Enhanced expression of hemoglobin scavenger receptor and heme oxygenase-1 is associated with aortic valve stenosis in patients undergoing hemodialysis

A high prevalence and a rapid progression of aortic valve stenosis (AS) in patients undergoing hemodialysis (HD) has been reported. In these circumstances, intraleaflet hemorrhage of aortic valve may be related to the development of AS in HD patients. We immunohistochemically examined the relationship among intraleaflet hemorrhage, neovascularization, hemoglobin scavenger receptor (CD163), and heme oxygenase-1 (HO-1) using surgically resected aortic valve specimens from AS patients undergoing HD. The study population consisted of 26 HD patients and 25 non-HD patients with severe AS who had undergone aortic valve replacement. Frozen aortic valve samples surgically obtained from AS patients were stained immunohistochemically with antibodies against smooth muscle cells, macrophages, glycophorin-A (a protein specific to erythrocyte membranes), CD31, CD163, and HO-1. Morphometric analysis demonstrated that the CD163-positive macrophage score, the number of CD31-positive microvessels, and the percentage of glycophorin-A and HO-1-positive area were significantly higher in HD patients than in non-HD patients (CD163-positive macrophage score, P < 0.0001; CD31-positive microvessels, P < 0.0001; glycophorin-A, P < 0.0001; HO-1, P < 0.0001). Double immunostaining for CD163 or HO-1 and macrophages revealed that the majority of CD163-or HO-1-positive cells were macrophages. Furthermore, CD163-positive macrophage score was positively correlated with glycophorin-A, HO-1-positive area, and the number of CD31-positive microvessels (glycophorin-A, R = 0.66, P < 0.0001; HO-1, R = 0.50, P < 0.0005; microvessels, R = 0.38, P < 0.01). These findings suggest a positive association among intraleaflet hemorrhage, neovascularization, and enhanced expression of CD163 and HO-1 as a response to intraleaflet hemorrhage in stenotic aortic valves in AS patients undergoing HD.