Stenotic aortic valves have dysfunctional mechanisms of anti-inflammation: Implications for aortic stenosis

ObjectiveAortic stenosis is an inflammatory disease, associated with increased tissue levels of interleukin-1 beta. We hypothesized that the antagonist of interleukin-1 beta, interleukin-1 receptor antagonist, is deficient in aortic valves and that its production by aortic valve interstitial cells is less in cells from stenotic valves than from controls.MethodsValve leaflets from stenotic aortic valves (n = 6) and from valves from hearts explanted at the time of cardiac transplantation (n = 6) were studied by immunostaining for interleukin-1 receptor antagonist. Aortic valve interstitial cells were isolated from valves, and receptor antagonist levels were determined from cell lysates (enzyme-linked immunosorbent assay). Osteogenic phenotype changes in valve cells stimulated by toll-like receptors 2 and 4 were determined by immunoblotting for bone morphogenetic protein-2 after treatment with and without interleukin-1 receptor antagonist (100 μg/mL). Statistics were by analysis of variance.ResultsInterleukin-1 receptor antagonist was abundant in nonstenotic aortic valve leaflets and virtually absent in leaflets from stenotic valves. Aortic valve interstitial cells from grossly normal leaflets produced significantly more receptor antagonist at baseline and in response to toll-like receptor 2 and 4 stimulation, than did cells from diseased valves (P < 0.05). Interleukin-1 receptor antagonist was able to significantly attenuate toll-like receptor 2, but not toll-like receptor 4, stimulated bone morphogenetic protein-2 production in aortic valve interstitial cells (P < .05).ConclusionsInterleukin-1 receptor antagonist–mediated mechanisms of anti-inflammation are dysfunctional in stenotic valves. We conclude that such impaired mechanisms of anti-inflammation may contribute to the pathogenesis of aortic stenosis.