The Haemodynamic and Pathophysiological Mechanisms of Calcific Aortic Valve Disease.
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ABSTRACT:
SUBMITTER: Hanna L
PROVIDER: S-EPMC9220142 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
Publications
The Haemodynamic and Pathophysiological Mechanisms of Calcific Aortic Valve Disease.
Hanna Lydia L Armour Chlöe C Xu Xiao Yun XY Gibbs Richard R
Biomedicines 20220603 6
The aortic valve (AoV) is the outflow valve for the left heart [...]. ...[more]
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Project description:Calcific aortic valve disease (CAVD) is a common heart valve disease, yet its underlying mechanism remains pooly understood. We aimed to explore the microRNAs funtion in CAVD and to develop novel miRNA therapy for CAVD.
2019-10-10 | GSE87885 | GEO
Project description:Calcific aortic valve disease (CAVD) is a highly prevalent cardiovascular disorder accounting for a rising economic and social burden on aging populations. In spite of continuing study on the pathophysiology of disease, there remain no medical therapies to prevent the progression of CAVD. The discovery of biomarkers represents a potentially complementary approach in stratifying risk and timing of intervention in CAVD and has the advantage of providing insight into causal factors for the disease. Biomarkers have been studied extensively in atherosclerotic cardiovascular disease, with success as additive for clinical and scientific purposes. Similar research in CAVD is less robust; however, the available studies of biomarkers in CAVD show promise for enhanced clinical decision making and identification of causal factors for the disease. This comprehensive review summarizes available established and novel biomarkers in CAVD, their contributions toward an understanding of pathophysiology, their potential clinical utility, and provides an outline to direct future research in the field.
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Project description:Calcific aortic valve stenosis (CAVS) is a major health problem facing aging societies. The identification of osteoblast-like and osteoclast-like cells in human tissue has led to a major paradigm shift in the field. CAVS was thought to be a passive, degenerative process, whereas now the progression of calcification in CAVS is considered to be actively regulated. Mechanistic studies examining the contributions of true ectopic osteogenesis, nonosseous calcification, and ectopic osteoblast-like cells (that appear to function differently from skeletal osteoblasts) to valvular dysfunction have been facilitated by the development of mouse models of CAVS. Recent studies also suggest that valvular fibrosis, as well as calcification, may play an important role in restricting cusp movement, and CAVS may be more appropriately viewed as a fibrocalcific disease. High-resolution echocardiography and magnetic resonance imaging have emerged as useful tools for testing the efficacy of pharmacological and genetic interventions in vivo. Key studies in humans and animals are reviewed that have shaped current paradigms in the field of CAVS, and suggest promising future areas for research.
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Project description:We report transcriptional profiles of aortic valve tissue from calcific aortic valve disease (CAVD) and normal control (non-CAVD). We collected the aortic valve tissues from five patients with CAVD who underwent aortic valve replacement due to severe aortic valve stenosis. Aortic valve samples from patients with non-calcified aortic valve resection due to heart transplantation (recipient heart) or aortic dissection were collected as the control (non-CAVD). The inclusion criteria for CAVD group were as follows: 50-75 years old; undergoing aortic valve replacement due to severe AVS with significantly valvular calcification. The inclusion criteria for non-CAVD group were as follows: non-calcified aortic valve resection due to heart transplantation (recipient heart) or aortic dissection. For each sample, total RNA was extracted, a cDNA library was generated, and an Illumina NovaSeq 6000 was used to sequence each sample. Stringtie software was used to count the fragment within each gene, and TMM algorithm was used for normalization. Differential expression analysis was performed using R package edgeR. Differentially expressed RNAs with |log2(FC)| value >1, q value [false discovery rate (FDR) adjusted P-value] <0.05, and one group’s mean fragments per kilobase of exon per million reads mapped (FPKM) >1, were assigned as differentially-expressed genes (DEGs).
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Project description:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism. 3 samples of aortic valve interstitial cells treated with DAPT were compared with 3 samples of aortic valve interstitial cells treated with DMSO
2011-08-25 | E-GEOD-31668 | biostudies-arrayexpress
Project description:Calcification of the aortic valve leads to increased leaflet stiffness resulting in development of calcific aortic valve disease (CAVD); however, the underlying molecular and cellular mechanisms of calcification are poorly understood. Here, we investigated gene expressions in relation to valvular calcification and promotion of CAVD progression.
2016-01-28 | GSE77287 | GEO
Project description:Calcific aortic valve disease (CAVD) can progress to symptomatic aortic stenosis in a subset of patients. The severity of aortic stenosis and the extent of valvular calcification can be evaluated readily by echocardiography, CT, and MRI using well-established imaging protocols. However, these techniques fail to address optimally other important aspects of CAVD, including the propensity for disease progression, risk of complications in asymptomatic patients, and the effect of therapeutic interventions on valvular biology. These gaps may be addressed by molecular imaging targeted at key biological processes such as inflammation, remodeling, and calcification that mediate the development and progression of CAVD. In this review, recent advances in valvular molecular imaging, including 18F-fluorodeoxyglucose (FDG) and 18F-sodium fluoride (NaF) PET, and matrix metalloproteinase-targeted SPECT imaging in the preclinical and clinical settings are presented and discussed.
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Project description:Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of expression Sox9 has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.
2011-08-26 | GSE31668 | GEO
Project description:Calcific aortic valve disease (CAVD) is highly prevalent and has no pharmaceutical treatment. Surgical replacement of the aortic valve has proved effective in advanced disease but is costly, time limited, and in many cases not optimal for elderly patients. This has driven an increasing interest in noninvasive therapies for patients with CAVD. Adaptive immune cell signaling in the aortic valve has shown potential as a target for such a therapy. Up to 15% of cells in the healthy aortic valve are hematopoietic in origin, and these cells, which include macrophages, T lymphocytes, and B lymphocytes, are increased further in calcified specimens. Additionally, cytokine signaling has been shown to play a causative role in aortic valve calcification both in vitro and in vivo. This review summarizes the physiological presence of hematopoietic cells in the valve, innate and adaptive immune cell infiltration in disease states, and the cytokine signaling pathways that play a significant role in CAVD pathophysiology and may prove to be pharmaceutical targets for this disease in the near future.
| S-EPMC6692729 | biostudies-literature
Project description:Calcific Aortic Valve Disease (CAVD) is the most frequent valvular heart disease in developed countries. It is characterized by a progressive calcification of aortic valve leaflets mediated by myeloid cells, such as monocytes and macrophages. However, the molecular mechanisms involved in their recruitment and activity are still poorly understood and limit the development of a pharmacological treatments. Previous studies have already demonstrated the role of macrophages in CAVD development. However, little is known about the implication of their precursors, monocytes. Thus, we hypothesized that circulating monocytes from CAVD patients have higher pro-calcific and pro-inflammatory capacities. We aimed first to assess the pro-calcifying potential of circulating monocytes from patients with CAVD and second to better understand the molecular mechanisms of this pro-calcific effect through a whole transcriptomic study. Methods : We first characterized monocytes sub-population, from PBMCs isolated from peripheral blood of healthy volunteers (Vol) and patients with CAVD or without CAVD (NCAVD), with flow cytometry. Then we analyzed the whole transcriptome of these monocytes by RNA sequencing (RNAseq) to identify dysregulated genes expression, further confirmed by RT-qPCR. Finally, after evaluation of monocytes secretome with multiplex analysis, we evaluated CAVD monocytes capacities to induce myofibroblastic transdifferenciation and osteoblastic differencitation of human valvular interstitial cells (hVIC) with immunocytochemistry (ICC) and O-cresolphtalein assay. Results : In CAVD (calcific aortic valve disease) monocytes, we observe a shift in their sub-populations, with an increased frequency of classical monocytes (CD14+CD16-) and a decreased frequency of non-classical monocytes (CD14+CD16++). Interestingly, we found specific upregulation of genes linked to both inflammation (PDK4) and calcification (ATP2B1), alongside the downregulation of immunomodulatory genes (DDR1, IKBKE) in monocytes from CAVD patients. Additionally, CAVD monocytes produce lower levels of immunomodulatory and anti-osteoblastogenic cytokines (IL3, CCL3), which promote myofibroblastic transdifferentiation (TIMP1, TNC) and osteoblastic differentiation (ALPL, OPG). This correlates with an increase in αsma+ and opn+ cells and a doubling of hVIC calcifications. Conclusions : We demonstrated for the first time that circulating monocytes from CAVD patients have higher pro-inflammatory and pro-calcific capacities that might promote CAVD development. Likewise, we identify dysregulated genes, which could be used as new therapeutic targets.
2025-02-24 | GSE290104 | GEO