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(Circulation. 2006;114:318-327.)
© 2006 American Heart Association, Inc.

Valvular Heart Disease

Glutaraldehyde-Fixed Bioprosthetic Heart Valve Conduits Calcify and Fail From Xenograft Rejection

Rizwan A. Manji, MD, PhD; Lin F. Zhu, MD; Nimrit K. Nijjar; David C. Rayner, MD; Greg S. Korbutt, PhD; Thomas A. Churchill, PhD; Ray V. Rajotte, PhD; Arvind Koshal, MD; David B. Ross, MD

From the Division of Cardiac Surgery (R.A.M., A.K., D.B.R.), the Surgical-Medical Research Institute (R.A.M., L.F.Z., N.K.N., G.S.K., T.A.C., R.V.R.), and the Department of Pathology (D.C.R.), University of Alberta, Edmonton, Canada.

Correspondence to Rizwan A. Manji, MD, PhD, 2D4.37 Walter MacKenzie Health Sciences Centre, 8440 112th St, Edmonton, Alberta, Canada, T6G 2B7. E-mail rizmanji{at}shaw.ca

Received March 18, 2005; revision received April 26, 2006; accepted May 4, 2006.

Background— Glutaraldehyde fixation (G-F) decreases but likely does not eliminate the antigenicity of bioprosthetic heart valves. Rejection (with secondary dystrophic calcification) may be why G-F xenograft valves fail, especially in young patients, who are more immunocompetent than the elderly. Therefore, we sought to determine whether rejection of G-F xenograft occurs and to correlate this with graft calcification.

Methods and Results— Ascending aortas/valves (from rats [syngeneic] or guinea pigs [xenogeneic]) were transplanted (fresh or after 48 hour of G-F) into the infrarenal aortas of young rat recipients for 20 days. A xenogeneic group was also treated with steroids until graft harvest. The valves and media/adventitia were scored blindly for inflammation (0 to 4). Percent graft infiltration by T cells/macrophages was determined (immunohistochemistry), and rat IgG ELISAs were performed. There was >3 times more valve inflammation, >10 times more valve T-cell/macrophage infiltrate, and >3 times antibody rise in the G-F xenogeneic groups compared with the fresh syngeneic or the G-F syngeneic groups (P<0.05). There was >2 times more adventitial inflammation and T-cell/macrophage infiltrate in the xenogeneic groups (P<0.05). Steroid treatment decreased inflammation and antibody rise in the xenogeneic groups (P<0.05). Correlation analysis revealed media/adventitia inflammation (P=0.02) and percent macrophage (P=0.01) infiltration to be predictors of calcification.

Conclusions— G-F xenografts have cellular/humoral rejection and calcify secondarily.

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