Cellular senescence evaluated by P16INK4a immunohistochemistry is a prevalent phenomenon in advanced calcific aortic valve disease

Background: Fibrosis, calcification, and ossification are histopathologic hallmarks of calcific aortic valve disease (CAVD), a leading cause of morbidity and mortality in the aging population. Cellular senescence contributes to a functional decay in chronic diseases by intensifying tissue remodeling and impairing tissue regeneration. We evaluated the expression of P16(INK4A) and P53 as surrogate markers of senescence in CAVD. Methods: Aortic valves from 27 individuals with severe CAVD requiring aortic valve replacement were selected for routine histologic processing. Immunohistochemical expression of P16(INK4A) and P53 was quantified using computerized image analysis on fields matching compartments with varying degrees of tissue remodeling. Results: All aortic valves demonstrated P16(INK4A) and P53-positive cells. The percentage of P16(INK4A)-positive cells, but not of P53, was higher in areas of calcification and/or ossification (57.21%+/- 26.31, n = 40) and severe fibrosis (54.79%+/- 27.19, n = 25) than in areas with minimal to mild tissue remodeling (13.69% +/- 11.88, n = 16, P < .0001). P16(INK4A) expression was observed in interstitial valve cells within all compartments proportional to the degree of fibrosis and did not correlate with age, severity of aortic stenosis, or P53 expression. Multiple linear regression analysis by backward elimination revealed P16(INK4A) expression was lower among statin users (P < .01). Conclusions: P16(INK4A)-expression is ubiquitous in calcified aortic valves and correlates with severity of tissue remodeling, suggesting a role of cellular senescence in the progression of CAVD. Further research is needed to identify possible treatment modalities as disease modifying agents for CAVD. (C) 2021 Elsevier Inc. All rights reserved.