Key result
End-stage stenotic aortic valves exhibited significantly increased apoptosis (40.7% vs 28.0%) and reduced proliferation (20.8% vs 30.1%) compared to mild-to-moderate sclerotic valves.
Cross-Sectional (n=30)
An imbalance between proliferation and apoptosis, along with cellular phenotypical shifts and matrix secretion, contributes to aortic valve stenosis and bioprosthesis degeneration, with FKBP12 expression suggesting potential therapeutic targets.
Suggests cell turnover imbalance as potential therapeutic target in aortic stenosis; hypothesis-generating and requires prospective validation before clinical consideration.
BACKGROUND: The pathomechanisms underlying aortic valve degeneration are incompletely understood. Therefore, the aim of our work was to assess the quantitative changes of proliferation and apoptosis accompanied by cellular phenotype alternations and matrix secretionin aortic sclerotic and stenotic valves and degenerative bioprostheses, as well as to detect the expression pattern of the rapamycin receptor FKBP12 across these three valve types. METHODS: Mild-to-moderate sclerotic and stenotic valves and degenerative bioprostheses from 30 patients (n = 10 per group) were collected at autopsy or by surgery. Ki67+, FKBP12+, alpha-actin+, HSP47+ and TUNEL+ apoptotic cells were analyzed by immunohistochemistry. RESULTS: The main finding was the reduced proliferation and increased apoptosis in stenotic valves (ST) compared to the sclerotic ones (SC) (proliferation: ST: 20.8 ± 2.0% vs. SC: 30.1 ±2.2%, apoptosis: ST: 40.7 ± 5.0% vs. SC: 28.0 ± 5.1%, p < 0.05, respectively). Analogical alternations were found in degenerative bioprostheses (BP) (proliferation: 4.8 ± 2.3%; apoptosis: 13.1 ± 6.8%). Corresponding changes were observed in the valve cellularity (ST: 893 ± 168, SC: 1034 ± 284, BP: 385 ± 179 cells/mm2, p < 0.05, respectively). The FKBP12 signaling was reduced in diseased valves and bioprostheses (ST: 28.1 ± 3.6%, SC: 42.2 ± 3.8%, BP: 5.8 ± 1.9%, p < 0.05, respectively). Further, the augmented alpha-actin expressionwas observed as the degenerative process progressed (ST: 30.3 ± 5.0%, SC: 22.6 ± 2.7%, BP:8.7 ± 4.0%, p < 0.05, respectively), followed by the upregulation of HSP47 (ST: 22.6 ± 2.8%,SC: 15.4 ± 2.1%, BP: 3.4 ± 1.0%, p < 0.05, respectively) and consecutive matrix accumulation. CONCLUSIONS: The imbalance between proliferation and apoptosis with cellular phenotypical shift and subsequent matrix secretion may contribute to aortic valve stenosis and bioprosthesis degeneration. The identification of FKBP12 expression may implicate potential therapeutic strategies.
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Tuleta et al. (2013) conducted a cross-sectional in Aortic valve degeneration (n=30). End-stage aortic valve stenosis vs. Mild-to-moderate aortic sclerosis was evaluated on Apoptosis rate (TUNEL+ cells) (p=<0.05). End-stage stenotic aortic valves exhibited significantly increased apoptosis (40.7% vs 28.0%) and reduced proliferation (20.8% vs 30.1%) compared to mild-to-moderate sclerotic valves.
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