| 1. |
- Senage, T., et al.
(författare)
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The role of antibody responses against glycans in bioprosthetic heart valve calcification and deterioration
- 2022
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Ingår i: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 28, s. 283-294
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Tidskriftsartikel (refereegranskat)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-alpha 1,3-galactose (alpha Gal) 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-alpha Gal and anti-Neu5Gc IgGs significantly increased one month after BHV implantation. The levels of these IgGs declined thereafter but anti-alpha Gal 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 alpha Gal and Neu5Gc antigens. These results indicate that BHVs manufactured using donor tissues deficient in alpha Gal and Neu5Gc could be less prone to immune-mediated deterioration and have improved durability. In a large cohort of patients who underwent aortic valve replacement, antibody responses to glycans present in bioprosthetic heart valves, notably galactose-alpha 1,3-galactose and N-glycolylneuraminic acid, were implicated in valve calcification and deterioration.
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| 2. |
- Reuven, E. M., et al.
(författare)
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Characterization of immunogenic Neu5Gc in bioprosthetic heart valves
- 2016
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Ingår i: Xenotransplantation. - : Wiley. - 0908-665X. ; 23:5, s. 381-392
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Tidskriftsartikel (refereegranskat)abstract
- Background: The two common sialic acids (Sias) in mammals are N-acetylneuraminic acid (Neu5Ac) and its hydroxylated form N-glycolylneuraminic acid (Neu5Gc). Unlike most mammals, humans cannot synthesize Neu5Gc that is considered foreign and recognized by circulating antibodies. Thus, Neu5Gc is a potential xenogenic carbohydrate antigen in bioprosthetic heart valves (BHV) that tend to deteriorate in time within human patients. Methods: We investigated Neu5Gc expression in non-engineered animal-derived cardiac tissues and in clinically used commercial BHV, and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG. Results: Neu5Gc was detected by immunohistochemistry in porcine aortic valves and in porcine and bovine pericardium. Qualitative analysis of Sia linkages revealed Siaα2-3>Siaα2-6 on porcine/bovine pericardium while the opposite in porcine aortic/pulmonary valve cusps. Similarly, six commercial BHV containing either porcine aortic valve or porcine/bovine/equine pericardium revealed Siaα2-3>Siaα2-6 expression. Quantitative analysis of Sia by HPLC showed porcine/bovine pericardium express 4-fold higher Neu5Gc levels compared to the porcine aortic/pulmonary valves, with Neu5Ac at 6-fold over Neu5Gc. Likewise, Neu5Gc was expressed on commercial BHV (186.3±16.9 pmol Sia/μg protein), with Neu5Ac at 8-fold over Neu5Gc. Affinity-purified human anti-Neu5Gc IgG showing high specificity toward Neu5Gc-glycans (with no binding to Neu5Ac-glycans) on a glycan microarray, strongly bound to all tested commercial BHV, demonstrating Neu5Gc immune recognition in cardiac xenografts. Conclusions: We conclusively demonstrated Neu5Gc expression in native cardiac tissues, as well as in six commercial BHV. These Neu5Gc xeno-antigens were recognized by human anti-Neu5Gc IgG, supporting their immunogenicity. Altogether, these findings suggest BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration warranting further investigation. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
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| 4. |
- Kienle, GS, et al.
(författare)
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Contributing to Global Health: Development of a Consensus-Based Whole Systems Research Strategy for Anthroposophic Medicine
- 2019
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Ingår i: Evidence-based complementary and alternative medicine : eCAM. - : Hindawi Limited. - 1741-427X .- 1741-4288. ; 2019, s. 3706143-
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Tidskriftsartikel (refereegranskat)abstract
- Background. Whole medicine and health systems like traditional and complementary medicine systems (T&CM) are part of healthcare around the world. One key feature of T&CM is its focus on patient-centered and multimodal care and the integration of intercultural perspectives in a wide range of settings. It may contribute to good health and well being for people as part of the Sustainable Development Goals of the United Nations. The authentic, rigorous, and fair evaluation of such a medical system, with its inherent complexity and individualization, imposes methodological challenges. Hence, we propose a broad research strategy to test and characterize its possible contribution to health. Methods. To develop a research strategy for a specific T&CM system, Anthroposophic Medicine (AM), applying multimodal integrative healthcare based on a four-level concept of man, we used a three-phase consensus process with experts and key stakeholders, consisting of (1) premeeting methodological literature and AM research review and interviews to supplement or revise items of the research strategy and tailor them to AM research, (2) face-to-face consensus meetings further developing and tailoring the strategy, and (3) postmeeting feedback and review, followed by finalization. Results. Currently, AM covers many fields of medical specialties in varied levels of healthcare settings, such as outpatient and inpatient; primary, secondary, and tertiary care; and health education and pedagogy. It is by definition integrated with conventional medicine in the public healthcare system. It applies specific medicines, nursing techniques, arts therapies, eurythmy therapy, rhythmical massage, counseling, and psychotherapy, and it is provided by medical doctors, nurses, therapists, midwives, and nutritionists. A research strategy authentic to this level of complexity should comprise items with a focus on (I) efficacy and effectiveness, divided into (a) evaluation of the multimodal and multidisciplinary medical system as a whole, or of complex multimodal therapy concept, (b) a reasonable amount of methodologically rigorous, confirmatory randomized controlled trials on exemplary pharmacological and nonpharmacological therapies and indications, (c) a wide range of interventions and patient-centered care strategies with less extensive formats like well-conducted small trails, observational studies, and high-quality case reports and series, or subgroup analyses from whole-system studies, or health service research; (II) safety; (III) economics; (IV) evidence synthesis; (V) methodologic issues; (VI) biomedical, physiological, pharmacological, pharmaceutical, psychological, anthropological, and nosological issues as well as innovation and development; (VI) patient perspective and involvement, public needs, and ethics; (VII) educational matters and professionalism; and (IX) disease prevention, health promotion, and public health. Conclusion. The research strategy extends to and complements the prevailing hierarchical system by introducing a broad “evidence house” approach to evaluation, something many health technology assessment boards today support. It may provide transparent and comprehensive insight into potential benefits or risks of AM. It can serve as a framework for an evidence-informed approach to AM for a variety of stakeholders and collaborating networks with the aim of improving global health.
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