Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

Büttner, Petra; Feistner, Lukas; Lurz, Philipp; Thiele, Holger; Hutcheson, Joshua D.; Schlotter, Florian

doi:10.3389/fcvm.2021.660797

Cited by 21 publications

(15 citation statements)

References 162 publications

(239 reference statements)

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“…Therefore, the routine use of CT could allow monitoring the valve remodeling process from its early stages (i.e., aortic valve sclerosis) that are primarily due to fibrotic processes. Finally, the quantification of aortic valve fibrosis by CT could make it possible to perform population-based studies and non-invasive assessment of novel therapies aimed at reducing or halting sex-related AS progression, acting in an optimal window of opportunity that may be early in the course of the disease (26).…”

Section: Discussionmentioning

confidence: 99%

Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis

et al. 2022

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BackgroundAortic stenosis (AS) is the most common valve disorder characterized by fibro-calcific remodeling of leaflets. Recent evidence indicated that there is a sex-related difference in AS development and progression. Fibrotic remodeling is peculiar in women’s aortic valves, while men’s leaflets are more calcified. Our study aimed to assess aortic valve fibrosis (AVF) in a severe AS cohort using non-invasive diagnostic tools and determine whether sex-specific pathological pathways and cell types are associated with severe AS.Materials and MethodsWe have included 28 men and 28 women matched for age with severe AS who underwent echocardiography and cardiac contrast-enhanced computed tomography (CT) before intervention. The calcium and fibrosis volumes were assessed and quantified using the ImageJ thresholding method, indexed calcium and fibrosis volume were calculated by dividing the volume by the aortic annular area. For a deeper understanding of molecular mechanisms characterizing AS disorder, differentially expressed genes and functional inferences between women and men’s aortic valves were carried out on a publicly available microarray-based gene expression dataset (GSE102249). Cell types enrichment analysis in stenotic aortic valve tissues was used to reconstruct the sex-specific cellular composition of stenotic aortic valves.ResultsIn agreement with the literature, our CT quantifications showed that women had significantly lower aortic valve calcium content compared to men, while fibrotic tissue composition was significantly higher in women than men. The expression profiles of human stenotic aortic valves confirm sex-dependent processes. Pro-fibrotic processes were prevalent in women, while pro-inflammatory ones, linked to the immune response system, were enhanced in men. Cell-type enrichment analysis showed that mesenchymal cells were over-represented in AS valves of women, whereas signatures for monocytes, macrophages, T and B cells were enriched men ones.ConclusionsOur data provide the basis that the fibro-calcific process of the aortic valve is sex-specific, both at gene expression and cell type level. The quantification of aortic valve fibrosis by CT could make it possible to perform population-based studies and non-invasive assessment of novel therapies to reduce or halt sex-related calcific aortic valve stenosis (CAVS) progression, acting in an optimal window of opportunity early in the course of the disease.

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Section: Discussionmentioning

confidence: 99%

Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis

et al. 2022

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“…The side of the valves facing the ventricle experiences laminar flow and is usually free of lesions. Interestingly, aortic stenosis is more often fibrotic in women and calcific in men [11].…”

Section: Valve Calcificationmentioning

confidence: 99%

Biomolecules Orchestrating Cardiovascular Calcification

2021

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Vascular calcification, once considered a degenerative, end-stage, and inevitable condition, is now recognized as a complex process regulated in a manner similar to skeletal bone at the molecular and cellular levels. Since the initial discovery of bone morphogenetic protein in calcified human atherosclerotic lesions, decades of research have now led to the recognition that the regulatory mechanisms and the biomolecules that control cardiovascular calcification overlap with those controlling skeletal mineralization. In this review, we focus on key biomolecules driving the ectopic calcification in the circulation and their regulation by metabolic, hormonal, and inflammatory stimuli. Although calcium deposits in the vessel wall introduce rupture stress at their edges facing applied tensile stress, they simultaneously reduce rupture stress at the orthogonal edges, leaving the net risk of plaque rupture and consequent cardiac events depending on local material strength. A clinically important consequence of the shared mechanisms between the vascular and bone tissues is that therapeutic agents designed to inhibit vascular calcification may adversely affect skeletal mineralization and vice versa. Thus, it is essential to consider both systems when developing therapeutic strategies.

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“…1 Aortic stenosis results from fibrotic remodeling and the formation of calcified nodules on the valve leaflet that impede and disrupt blood flow, causing excessive strain on the cardiac tissue, increasing the risk of stroke, and leading to heart failure. 2 CAVD severity and incidence increase with age. CAVD prevalence rapidly increases with age and is >1,000 per 100,000 individuals ≥75 years of age.…”

Section: Introductionmentioning

confidence: 99%

Non-canonical Telomerase Reverse Transcriptase Controls Osteogenic Reprogramming of Aortic Valve Cells Through STAT5

Cuevas

Hortells

Chu

et al. 2022

Preprint

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BackgroundCalcific aortic valve disease (CAVD) is the pathological remodeling of the valve leaflets which leads to heart failure and high stroke risk. While several mechanisms are known to drive cardiovascular calcification, the initial steps orchestrating the osteogenic reprogramming of cells are not fully understood. Non-canonical functions of telomerase reverse transcriptase (TERT) include service as a cofactor to stimulate gene transcription, and TERT overexpression primes mesenchymal stem cells to differentiate into osteoblasts. We investigated whether TERT contributes to osteogenic reprogramming of valve interstitial cells.MethodsBaseline transcription of TERT and osteogenic markers, senescence, DNA damage, and telomere length in valve tissue and primary aortic valve interstitial cells (VICs) from control and CAVD patients were assessed. TERT expression was depleted in cells using lentiviral vectors. Cells from Tert+/+ and Tert-/- mice were used to validate human findings. Immunofluorescence staining, proximity ligation assay, and chromatin immunoprecipitation assay were used in mechanistic experiments.ResultsTERT protein was highly expressed in calcified valve leaflets, without changes in telomere length, DNA damage, or senescence. These phenotypic features were retained in primary VICs isolated and cultured from those diseased tissues. TERT levels were increased with osteogenic or inflammatory stimuli, and genetic deletion or reduction of TERT prevented calcification of VICs isolated from humans and mice. Similar results were seen in smooth muscle cells (SMCs) and mesenchymal stem cells (MSCs). TERT and Signal Transducer and Activator of Transcription 5A/B (STAT5) colocalize and bind to the Runt-Related Transcription Factor 2 (RUNX2) gene promoter, and TERT and STAT5 co-localized in calcified valve tissues. Pharmacological inhibition of STAT5A prevented calcification in vitro.ConclusionsThese data show that non-canonical TERT activity is required for the calcification of VICs. TERT partners with STAT5A to bind to and activate the RUNX2 gene promoter. These data identify a novel therapeutic target to abate vascular calcification.Novelty and SignificanceWhat Is Known?Calcific aortic valve disease (CAVD) is the most prevalent form of aortic valve pathology. CAVD strongly correlates with age and leads to heart failure and a high risk of stroke. Currently, the only therapeutic option is valve replacement, which comes with significant healthcare costs and additional risks to patients.Runt-related transcription factor 2 (RUNX2) is the master transcription factor required for osteogenic differentiation of osteoblasts and osteogenic reprogramming of vascular cells, yet the early events driving its transcription in valve cells are not well defined.Overexpression of TERT primes mesenchymal stem cells to differentiate down the osteoblast lineage, suggesting that TERT signaling plays an important role in cell differentiation and phenotype.What New Information Does This Article Contribute?TERT protein is highly expressed in calcified aortic leaflets and valve interstitial cells, independent of changes in telomere length.Genetic loss or depletion of TERT blocks calcification in valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells.TERT co-localizes with STAT5 in the cytosol and on the RUNX2 gene promoter, the master regulator of osteogenic transcriptional programs.Pharmacological inhibition of STAT5 prevents calcification of human valve interstitial cells, coronary smooth muscle cells, and mesenchymal stem cells.What are the clinical implications?We have identified TERT/STAT5 as novel signaling axis that promotes the early transcriptional reprogramming in cardiovascular cells. Inhibiting TERT and STAT5 interaction and activity can be leveraged for the development of pharmacological or biological therapeutic strategies to halt or prevent calcification in the aortic valve and perhaps other cardiovascular tissues.Surgical procedures are currently the only treatment option for patients with CAVD. Discovering the early events driving vascular calcification identifies novel and druggable targets for the development of non-surgical therapies.

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Dissecting Calcific Aortic Valve Disease—The Role, Etiology, and Drivers of Valvular Fibrosis

Cited by 21 publications

References 162 publications

Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis

Sex-Specific Cell Types and Molecular Pathways Indicate Fibro-Calcific Aortic Valve Stenosis

Biomolecules Orchestrating Cardiovascular Calcification

Non-canonical Telomerase Reverse Transcriptase Controls Osteogenic Reprogramming of Aortic Valve Cells Through STAT5

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