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The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration

Thomas Senage 1, 2 Anu Paul 3, 4 Thierry Le Tourneau 1 Imen Fellah-Hebia 1 Marta Vadori 5 Salam Bashir 3 Manuel Galiñanes 6 Tomaso Bottio 7 Gino Gerosa 5 Arturo Evangelista 8 Luigi Badano 9, 10 Alberto Nassi 7 Cristina Costa 11 Galli Cesare 12 Rizwan Manji 13 Caroline Cueff de Monchy 1 Nicolas Piriou 1 Romain Capoulade 1 Jean-Michel Serfaty 1 Guillaume Guimbretière 1 Etienne Dantan 2 Alejandro Ruiz-Majoral 11 Guénola Coste Du Fou 1 Shani Leviatan Ben-Arye 3 Liana Govani 3 Sharon Yehuda 3 Shirley Bachar Abramovitch 3 Ron Amon 3 Eliran Moshe Reuven 3 Yafit Atiya-Nasagi 3, 14 Hai Yu 15 Laura Iop 7 Kelly Casós 6, 16 Sebastián Kuguel 16 Arnau Blasco-Lucas 6, 11 Eduard Permanyer 6, 17 Fabrizio Sbraga 11 Roger Llatjós 11 Gabriel Moreno-Gonzalez 11, 16 Melchor Sánchez-Martínez 18, 19 Michael Breimer 20 Jan Holgersson 20 Susann Teneberg 20 Marta Pascual-Gilabert 21 Alfons Nonell-Canals 18, 22 Yasuhiro Takeuchi 23 Xi Chen 15 Rafael Mañez 16, 24 Jean-Christian Roussel 1, * Jean-Paul Soulillou 25, * Emanuele Cozzi 7, * Vered Padler-Karavani 3, * 
Abstract : Abstract Bioprosthetic heart valves (BHVs) are commonly used to replace severely diseased heart valves but their susceptibility to structural valve degeneration (SVD) limits their use in young patients. We hypothesized that antibodies against immunogenic glycans present on BHVs, particularly antibodies against the xenoantigens galactose-α1,3-galactose (αGal) and N -glycolylneuraminic acid (Neu5Gc), could mediate their deterioration through calcification. We established a large longitudinal prospective international cohort of patients ( n = 1668, 34 ± 43 months of follow-up (0.1–182); 4,998 blood samples) to investigate the hemodynamics and immune responses associated with BHVs up to 15 years after aortic valve replacement. Early signs of SVD appeared in <5% of BHV recipients within 2 years. The levels of both anti-αGal and anti-Neu5Gc IgGs significantly increased one month after BHV implantation. The levels of these IgGs declined thereafter but anti-αGal IgG levels declined significantly faster in control patients compared to BHV recipients. Neu5Gc, anti-Neu5Gc IgG and complement deposition were found in calcified BHVs at much higher levels than in calcified native aortic valves. Moreover, in mice, anti-Neu5Gc antibodies were unable to promote calcium deposition on subcutaneously implanted BHV tissue engineered to lack αGal and Neu5Gc antigens. These results indicate that BHVs manufactured using donor tissues deficient in αGal and Neu5Gc could be less prone to immune-mediated deterioration and have improved durability.
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https://www.hal.inserm.fr/inserm-03580771
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Submitted on : Friday, February 18, 2022 - 5:16:04 PM
Last modification on : Thursday, September 1, 2022 - 11:10:07 AM

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Thomas Senage, Anu Paul, Thierry Le Tourneau, Imen Fellah-Hebia, Marta Vadori, et al.. The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration. Nature Medicine, Nature Publishing Group, 2022, Online ahead of print. ⟨10.1038/s41591-022-01682-w⟩. ⟨inserm-03580771⟩

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