Inflammatory and immune checkpoint markers are associated with the severity of aortic stenosis

Abstract

Objective: Aortic stenosis (AS) is a disease characterized by narrowing of the aortic valve (AV) orifice. In relation to this disease, the purpose of this study was to elucidate the relationships among factors such as expression of programmed cell death-1 ligand (PD-L1, which is the ligand of PD-1 protein; together, they play a central role in the inhibition of T lymphocyte function), clinicopathologic characteristics, infiltrating immune cells, and disease severity.Methods: We performed immunohistochemical analysis on the surgically-resected AVs of 53 patients with AS. We used the resultant data to identify relationships among PD-L1 expression, disease severity, and the infiltration of immune cells including cluster of differentiation (CD8)-positive T lymphocytes, cluster of differentiation 163 (CD163)-positive macrophages, and forkhead box protein 3 (FOXP3)positive regulatory T lymphocytes (Tregs).Results: PD-L1 expression in resected AVs was significantly associated with being nonsmoker, valve calcification, and the infiltration of CD8-positive T cells and CD163-positive macrophages. Disease severity and valve calcification were significantly associated with low infiltration of FOXP3-positive Tregs and high infiltration of CD8-positive T cells and CD163-positive macrophages. Moreover, calcified AVs with high PD-L1 expression showed active inflammation without FOXP3-positive Tregs but with high levels of CD8-positive T lymphocytes and CD163-positive macrophages.Conclusions: Immune cell infiltration in the AVs and expression of the immune checkpoint protein PD-L1 were associated with the calcification of AS and disease severity. (JTCVS Open 2021;5:1-12)High PD-L1 and active inflammation were associated with calcified AS.

Comparative analysis of calcified soft tissues revealed shared deregulated pathways

“…Furthermore, PD-L1 protein level was previously shown to be positively associated with aortic valve calcification ( Erkhem-Ochir et al, 2020 ). Here we show that CD274 (encodes PD-L1) was up-regulated with calcification grade in artery tibial and aorta, but not in coronary artery and pituitary.…”

Commentary: Suppressing the inflammatory response—can it be an alternative to surgical aortic valve replacement and transcatheter aortic valve replacement for patients with calcific aortic stenosis?

“…1 The expression of the immune checkpoint protein, programmed cell death 1 protein and its ligand (PD-L1) have been found to inhibit T cell receptor-mediated lymphocyte proliferation and cytokine secretory function. 2 In this issue of the Journal, Erkhem-Ochir and colleagues 3 report the results of an immunohistochemical analysis of aortic valve leaflets in 53 patients undergoing SAVR for severe AS to examine the association of PD-L1 expression and active inflammation in severe calcific AS. PD-L1 expression was significantly associated with infiltration of CD8 þ T lymphocytes and CD163 þ macrophages in aortic leaflet tissue.…”

“…In this issue of the Journal , Erkhem-Ochir and colleagues 3 report the results of an immunohistochemical analysis of aortic valve leaflets in 53 patients undergoing SAVR for severe AS to examine the association of PD-L1 expression and active inflammation in severe calcific AS. PD-L1 expression was significantly associated with infiltration of CD8 + T lymphocytes and CD163 + macrophages in aortic leaflet tissue.…”

Commentary: Immune cell infiltration in aortic stenosis: Cause or consequence?

“…In this issue of the Journal , Erkhem-Ochir and colleagues 2 attempted to shed light on the association of immune checkpoint markers with inflammatory infiltration and the progression of calcification of aortic valve leaflets. In their study of surgically resected aortic valve leaflets, they demonstrated an association between high levels of programmed death (PD) ligand 1 (PDL-1) expression, inflammation, and severity of leaflet calcification.…”