2013 - IXA 2013 Congress


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Early Morning Workshop 3: Strategies for Overcoming Xenograft Loss

36.3 - Xenograft Rejection of Bioprosthetic Heart Valves

Presenter: Rizwan A., Manji, Blacksburg, Canada
Authors:

 

Xenograft rejection of bioprosthetic heart valves

Rizwan A. Manji (1), Alan H. Menkis (1), David K.C. Cooper (2)

(1) Cardiac Sciences Program, Winnipeg Regional Health Authority and Department of Surgery, University of Manitoba, Winnipeg, Manitoba, Canada

(2) Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA

There is no “ideal” valve for children and young adults who need heart valve replacement.  The two primary heart valve substitutes are mechanical heart valves (MHV) or gluteraldehyde-fixed bioprosthetic heart valves (GBHV).  MHV have long-term durability but patients have a 1-2% per year cumulative risk of bleeding or thrombosis related to the mandatory anticoagulation that is required.  Thus, a 25 year-old patient with a MHV has a 50-100% chance of a major complication (which may be fatal) related to anticoagulation by the age of 75 years.  

GBHV are porcine heart valves or bovine pericardium fashioned into valves that have been gluteraldehyde-fixed to preserve the valve and decrease antigenicity. GBHV do not require anticoagulation, but suffer from poor durability, especially in children and young adults where a GBHV will fail within a matter of months to a few years. This was thought to be related to the more active calcium metabolism in these age groups. Such patients will need repeated valve replacements, each with a 2 to 3-fold greater risk than the primary operation.

The poor durability of a GBHV is related to structural valve deterioration, largely due to calcification of the valve, which leads to narrowing of the valve and/or tearing of the cusps.  The standard belief is that calcification and structural valve deterioration is a chemical process related to the effect of gluteraldehyde on the valve, calcium ions in the blood, and “wear and tear”.  However, GBHV are a form of xenotransplantation, and increasing evidence is emerging that they generate an immune response (xenograft rejection).

We will review some of the histological and immunohistological studies indicating that there is an immune response (both humoral and cellular) to a GBHV, and demonstrate that the problem of calcification of the valves is related to the inflammatory response.  We will review the potential importance of galactose-α1,3-galactose (α-Gal) and non-Gal antigens (e.g., N-glycolylneuraminic acid) in the failure of a GBHV, and discuss the promise of genetically-modified pigs that may one day provide the “ideal” heart valve for patients (both young and old) needing valve replacement. If genetically-modified pigs can provide valves that stimulate no (or a less intense) immune response, this will be paradigm-shifting in the world of cardiac surgery.


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