Features of IgG subclass deposition in the biological component of epoxy-treated xenogenic bioprosthetic heart valves

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

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

13. 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.

14. 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.

15. 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.

16. 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.

17. 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.

18. Rosales C. Fcγ receptor heterogeneity in leukocyte functional responses. Front Immunol. 2017; 8: 280. doi: 10.3389/fimmu.2017.00280.

19. 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.

20. 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.

21. 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.

22. 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.

23. 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.

24. 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.

25. 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.

26. 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.