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Molecular imaging of calcific aortic valve disease.

ABSTRACT: 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.

SUBMITTER: Jung JJ

PROVIDER: S-EPMC6054901 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Molecular imaging of calcific aortic valve disease.

Jung Jae-Joon JJ Jadbabaie Farid F Sadeghi Mehran M MM

Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology 20180122 4

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 interven ...[more]

PMID: 29359271

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Multimodality and molecular imaging of matrix metalloproteinase activation in calcific aortic valve disease.

Project description:UNLABELLED:Calcific aortic valve disease (CAVD) is the most common cause of aortic stenosis. Matrix metalloproteinases (MMPs) are upregulated in CAVD and contribute to valvular remodeling and calcification. We investigated the feasibility and correlates of MMP-targeted molecular imaging for detection of valvular biology in CAVD. METHODS:Apolipoprotein E-deficient (apoE(-/-)) mice were fed a Western diet (WD) for 3, 6, and 9 mo (n = 108) to induce CAVD. Wild-type mice served as the control group (n = 24). The development of CAVD was tracked with CT, echocardiography, MMP-targeted small-animal SPECT imaging using (99m)Tc-RP805, and histologic analysis. RESULTS:Key features of CAVD—leaflet thickening and valvular calcification—were noted after 6 mo of WD and were more pronounced after 9 mo. These findings were associated with a significant reduction in aortic valve leaflet separation and a significant increase in transaortic valve flow velocity. On in vivo SPECT/CT images, MMP signal in the aortic valve area was significantly higher at 6 mo in WD mice than in control mice and decreased thereafter. The specificity of the signal was demonstrated by blocking, using an excess of nonlabeled precursor. Similar to MMP signal, MMP activity as determined by in situ zymography and valvular inflammation by CD68 staining were maximal at 6 mo. In vivo (99m)Tc-RP805 uptake correlated significantly with MMP activity (R(2) = 0.94, P < 0.05) and CD68 expression (R(2) = 0.98, P < 0.01) in CAVD. CONCLUSION:MMP-targeted imaging detected valvular inflammation and remodeling in a murine model of CAVD. If this ability is confirmed in humans, the technique may provide a tool for tracking the effect of emerging medical therapeutic interventions and for predicting outcome in CAVD.

| S-EPMC4454445 | biostudies-literature

Dysregulated microRNAs in calcific aortic valve disease

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

Biomarkers of Calcific Aortic Valve Disease.

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.

| S-EPMC5364059 | biostudies-literature

Transcriptional Profiles of Aortic Valve from Calcific Aortic Valve Disease and Normal Control.

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).

2023-06-28 | GSE235995 | GEO

The alterations of gene expression in aortic valve from calcific aortic valve disease patients

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

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

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

Inhibitory Role of Notch1 in Calcific Aortic Valve Disease

2011-08-26 | GSE31668 | GEO

Adaptive immune cells in calcific aortic valve disease.

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

Inhibitory role of Notch1 in calcific aortic valve disease.

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 Sox9 expression 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.

| S-EPMC3218038 | biostudies-literature

Autotaxin and Lipoprotein Metabolism in Calcific Aortic Valve Disease.

Project description:Calcific aortic valve disease (CAVD) is a complex trait disorder characterized by calcific remodeling of leaflets. Genome-wide association (GWA) study and Mendelian randomization (MR) have highlighted that LPA, which encodes for apolipoprotein(a) [apo(a)], is causally associated with CAVD. Apo(a) is the protein component of Lp(a), a LDL-like particle, which transports oxidized phospholipids (OxPLs). Autotaxin (ATX), which is encoded by ENPP2, is a member of the ecto-nucleotidase family of enzymes, which is, however, a lysophospholipase. As such, ATX converts phospholipids into lysophosphatidic acid (LysoPA), a metabolite with potent and diverse biological properties. Studies have recently underlined that ATX is enriched in the Lp(a) lipid fraction. Functional experiments and data obtained in mouse models suggest that ATX mediates inflammation and mineralization of the aortic valve. Recent findings also indicate that epigenetically-driven processes lower the expression of phospholipid phosphatase 3 (PLPP3) and increased LysoPA signaling and inflammation in the aortic valve during CAVD. These recent data thus provide novel insights about how lipoproteins mediate the development of CAVD. Herein, we review the implication of lipoproteins in CAVD and examine the role of ATX in promoting the osteogenic transition of valve interstitial cells (VICs).

| S-EPMC6405425 | biostudies-literature

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