Tagged: Immunology

Current bioprosthetic heart valves substitutes: 100% biocompatible?

shutterstock_153833795

Over 400.000 heart valves are replaced worldwide every year. Distrophic calcification and inflammation lead these prostheses to failure in the middle-long term in over 50% of patients, especially in the youngers that require recurrent re-operations [1]. When an aortic valve must be replaced, 80% of the times a biological heart valve substitute (BHVs) is used. These valves are engineered using porcine aortic valves or pericardium from different animal species like pig, sheep and horse that is properly assembled to build a prosthesis. Biological valves are of course different from mechanical valves that are made of pyrolytic carbon or other different materials.

BHVs are subjected to a treatment, called fixation, before being commercialised and implanted into humans. This process, performed with a chemical agent named glutaraldehyde (GLU), is fundamental for many reasons, for example in order to increase tissue mechanical strength, to sterilize the prostheses and preserve it prior to use but mainly to act as a shield for molecules that, if not suitably inactivated, cause a rejection of implanted tissue. Despite its importance, GLU is not able to mask completely these molecules and in the mid-long term it faces a chemical binding degeneration due to the mechanical stress to which bioprostheses are subject when implanted and put into operation. Multiple factors lead to the replacement of GLU-treated BHVs approx. after 10 years following the original implant due to tissue calcification and consequent stenosis of the valve, i.e. a narrowing of the internal diameter of the valve preventing an effective blood flow. BHVs degeneration was recently confirmed to be correlated to GLU masking efficiency of xenogeneic tissues which contain proteins, sugars and molecules that are proper of derivation species, whose complete elimination or inactivation is necessary to meet the requirements for clinical use. Particularly, the residual presence of a specific molecule called alpha-Gal (epitope), significantly increases the level of antibodies against galactose, starting from day 10 following BHV implantation, reaching a maximum peak at around 3 months after it [3].

This sugar moiety is expressed in most mammalian tissues, except humans and higher primates. In humans, continuous antigenic stimulation by the gastrointestinal flora (expressing the epitope) ends with the production of anti-alpha-Gal antibodies accounting for 1-3% of the total amount in the blood stream. A new developed test demonstrated that around 30% of alpha-Gal epitopes in BHVs are still reactive even after fixation with GLU, prior to be implanted. It’s likely the time to try to produce alpha-Gal free BHVs that are likely to longer-lasting, resulting in a better quality of life for patients. The removal of the alpha-Gal molecules detected in a tissue might also provide new insight of deleterious effects possibly related to the presence of secondary substances whose role is currently overshadowed by the preponderant reactions of the alpha-Gal [4].

_____________________________________

References:

1. Zilla P et al. – Prosthetic heart valves: catering for the few. Biomaterials 2008;29(4):385-406.

2. Bloch O et al. – Immune response in patients receiving a bioprosthetic heart valve: lack of response with decellularized valves. Tissue Eng Part A 2011;17(19-20):2399-2405.

3. Naso F et al. – First quantitative assay of alpha-Gal in soft tissues: presence and distribution of the epitope before and after cell removal from xenogeneic heart valves. Acta Biomater. 2011;7(4):1728-1734.

4. Naso F et al. – First quantification of alpha-Gal epitope in current glutaraldehyde-fixed heart valve bioprostheses. Xenotransplantation. 2013;20(4):252-261.