Background: The mechanisms responsible for the more rapid progression of aortic stenosis (AS) in patients with bicuspid aortic valve (BAV) than in those with tricuspid aortic valve (TAV) are unknown. Neopterin, a by-product of the guanosine triphosphate pathway, is produced by activated macrophages on stimulation by interferon-γ from T-lymphocytes and is capable of enhancing the oxidative potential of reactive oxygen species. To elucidate the role of neopterin in the aortic valve of AS patients with BAV, we immunohistochemically studied the presence of neopterin in aortic valve specimens from AS patients with either TAV or BAV.
Methods: Frozen aortic valve samples were obtained surgically from AS patients with TAV (n=34) or BAV (n=34) and stained with antibodies against macrophages, T-lymphocytes, neopterin and 4-HNE (4-hydroxy-2-nonenal), an index of lipid peroxidation. The immunoreactivity of macrophages, T-lymphocytes, neopterin and 4-HNE was quantified using computer-aided planimetry. To identify the cell type that stained positive for neopterin, double immunostaining was also performed.
Results: Quantitative analysis demonstrated that the macrophage-, neopterin-, and 4-HNE-positive areas and number of T-lymphocytes were significantly higher in AS patients with BAV than with TAV (macrophage, P<0.005; neopterin, P<0.0001; 4-HNE, P<0.05; T-lymphocyte, P<0.0001). The neopterin-positive area correlated positively with the number of T-lymphocytes (R=0.54, P<0.0001). In addition, the neopterin-positive area correlated positively with the 4-HNE -positive area (R=0.67, P<0.0001). To identify cell types of neopterin-positive cells, double immunostaining for neopterin and macrophages demonstrated that neopterin-positive cells were macrophages.
Conclusions: These findings indicate that neopterin in accumulated macrophages may increase oxidative stress and contribute to rapid progression of AS in BAV patients.