Abstract
Bioprosthetic heart valve calcification may result from interactions between the host's immune system and the glutaraldehyde (GA)-fixed tissue that makes up the leaflets. We hypothesized that antagonizing interleukin-8 (IL-8) receptors, CXCR-1 and CXCR-2, may prevent the calcification of GA-fixed porcine aortic valves implanted subcutaneously in rats. Three-week-old Sprague Dawlay males were transplanted with 2 aortic valve leaflets isolated from pigs and implanted into the dorsal wall. Four groups of 3–4 rats (6–8 independent leaflets each time) were compared: glutaraldehyde (GA)-free leaflets, GA-fixed leaflets (0.6% GA for 24 h before implantation), GA-fixed leaflets and treatment of rats with 1 mg/kg SCH5217123 (a CXCR1/2 antagonist) injected once a day locally subcutaneously (SC) or intraperitoneally (IP). Fourteen days later, rats underwent blood leukocyte count and CT-scan, before porcine leaflets explantation and histology and biochemistry analyses. As expected, strong calcification of ectopic valves was induced by the GA. However, we observed a significant about 40% decrease in this effect when rats were treated with the SCH527123. These effects were confirmed by CT-scan acquisitions and Alizarin red staining of valves. Besides, GA pre-incubation of valves significantly increased leukocytes count in rat blood, an effect that is significantly prevented by IP SCH527123 (6.9, 16.6 and 6.8 × 10 9 /L in the GA-free, GA and GA + IP SCH527123 groups respectively, P = 0.0129). Immunohistochemistry of ectopic valves highlighted higher infiltration of CD3 (lymphocytes) and CD68 (macrophages) cells in the GA group compared to the GA-free and GA + SCH527123 groups. Therefore, the calcification of GA-fixed porcine aortic valve leaflets, implanted subcutaneously in rats, is significantly prevented by antagonizing IL-8 receptors with SCH527123. This effect might partly result from an inhibition of the GA-induced leukocytes activation and recruitment into the graft tissue.
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