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ApoC-III is a novel inducer of calcification in human aortic valves.

ABSTRACT: Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein-lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker.

SUBMITTER: Schlotter F

PROVIDER: S-EPMC7948477 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Calcific aortic valve disease (CAVD) is an inexorably degenerative pathology characterized by progressive calcific lesion formation on the valve leaflets. The interaction of valvular cells in advanced lesion environments is not well understood yet highly relevant as clinically detectable CAVD exhibits calcifications composed of non-stoichiometric hydroxyapatite (HA). In this study, Fourier transform infrared spectroscopic imaging was used to spatially analyze mineral properties as a function of disease progression. Crystallinity (size and perfection) increased with increased valve calcification. To study the relationship between crystallinity and cellular behavior in CAVD, valve cells were seeded into 3D mineral-rich collagen gels containing synthetic HA particles, which had varying crystallinities. Lower crystallinity HA drove myofibroblastic activation in both valve interstitial and endothelial cells, as well as osteoblastic differentiation in interstitial cells. Additionally, calcium accumulation within gels depended on crystallinity, and apoptosis was insufficient to explain differences in HA-driven cellular activity. The protective nature of endothelial cells against interstitial cell activation and calcium accumulation was completely inhibited in the presence of less crystalline HA particles. Elucidating valve cellular behavior post-calcification is of vital importance to better predict and treat clinical pathogenesis, and mineral-containing hydrogel models provide a unique 3D platform to evaluate valve cell responses to a later stage of valve disease.Statement of significanceWe implement a 3D in vitro platform with embedded hydroxyapatite (HA) nanoparticles to investigate the interaction between valve interstitial cells, valve endothelial cells, and a mineral-rich extracellular environment. HA nanoparticles were synthesized based on analysis of the mineral properties of calcific regions of diseased human aortic valves. Our findings indicate that crystallinity of HA drives activation and differentiation in interstitial and endothelial cells. We also show that a mineralized environment blocks endothelial protection against interstitial cell calcification. Our HA-containing hydrogel model provides a unique 3D platform to evaluate valve cell responses to a mineralized ECM. This study additionally lays the groundwork to capture the diversity of mineral properties in calcified valves, and link these properties to progression of the disease.

Project description:BackgroundThe durability of transcatheter aortic valves (TAVs) remains their greatest disadvantage, given that fixed tissue leaflets are not immune to structural degeneration from calcification and thrombosis. Therefore, a second intervention is necessary, especially given that TAV in low-risk patients has shown noninferior outcomes compared with surgery. This study aimed to assess the hemodynamic and turbulent properties of the flow downstream with different TAV-in-TAV configurations, to offer basic hemodynamic guidance for future interventions when currently implanted valves structurally degrade.MethodsSix TAV-in-TAV configurations were chosen: 23 mm Evolut-in-26 mm Evolut, 23 mm Evolut-in-23 mm SAPIEN 3, 26 mm Evolut-in-26 mm Evolut, 26 mm Evolut-in-23 mm SAPIEN 3, 23 mm SAPIEN3-in-26 mm Evolut, and 23 mm SAPIEN3-in-23 mm SAPIEN 3. Their hemodynamic performance was assessed in a pulse duplicator for 100 cycles. High-speed imaging and particle image velocimetry were performed to assess turbulence. Effective orifice area (EOA), pinwheeling index (PI), and Reynolds shear stress (RSS) were evaluated.ResultsThe largest mean EOA was obtained with 23 mm SAPIEN-in-26 mm Evolut (2.07 ± 0.06 cm2), and the smallest was obtained with 23 mm Evolut-in-23 mm SAPIEN (1.50 ± 0.04 cm2) (P < .001). The highest mean PI was obtained with SAPIEN-in-SAPIEN (26.5 ± 2.00%), and the lowest was obtained with 26 mm Evolut-in-26 mm Evolut (7.5 ± 1.6%) (P < .01). At peak systole, the least detrimental RSS range was obtained with 23 mm Evolut-in-26 mm Evolut (up to ∼340 Pa), and the most detrimental RSS range was obtained with 23 mm Evolut-in-SAPIEN (∼900 Pa) (P < .01).ConclusionsThis study shows that best hemodynamic parameters are TAV-specific (implanted and to be implanted). In addition, it shows that RSS levels, which are indicative of turbulence levels and associated with blood damage, are 2- to 3-fold higher after TAV-in-TAV.

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ApoC-III is a novel inducer of calcification in human aortic valves.

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