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.
Highlights
Heart valve disorders are among the most common cardiovascular diseases
The Translink multicenter study was designed to investigate early and long-term humoral immune responses elicited by implanted aortic Bioprosthetic heart valves (BHVs) up to approximately 15 years postimplantation (Fig. 1a) and their clinical impact
The patients enrolled in groups B1 and B2 were followed by echocardiography for hemodynamic, leaflet function and calcification; blood samplings were taken to assess antibody responses against αGal and Neu5Gc (Fig. 1c)
Summary
Heart valve disorders are among the most common cardiovascular diseases. Aortic valve stenosis represents >40% of valvular heart diseases affecting 2% of the Western population[1]. SVD pathophysiology is mediated by progressive leaflet tissue stiffening and calcification, eliciting valve narrowing and/or leakage (stenosis/regurgitation)[5]. This is suggested to be initiated by passive accumulation of calcium or by an atherosclerotic-like process[5]. Tissues used for BHV production (bovine and equine pericardia or porcine aortic valve leaflets) contain diverse glycosphingolipids/glycoproteins[20] with Neu5Gc or αGal[21], in porcine heart valves[22]. Bovine pericardia express the highest levels of αGal/Neu5Gc-N-glycans[20] Both αGal and Neu5Gc are immunogenic, cannot be synthesized in humans each due to a specific gene inactivation and are suggested to impact transplant rejection risk[23] and BHV deterioration[24]
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