Enhanced Expression of Hemoglobin Scavenger Receptor is Associated With Aortic Valve Stenosis in Patients With Bicuspid Aortic Valve

Abstract

Recent studies suggest that intraleaflet hemorrhage is more common in bicuspid aortic valves (BAV) than in tricuspid valves (TAV), possibly contributing to the faster progression of aortic stenosis (AS) in BAV. Hemoglobin (Hb)-induced oxidative damage occurs via haptoglobin (Hp), which irreversibly binds extracorpuscular Hb, forming an Hp-Hb complex. In valve leaflets, this complex is cleared only by macrophages mediated by the CD163 receptor. Oxidative stress has also been implicated in AS progression. In this study, we examined the relationship between intraleaflet hemorrhage, oxidative stress, and CD163 expression in aortic valves from AS patients with TAV (n = 35) or BAV (n = 34). Valve specimens were collected during surgery. Immunohistochemistry was performed using antibodies against macrophages, glycophorin A (an erythrocyte membrane marker), CD31, CD163, and 4-hydroxy-2-nonenal (4-HNE), a marker of lipid peroxidation. Quantitative analysis showed that BAV specimens had significantly greater macrophage infiltration, glycophorin A, 4-HNE, microvessel density, and CD163-positive macrophages than TAV (all p <0.05). CD163-positive macrophage scores positively correlated with 4-HNE and glycophorin A areas (both p <0.0005). These results indicate a strong association between CD163 expression and both intraleaflet hemorrhage and lipid peroxidation. In conclusion, intraleaflet hemorrhage–associated oxidative stress may promote rapid AS progression in BAV patients.