Bioprosthetic valves and laudable inflammation?

from the University of Alberta (Canada) report a series of animal experiments designed to test the mythic role of gluteraldehyde in preventing recognition of bioprosthetic heart valve antigenicity with subsequent rejection and failure. Gluteraldehyde–cross-linked xenograft tissues (initially porcine) have been used in the manufacturing of stented (and now stentless) heart valves since 1970. Original theories for the clinical efficacy of gluteraldehyde were based on its ability to irreversibly cross-link collagen and thus to increase mechanical strength and durability over fresh untanned cardiovascular tissues. Porcine valve leaflets, bovine pericardium, equine pericardium, and bovine jugular vein, among other structures, have been treated this way for clinical applications. Since its introduction, however, limitations and unexpected consequences of gluteraldehyde and similar chemical treatments have been recognized clinically. As pointed out by the authors, durability is quite variable, tending to be better in older patients whereas younger patients suffer early deterioration, calcification, and fibrocalcific failure.2,3 The good news has been that the failures tend to be progressive rather than catastrophic, leading to semielective reoperations. Additionally, the xenograft bioprostheses have been extremely helpful in avoiding warfarin in the very young and the very old, reducing the risk of thromboembolism. The traditional explanation for the fibrocalcific degeneration of the nonvital gluteraldehyde-treated bioprosthetic heart valves has been a combination of physical and chemical effects leading to calcification and a fixation of the structural proteins that prevent protein recycling and renewal. Mechanical theories of fatigue-induced wear resulting in calcification have been proposed, especially along the flexion lines of the cusps. Others have proposed that the gluteraldehyde has serendipitously “masked” the antigenicity of xenograft proteins, retained cells, and cellular debris, thus prolonging the period to calcification. This well-designed series of studies buttresses other studies demonstrating that gluteraldehyde fixation does not eliminate antigenicity of bioprosthetic heart valves and that one of the primary causes of fibrocalcific failure is immune rejection.4–6 Important implications are in 4 areas: (1) proper assessment of durability and clinical performance of manufactured valve xenograft bioprostheses; (2) recognition of inflammation-driven calcification potential of all types of biological valves, including allografts (homografts), autografts, and new treatments of xenograft tissues designed to make available donor structural proteins for turnover (eg, decellularized xenograft valves); (3) choice of appropriate preclinical surgical implant test species to qualify biological tissues for implantation in humans; and (4) thorough failure modes and effects analysis driving regulatory end points and clinical qualification of new valve options, including new treatments of cross-linked xenograft valves, decellularized allograft/xenograft valves, and “tissueengineered” in vivo recellularized or bioreactor cell–seeded valves based on allograft or xenograft scaffolds.