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

Outcomes research; Risk factorsInvestigación de resultados; Factores de riesgoRecerca dels resultats; Factors de riscBioprosthetic 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.This work was supported by the European Union Seventh Framework Program (FP7/2007/2013) under grant agreement no. 603049 for the Translink Consortium. This research was also funded by a European Union H2020 Program grant no. ERC-2016-STG-716220 to V.P-K. and by the Elizabeth and Nicholas Slezak Super Center for Cardiac Research and Medical Engineering (to V.P-K.). This work was supported by an Institut National de la Santé et de la Recherche Médicale translational grant no. 2012-2016 to T.L.T. This work was supported by the Ministerio de Economía y Competitividad-ISCiii (PI15/00181) and the PERIS SLT002/16/00445 funded by the Department of Health of Generalitat de Catalunya (both granted to C.C.), and cofunded by FEDER (European Regional Development Fund), a way to build Europe. This work was supported by an Israel Ministry of Science & Technology PhD fellowship to S.B. We thank L. Adler for her assistance in the affinity purification of anti-Neu5Gc antibodies and IgG subclass analysis. Finally, we thank N. Bovin from the Shemyakin–Ovchinnikov Institute of Bioorganic Chemistry, who provided the Bdi-C3 PAA substrate needed to develop the anti-αGal assays

Response of the human myocardium to ischemic injury and preconditioning: The role of cardiac and comorbid conditions, medical treatment, and basal redox status

Vàlvula aòrtica; Isquèmia; MiocardiVálvula aórtica; Isquemia; MiocardioAortic valve; Ischemia; MyocardiumBackground The diseased human myocardium is highly susceptible to ischemia/reoxygenation (I/R)-induced injury but its response to protective interventions such as ischemic preconditioning (IPreC) is unclear. Cardiac and other pre-existing clinical conditions as well as previous or ongoing medical treatment may influence the myocardial response to I/R injury and protection. This study investigated the effect of both on myocardial susceptibility to I/R-induced injury and the protective effects of IPreC. Methods and results Atrial myocardium from cardiac surgery patients (n = 300) was assigned to one of three groups: aerobic control, I/R alone, and IPreC. Lactate dehydrogenase leakage, as a marker of cell injury, and cell viability were measured. The basal redox status was determined in samples from 90 patients. The response to I/R varied widely. Myocardium from patients with aortic valve disease was the most susceptible to injury whereas myocardium from dyslipidemia patients was the least susceptible. Tissue from females was better protected than tissue from males. Myocardium from patients with mitral valve disease was the least responsive to IPreC. The basal redox status was altered in the myocardium from patients with mitral and aortic valve disease. Conclusions The response of the myocardium to I/R and IPreC is highly variable and influenced by the underlying cardiac pathology, dyslipidemia, sex, and the basal redox status. These results should be taken into account in the design of future clinical studies on the prevention of I/R injury and protection.This study was supported by the Instituto de Salud Carlos III (FIS) [grant number 12/00119]