ONSET AND PROGRESSION OF EXPERIMENTAL BIOPROSTHETIC HEART-VALVE CALCIFICATION

Abstract

Calcification, the major cause of bioprosthetic heart valve failures, is a serious clinical problem with uncertain pathogenesis. The progressive chemical and morphologic sequence of mineralization in glutaraldehyde-treated porcine aortic valve cusps implanted subcutaneously in rats was defined and the pathology and pathophysiology of calcification in subcutaneous implants were compared with that of orthotopic valve replacements in calves. Cusps were implanted subcutaneously in 3 wk old rats for 24 h to 18 wk. Cuspal Ca was 114 .+-. 18 .mu.g/mg of dry weight (mean .+-. SEM) at day 21 and 218 .+-. 6 at day 56 of implantation and unchanged thereafter. The earliest mineral deposits, noted at 48 h, were associated with devitalized porcine connective tissue cells, but by 7 days, mineral deposits also involved collagen bundles. Scanning electron microscopy with energy-dispersive X-ray analysis demonstrated predominant accumulation in the spongiosa with a spongiosa to fibrosa energy-dispersive X-ray analysis count ratio of Ca of 15 at 21 days. In stent-mounted glutaraldehyde-preserved porcine valves implanted in 5 calves as mitral replacements for 69 to 142 days, cuspal Ca was 86 .mu.g/mg (mean) (range 47-128). Calf implants also had cell oriented and collagen calcification predominating in the valvar spongiosa. In rat subcutaneous and calf mitral valve models, early diffuse calcific microcrystals evolved into confluent nodules that disrupted tissue architecture. Calcification of glutaraldehyde-preserved porcine aortic valves implanted subcutaneously in rats begins within 48 h. Earliest deposits are localized to residual porcine connective tissue cells, but later deposits also involve collagen fibrils. Mineralization is most prominent in the spongiosa. The pathology of calcification in rat subcutaneous implants and calf mitral replacements is comparable, suggesting a common pathophysiology. Calcific nodule formation most likely initiates clinical failures.