Date Published: September 01, 2016
Author(s): Christopher McGregor, Guerard Byrne, Benyamin Rahmani, Elisa Chisari, Konstantina Kyriakopoulou, Gaetano Burriesci.
Humans make high levels of antibody to carbohydrates with terminal galactose α 1,3 galactose (Gal) modifications. This Gal antigen is widely expressed in other mammals and is present on an array of current animal derived biomedical devices including bioprosthetic heart valves. There is growing interest in using Gal-free animal tissues from Gal knockout pigs (GTKO) as these tissues would not be affected by anti-Gal antibody mediated injury. In this study we compare the composition and biophysical characteristics of glutaraldehyde fixed porcine pericardium from standard and GTKO pigs. We show that with the exception of the Gal antigen which is only present in standard pig tissue both GTKO and standard pig tissue have the same general morphology and collagen content. Moreover uniaxial stress testing and suture retention testing indicate the tissues are equivalent in tensile strength. These studies indicate that genetic disruption of the α-galactosyltransferase (GGTA-1) which blocks synthesis of the Gal antigen has no significant impact on the structural integrity of porcine pericardium and suggest that this tissue could be directly substituted for standard pig pericardium in biomedical devices such as bioprosthetic heart valves.
Surgical heart valve replacement is a proven life saving therapy to treat heart valve dysfunction due to birth defects, infection and the effects of aging. Bioprosthetic heart valves (BHV) made from glutaraldehyde fixed animal tissues are an effective durable therapy in older patients (>60 years) but exhibit age-dependent structural valve degeneration (SVD) in younger patients (<60 years). SVD is principally caused by BHV calcification. Immune injury contributes to age-dependent SVD through the interaction of galactose α 1,3 galactose (Gal) a dominant xenogeneic antigen present on commercial BHVs and universally abundant human anti-Gal antibody. This study measures the tissue equivalency between standard pig pericardium and Gal-free pericardium from genetically modified pigs as a first step towards making Gal-free BHVs.
Bioprosthetic heart valves (BHVs) have been produced from bovine and porcine tissues for over 50 years. These devices have been very successful as valve replacement therapy to treat heart valve disease and recent trends show a significant shift towards their use compared to mechanical heart valves (MHVs) . BHVs have better hemodynamic properties compared to MHVs and generally do not require chronic anticoagulant therapy which is necessary for MHVs . Nevertheless, despite more than half a century of extensive scientific and clinical investigations, current BHVs remain associated with limited durability due to structural valve degeneration (SVD) caused by dystrophic calcification, inflammation, and leaflet tearing resulting in failure of the prosthesis. The frequency of SVD is not constant but is strongly affected by patient age . At 15 years post-surgery 60–70% of older patients (>75 years) have freedom from SVD. This falls to 55% in patients aged 60–75 years. Up to 100% of BHVs fail within 5 years in patients <35 years of age . This study was designed to compare the composition and physical characteristics of WT and GTKO fixed porcine pericardium to test for physical equivalence. The mutation of the GGTA-1 gene in GTKO pigs only affects the terminal addition of alpha 1,3 linked galactose to lactosamine. This change would not be expected to substantially affect the physical properties of the tissue and we find no evidence that WT and GTKO pericardium exhibit a compositional change, other than the absence of the Gal antigen in GTKO pericardium, or any differences in the tensile stress properties of the fixed tissue. Similarly bovine pericardium and porcine swine intestine submucosa treated with alpha-galactosidase or in some instances decellularized by detergent extraction have also been reported to show elimination of the Gal antigen and physical equivalence to untreated tissue , ,  further supporting our finding that the genetic elimination of Gal does not significantly alter pericardial tissue integrity. The authors do not have any conflict of interest to disclose. Source: http://doi.org/10.1016/j.actbio.2016.06.007