scholarly journals Matrix Metalloproteinase-2 Isoforms Differ within the Aortic Wall of Ascending Aortic Aneurysms Associated with Bicuspid Aortic Valve

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Ramona Schmitt ◽  
Anke Tscheuschler ◽  
Philipp Laschinski ◽  
Philipp Discher ◽  
Jana Fuchs ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Matrix Metalloproteinase ◽  
Bicuspid Aortic Valve ◽  
Aortic Wall ◽  
Aortic Aneurysms ◽  
Matrix Metalloproteinase 2 ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tissue Levels ◽  
Protein Levels ◽  
Underlying Pathogenesis

The pathogenesis of ascending thoracic aortic aneurysm (aTAA) is thought to differ between patients with bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV), and one of the causes is different hemodynamics. Influenced by hemodynamics, the tissue levels of proteins associated with aTAA might differ between aTAAs with BAV and TAV and between different localities within the aortic wall. We therefore analyzed aTAA tissue levels of MMP-2 (matrix metalloproteinase-2) isoforms (Pro-MMP-2, active MMP-2, and total MMP-2) and tissue levels of MMP-14, TIMP-2 (tissue inhibitor of metalloproteinase-2), MMP-9, and TIMP-1 in 19 patients with BAV and 23 patients with TAV via gelatin zymography and enzyme-linked immunosorbent assay (ELISA), respectively. TAV and BAV groups’ protein levels did not differ significantly. Whereas the TAV group exhibited no significant differences in protein levels between the aneurysm’s anterior and posterior parts, the BAV group revealed significantly higher levels of Pro-MMP-2, total MMP-2, and TIMP-2 in the aneurysm’s posterior parts (mean Pro-MMP-2 200.52 arbitrary units (AU) versus 161.12 AU, p=0.007; mean total MMP-2 235.22 AU versus 193.68 AU, p=0.002; mean TIMP-2 26.90 ng/ml versus 25.36 ng/ml, p=0.009), whereas the other proteins did not differ significantly within the aortic wall. Thus, MMPs are distributed more heterogeneously within the aortic wall of aTAAs associated with BAV than in those associated with TAV, which is a new aspect for understanding the underlying pathogenesis. This heterogeneous protein level distribution might be attributable to differences in the underlying pathogenesis, especially hemodynamics. This result is important for further studies as it will be essential to specify the location of samples to ensure data comparability regarding the main goals of understanding the pathogenesis of aTAA, optimizing treatments, and establishing a screening method for its potentially deadly complications.

Plasma Matrix Metalloproteinase Levels Do Not Predict Tissue Levels in Abdominal Aortic Aneurysms Suitable for Elective Repair

Vascular ◽  
2008 ◽  
Vol 16 (5) ◽  
pp. 248-252 ◽  
Author(s):  
W. Richard W. Wilson ◽  
Edward C. Choke ◽  
Joseph Dawson ◽  
Ian M. Loftus ◽  
Matthew M. Thompson
Keyword(s):  
Matrix Metalloproteinase ◽  
Aortic Aneurysms ◽  
Enzyme Linked Immunosorbent Assay ◽  
Tissue Levels ◽  
Aneurysm Wall ◽  
Abdominal Aortic ◽  
Elective Repair ◽  
Circulating Levels ◽  
Aneurysm Diameter

The role of matrix metalloproteinases (MMPs) in abdominal aortic aneurysm (AAA) pathogenesis is well described. However, a clear role for the MMPs in disease prediction has not been established. The aim of this study was to determine if circulating levels of MMPs correlated with AAA diameter and with MMP concentrations within the aneurysm wall. Preoperative plasma samples and intraoperative infrarenal AAA sac biopsies were taken in a standard fashion from 31 patients undergoing elective repair. The concentrations of MMP-1, MMP-2, MMP-3, MMP-9, tissue inhibitor of matrix metalloproteinase (TIMP)-1, and TIMP-2 were quantified in plasma and aneurysm wall homogenates using enzyme-linked immunosorbent assay. Comparison used the Spearman correlation. There were no correlations between the paired plasma and aneurysm wall concentrations for any MMP or TIMP. Correlation between MMP-9 levels in the aneurysm wall and aneurysm diameter was negative ( r = −.42, p = .019). Other correlations between plasma and tissue levels with aneurysm diameter were nonsignificant.

Abstract 15097: Altered TGFβ Signalling Effector Molecules Contribute to Bicuspid Aortic Valve-associated Thoracic Aortopathy

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Candice L Dilworth ◽  
Francesca Sadnick ◽  
Sari Padang ◽  
Yaxin Lu ◽  
Elizabeth N Robertson ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Aortic Aneurysms ◽  
Extra Cellular Matrix ◽  
Matrix Metalloproteinase 2 ◽  
Compensatory Mechanism ◽  
Aortic Dilatation ◽  
Matrix Degradation ◽  
Tgfβ Signalling ◽  
Cellular Matrix

Upregulated TGFβ signalling plays a key role in mediating congenital thoracic aortic aneurysms (TAA), and has been implicated in bicuspid aortic valve-associated TAA (BAV-TAA). TGFβ is normally stored within the extra-cellular matrix via sequestration proteins bound to the microfibrillar protein, fibrillin. TGFβ is released in response to changes in these sequestration proteins, allowing TGFβ to exert its signalling effects. We hypothesised that in BAV-TAA the upregulation of TGFβ signalling will pathologically alter effector molecule expression, causing matrix degradation and altered TGFβ sequestration. Immunohistochemistry was used to quantify protein expression in aortic tissue from 8 human BAV-TAA and 6 normal controls. In BAV-TAA, TGFβ expression was elevated in all layers (2.5:1; p<0.05), particularly in the adventitia (3.4:1; p<0.001). Microfibril-associated glycoprotein-1 (MAGP-1), which promotes TGFβ release, was elevated (2:1; p<0.03), while latent TGFβ binding protein-1 (LTBP-1), which promotes TGFβ sequestration, was decreased (0.3:1; p=0.03). Matrix metalloproteinase-2 (MMP-2) and MMP-9 expression was elevated (2.6:1; p<0.005, 1.5:1; p<0.05, respectively), and MMP-3 expression was decreased (0.5:1; p<0.05). Fibrillin-1 expression was not altered. The observed changes in TGFβ sequestration proteins will increase unbound TGFβ, leading to upregulation of downstream signalling. The elevated levels of MMP-2 and MMP-9 mediate pathological matrix remodelling, leading to aortic dilatation. The paradoxical decrease in MMP-3 may represent a compensatory mechanism that attempts to reduce overall pathological MMP activity, in order to limit damage to the aortic wall. In conclusion, in BAV-TAA excessive TGFβ signalling is potentiated by reduced TGFβ sequestration, causing extra-cellular matrix degradation by MMPs. This supports the rationale for the use of angiotensin II receptor blockers in BAV-TAA.

Proximal aortic aneurysms: correlation of maximum aortic diameter and aortic wall thickness

2021 ◽  
Author(s):  
Josephina Haunschild ◽  
Sarah Jane Barnard ◽  
Martin Misfeld ◽  
Diyar Saeed ◽  
Piroze Davierwala ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Wall Thickness ◽  
Aortic Wall ◽  
Positive Family History ◽  
Aortic Aneurysms ◽  
Aortic Diameter ◽  
The Media ◽  
Aortic Wall Thickness ◽  
Relationship Of

Abstract OBJECTIVES The goal of therapy of proximal aortic aneurysms is to prevent an aortic catastrophe, e.g. acute dissection or rupture. The decision to intervene is currently based on maximum aortic diameter complemented by known risk factors like bicuspid aortic valve, positive family history or rapid growth rate. When applying Laplace’s law, wall tension is determined by pressure × radius divided by aortic wall thickness. Because current imaging modalities lack precision, wall thickness is currently neglected. The purpose of our study was therefore to correlate maximum aortic diameter with aortic wall thickness and known indices for adverse aortic events. METHODS Aortic samples from 292 patients were collected during cardiac surgery, of whom 158 presented with a bicuspid aortic valve and 134, with a tricuspid aortic valve. Aortic specimens were obtained during the operation and stored in 4% formaldehyde. Histological staining and analysis were performed to determine the thickness of the aortic wall. RESULTS Patients were 62 ± 13 years old at the time of the operation; 77% were men. The mean aortic dimensions were 44 mm, 41 mm and 51 mm at the aortic root, sinotubular junction and ascending aorta, respectively. Aortic valve stenosis was the most frequent (49%) valvular dysfunction, followed by aortic valve regurgitation (33%) and combined dysfunction (10%). The maximum aortic diameter at the ascending level did not correlate with the thickness of the media (R = 0.07) or the intima (R = 0.28) at the convex sample site. There was also no correlation of the ascending aortic diameter with age (R = −0.18) or body surface area (R = 0.07). The thickness of the intima (r = 0.31) and the media (R = 0.035) did not correlate with the Svensson index of aortic risk. Similarly, there was a low (R = 0.29) or absent (R = −0.04) correlation between the aortic size index and the intima or media thickness, respectively. There was a similar relationship of median thickness of the intima in the 4 aortic height index risk categories (P &lt; 0.001). CONCLUSIONS Aortic diameter and conventional indices of aortic risk do not correlate with aortic wall thickness. Other indices may be required in order to identify patients at high risk for aortic complications.

Matrix Metalloproteinase-2 and -9 Levels in Patients with Dilated Ascending Aorta and Bicuspid Aortic Valve

2012 ◽  
Vol 30 (2) ◽  
pp. 121-126 ◽  
Author(s):  
Okay Abaci ◽  
Cuneyt Kocas ◽  
Kadriye Orta Kilickesmez ◽  
Sinan Uner ◽  
Serdar Kucukoglu
Keyword(s):  
Aortic Valve ◽  
Matrix Metalloproteinase ◽  
Bicuspid Aortic Valve ◽  
Ascending Aorta ◽  
Matrix Metalloproteinase 2

scholarly journals Bicuspid aortic valve morphology and aortic valvular outflow jets: an experimental analysis using an MRI-compatible pulsatile flow circulation system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kaoru Hattori ◽  
Natsuki Nakama ◽  
Jumpei Takada ◽  
Gohki Nishimura ◽  
Ryo Moriwaki ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Pulsatile Flow ◽  
Aortic Wall ◽  
Ascending Aorta ◽  
Circulation System ◽  
Resonance Imaging ◽  
Left Posterior ◽  
Flow Circulation ◽  
The Right

AbstractThe characteristics of aortic valvular outflow jet affect aortopathy in the bicuspid aortic valve (BAV). This study aimed to elucidate the effects of BAV morphology on the aortic valvular outflow jets. Morphotype-specific valve-devising apparatuses were developed to create aortic valve models. A magnetic resonance imaging-compatible pulsatile flow circulation system was developed to quantify the outflow jet. The eccentricity and circulation values of the peak systolic jet were compared among tricuspid aortic valve (TAV), three asymmetric BAVs, and two symmetric BAVs. The results showed mean aortic flow and leakage did not differ among the five BAVs (six samples, each). Asymmetric BAVs demonstrated the eccentric outflow jets directed to the aortic wall facing the smaller leaflets. In the asymmetric BAV with the smaller leaflet facing the right-anterior, left-posterior, and left-anterior quadrants of the aorta, the outflow jets exclusively impinged on the outer curvature of the ascending aorta, proximal arch, and the supra-valvular aortic wall, respectively. Symmetric BAVs demonstrated mildly eccentric outflow jets that did not impinge on the aortic wall. The circulation values at peak systole increased in asymmetric BAVs. The bicuspid symmetry and the position of smaller leaflet were determinant factors of the characteristics of aortic valvular outflow jet.

Abstract 15169: De Novo Variants of USP10 in Early Onset Bicuspid Aortic Valve Disease

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Siddharth K Prakash ◽  
Angela T Yetman ◽  
Hector I Michelena ◽  
Malenka M Bissell ◽  
Yuli Y Kim ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Early Onset ◽  
Rare Variants ◽  
De Novo ◽  
Late Onset ◽  
Copy Number Variants ◽  
Aortic Aneurysms ◽  
Thoracic Aortic Aneurysms ◽  
Aortic Dissections

Introduction: Bicuspid Aortic Valve (BAV), the most common congenital heart defect, is a major cause of aortic regurgitation or stenosis requiring valve replacement and thoracic aortic aneurysms predisposing to acute aortic dissections (TAD). The spectrum of BAV ranges from severe early onset valve and aortic complications to sporadic late onset disease. Hypothesis: Early onset BAV (EBAV) cases with valve or aortic complications that require intervention prior to age 30 are enriched for rare genetic variants that cause BAV and TAD. Methods: We performed whole exome sequencing of 147 EBAV cases in 141 families who were enrolled in the UTHealth Bicuspid Aortic Valve Research Registry. Candidate variants in the EBAV cohort (26% female, mean age 18, 44% with TAD) were compared to unselected controls from the Genome Aggregation Database (gnoMAD) and the Database of Genotypes and Phenotypes (dbGAP). We considered variants with minor allele frequencies (MAF) < 1%, Combined Annotation Dependent Depletion (CADD) scores > 25, and damaging (Polyphen-2) or deleterious (SIFT) functional prediction scores. Genomic copy number variants (CNVs) were detected using CoNIFER and prioritized when deletions involved genes with probability of loss intolerance (pLI) > 0.9. Variants were validated using quantitative PCR or Sanger sequencing. Results: We identified 6 rare variants of USP10 in 6 EBAV families (4% of cohort): 4 CNVs (2 duplications and 2 deletions) that are rare in dbGAP controls (4 in 15,414) and 2 deleterious rare missense variants (MAF<5x10 -5 in gnoMAD). Two of the 4 CNVs were de novo events in trios. In contrast, rare deleterious variants of the known causal BAV genes NOTCH1 (1), ROBO4 (1), GATA4 (1), GATA5 (1), and SMAD6 (4) were found in 7 total families. USP10 encodes a ubiquitin peptidase that is required for endothelial Notch signaling during vascular development. Conclusions: We identified rare and de novo variants of USP10 that implicate USP10 as a new candidate gene for BAV.

Abstract 102: Granular Media Calcinosis in the Aortic Wall of Patients With Bicuspid and Tricuspid Aortic Valves

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Sandy von Salisch ◽  
Josephina Haunschild ◽  
Martin Misfeld ◽  
Michael A Borger ◽  
Stefan Dhein ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Bicuspid Aortic Valve ◽  
Granular Media ◽  
Aortic Wall ◽  
Aortic Disease ◽  
Dissecting Aneurysm ◽  
Media Thickness ◽  
Significant Difference ◽  
The Media ◽  
Aneurysm Dissection

Background: Bicuspid aortic valve is the most frequent congenital cardiac abnormality and associated with proximal aortic disease (i.e. aneurysm, dissection or rupture). Granular media calcinosis(GMC)--suggested to increase stiffness and play a pathogenetic role in dissecting aneurysm--has not yet been quantified in BAV. Methods: Specimen of the proximal aortic wall from 76 patients--32 with tricuspid (TAV) and 44 with bicuspid aortic valve (BAV)--were obtained during surgery to quantify media thickness and GMC by von Kossa staining (panel C), comparing the convexity (Cvx) and concavity (Ccv) in BAV vs. TAV. Results: Interlamellar GMC affected the most central layers of the media and those adjacent to the outer adventitia with a doubling within both--the Cvx and Ccv--of pts with BAV compared to patients with TAV (13.3±9.6 vs. 6.6±7.4 and 12.8±10.8 vs. 6.4±7.1; p<0.05, panel A) was seen, but neither a difference in calcification between the Ccx and the Ccv side within the BAV nor the TAV group. No association between age and calcification grade , neither in the Cvx nor the Ccv (r=0.132, p=0.218 and 0.103, p=0.341) was seen. There was a significant difference in the total media thickness between BAV and TAV at the Cvx (867±162μm vs . 993±158μm; p<0.05) and the Ccv (1005 ± 236 vs 1223 ± 217μm; p<0.05, panel B). Independent of aortic valve morphology, the Cvx was thinner than the Ccv side (TAV: 993 ± 158 vs.1223 ± 217μm; p<0.001; BAV: 869 ± 162 vs.1005 ± 236μm; p<0.05, panel B). Conclusion: BAVs had significantly thinner media and twice as much GMC than their tricuspid peers possibly associated with the loosening of the bond between the elastic lamellae causing a decrease in elasticity possibly explaining a higher risk for dissection and rupture.

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