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

Thomas Senage, Anu Paul, Thierry Le Tourneau, Imen Fellah-Hebia, Marta Vadori, Salam Bashir, Manuel Galiñanes, Tomaso Bottio, Gino Gerosa, Arturo Evangelista, Luigi P. Badano, Alberto Nassi, Cristina Costa, Galli Cesare, Rizwan A. Manji, Caroline Cueff de Monchy, Nicolas Piriou, Romain Capoulade, Jean Michel Serfaty, Guillaume GuimbretièreEtienne Dantan, Alejandro Ruiz-Majoral, Guénola Coste du Fou, Shani Leviatan Ben-Arye, Liana Govani, Sharon Yehuda, Shirley Bachar Abramovitch, Ron Amon, Eliran Moshe Reuven, Yafit Atiya-Nasagi, Hai Yu, Laura Iop, Kelly Casós, Sebastián G. Kuguel, Arnau Blasco-Lucas, Eduard Permanyer, Fabrizio Sbraga, Roger Llatjós, Gabriel Moreno-Gonzalez, Melchor Sánchez-Martínez, Michael E. Breimer, Jan Holgersson, Susann Teneberg, Marta Pascual-Gilabert, Alfons Nonell-Canals, Yasuhiro Takeuchi, Xi Chen, Rafael Mañez*, Jean Christian Roussel*, Jean Paul Soulillou*, Emanuele Cozzi*, Vered Padler-Karavani*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)283-294
Number of pages12
JournalNature Medicine
Volume28
Issue number2
DOIs
StatePublished - Feb 2022

Funding

FundersFunder number
Seventh Framework Programme603049
European CommissionERC-2016-STG-716220
Institut national de la santé et de la recherche médicale2012-2016
Ministerio de Economía y CompetitividadPI15/00181, SLT002/16/00445
Seventh Framework ProgrammeFP7/2007/2013
Ministry of Science and Technology, Israel
Nicholas and Elizabeth Slezak Super Center for Cardiac Research and Biomedical Engineering
European Regional Development Fund
Departament de Salut, Generalitat de Catalunya

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