Umeno T et al. Bioprosthetic valve deterioration: accumulation of circulating proteins and macrophages in the valve interstitium. JACC Basic Transl Sci. 2023; 8 (7): 862–880. doi: 10.1016/j.jacbts.2023.01.003.Nair V, Law KB, Li AY, Phillips KR, David TE, Butany J. Characterizing the inflammatory reaction in explanted Medtronic Freestyle stentless porcine aortic bioprosthesis over a 6-year period. Cardiovasc Pathol. 2012; 21 (3): 158–168. doi: 10.1016/j.carpath.2011.05.003.Nair V, Law KB, Li AY, Phillips KR, David TE, Butany J. Characterizing the inflammatory reaction in explanted Medtronic Freestyle stentless porcine aortic bioprosthesis over a 6-year period. Cardiovasc Pathol. 2012; 21 (3): 158–168. doi: 10.1016/j.carpath.2011.05.003.Manji RA, Hara H, Cooper DK. Characterization of the cellular infiltrate in bioprosthetic heart valves explanted from patients with structural valve deterioration. Xenotransplantation. 2015; 22 (5): 406–407. doi: 10.1111/xen.12187.Manji RA, Hara H, Cooper DK. Characterization of the cellular infiltrate in bioprosthetic heart valves explanted from patients with structural valve deterioration. Xenotransplantation. 2015; 22 (5): 406–407. doi: 10.1111/xen.12187.Senage T, Paul A, Le Tourneau T, Fellah-Hebia I, Vadori M, Bashir S et al. The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration. Nat Med. 2022; 28 (2): 283–294. doi: 10.1038/s41591-022-01682-w.Senage T, Paul A, Le Tourneau T, Fellah-Hebia I, Vadori M, Bashir S et al. The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration. Nat Med. 2022; 28 (2): 283–294. doi: 10.1038/s41591-022-01682-w.Siddiqui RF, Abraham JR, Butany J. Bioprosthetic heart valves: modes of failure. Histopathology. 2009; 55 (2): 135–144. doi: 10.1111/j.1365-2559.2008.03190.x.Siddiqui RF, Abraham JR, Butany J. Bioprosthetic heart valves: modes of failure. Histopathology. 2009; 55 (2): 135–144. doi: 10.1111/j.1365-2559.2008.03190.x.Rosales C. Fcγ receptor heterogeneity in leukocyte functional responses. Front Immunol. 2017; 8: 280. doi: 10.3389/fimmu.2017.00280.Rosales C. Fcγ receptor heterogeneity in leukocyte functional responses. Front Immunol. 2017; 8: 280. doi: 10.3389/fimmu.2017.00280.Böer U, Schridde A, Anssar M, Klingenberg M, Sarikouch S, Dellmann A et al. The immune response to crosslinked tissue is reduced in decellularized xenogeneic and absent in decellularized allogeneic heart valves. Int J Artif Organs. 2015; 38 (4): 199–209. doi: 10.5301/ijao.5000395.Böer U, Schridde A, Anssar M, Klingenberg M, Sarikouch S, Dellmann A et al. The immune response to crosslinked tissue is reduced in decellularized xenogeneic and absent in decellularized allogeneic heart valves. Int J Artif Organs. 2015; 38 (4): 199–209. doi: 10.5301/ijao.5000395.Gates KV, Xing Q, Griffiths LG. Immunoproteomic identification of noncarbohydrate antigens eliciting graftspecific adaptive immune responses in patients with bovine pericardial bioprosthetic heart valves. Proteomics Clin Appl. 2019; 13 (4): e1800129. doi: 10.1002/prca.201800129.Gates KV, Xing Q, Griffiths LG. Immunoproteomic identification of noncarbohydrate antigens eliciting graftspecific adaptive immune responses in patients with bovine pericardial bioprosthetic heart valves. Proteomics Clin Appl. 2019; 13 (4): e1800129. doi: 10.1002/prca.201800129.Костюнин АЕ, Глушкова ТВ, Резвова МА, Клышников КЮ, Онищенко ПС, Овчаренко ЕА. N-гликолилнейраминовая кислота как возможный триггер иммунного отторжения эпоксиобработанных ксеноперикардиальных биопротезов клапанов сердца. Комплексные проблемы сердечно-сосудистых заболеваний. 2023; 12 (3): 173–180. doi: 10.17802/2306-1278-2023-12-3-173-180.Kostyunin AE, Glushkova TV, Rezvova MA, Klyshnikov KYu, Onishchenko PS, Ovcharenko EA. N-glycolylneuraminic acid as a possible trigger for immune rejection of epoxy-treated xenopericardial heart valve bioprostheses. Complex Issues of Cardiovascular Diseases. 2023; 12 (3): 173–180. (In Russ.). doi: 10.17802/2306-1278-2023-12-3-173-180.Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD et al. QuPath: Open source software for digital pathology image analysis. Sci Rep. 2017; 7 (1): 16878. doi: 10.1038/s41598-017-17204-5.Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD et al. QuPath: Open source software for digital pathology image analysis. Sci Rep. 2017; 7 (1): 16878. doi: 10.1038/s41598-017-17204-5.Mukhamadiyarov RA, Bogdanov LA, Glushkova TV, Shishkova DK, Kostyunin AE, Koshelev VA et al. EMbedding and backscattered scanning electron microscopy: a detailed protocol for the whole-specimen, high-resolution analysis of cardiovascular tissues. Front Cardiovasc Med. 2021; 8: 739549. doi: 10.3389/fcvm.2021.739549.Mukhamadiyarov RA, Bogdanov LA, Glushkova TV, Shishkova DK, Kostyunin AE, Koshelev VA et al. EMbedding and backscattered scanning electron microscopy: a detailed protocol for the whole-specimen, high-resolution analysis of cardiovascular tissues. Front Cardiovasc Med. 2021; 8: 739549. doi: 10.3389/fcvm.2021.739549.Human P, Zilla P. Characterization of the immune response to valve bioprostheses and its role in primary tissue failure. Ann Thorac Surg. 2001; 71 (5 Suppl): S385– S388. doi: 10.1016/s0003-4975(01)02492-4.Human P, Zilla P. Characterization of the immune response to valve bioprostheses and its role in primary tissue failure. Ann Thorac Surg. 2001; 71 (5 Suppl): S385– S388. doi: 10.1016/s0003-4975(01)02492-4.Lila N, McGregor CG, Carpentier S, Rancic J, Byrne GW, Carpentier A. Gal knockout pig pericardium: new source of material for heart valve bioprostheses. J Heart Lung Transplant. 2010; 29 (5): 538–543. doi: 10.1016/j.healun.2009.10.007.Lila N, McGregor CG, Carpentier S, Rancic J, Byrne GW, Carpentier A. Gal knockout pig pericardium: new source of material for heart valve bioprostheses. J Heart Lung Transplant. 2010; 29 (5): 538–543. doi: 10.1016/j.healun.2009.10.007.McGregor CG, Carpentier A, Lila N, Logan JS, Byrne GW. Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves. J Thorac Cardiovasc Surg. 2011; 141 (1): 269–275. doi: 10.1016/j.jtcvs.2010.08.064.McGregor CG, Carpentier A, Lila N, Logan JS, Byrne GW. Cardiac xenotransplantation technology provides materials for improved bioprosthetic heart valves. J Thorac Cardiovasc Surg. 2011; 141 (1): 269–275. doi: 10.1016/j.jtcvs.2010.08.064.

The authors declare that there are no conflicts of interest present.