scholarly journals Age-related changes in aortic 3D blood flow velocities and wall shear stress: Implications for the identification of altered hemodynamics in patients with aortic valve disease

2015 ◽  
Vol 43 (5) ◽  
pp. 1239-1249 ◽  
Author(s):  
Pim van Ooij ◽  
Julio Garcia ◽  
Wouter V. Potters ◽  
S. Chris Malaisrie ◽  
Jeremy D. Collins ◽  
...  
2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
T Gross ◽  
D Lindner ◽  
F M Ojeda ◽  
S Blankenberg ◽  
H Reichenspurner ◽  
...  

Abstract Objectives Recent studies have shown that shear stress can alter the integrity and gene expression of the aortic wall. We aim to analyze the link between jet dynamic, histological alterations, and gene expression patterns of the proximal aorta in patients with aortic valve disease. Methods We prospectively identified a total of 139 consecutive patients who were referred for aortic valve replacement (AVR) from January 2012 through December 2015. All patients underwent pre-operative MRI assessment to determine the maximal shear stress area of the proximal aorta. Depending of the aorta diameter we subdivided our study population in three subgroup (i.e., patients with a diameter ≤40mm, 41–49mm and ≥50mm). Based on the MRI results, two aortic wall tissue samples were collected during surgery. One sample were acquired from an area of low wall shear stress (WSS) and the second from the area of maximal WSS. The samples were graded in seven histopathologic features. For RNA isolation the tissue was disrupted using a Tissue Lyser II (Qiagen). For the gene expression analysis of h18S, hCCL2, hCOL1A1, hVCAM1, and hELN reverse transcription of RNA was carried out using the High-capacity cDNA kit (life-technologies,USA). Therefore, 125 ng total RNA from tissue samples were reversely transcribed into cDNA. Results Regardless of the aortic valve functional lesion (i.e., stenosis or regurgitation), the maximal area of WSS was in the major curvature of the proximal aorta (73%, n=102). We observed that in both tissue samples just the orientation of vascular smooth muscle cell was strongly related to the diameter of the ascending aorta (p=0.004 vs. p=0.0032). In the whole study population any significant correlation was found between maximal cross-sectional aortic diameter and genes expression. However, in the subgroup analysis we identified that the tissue samples who were exposed to higher wall shear stress and presented a diameter ≥50mm, showed a statically significant gene over-expresion of COL1A1 (p=0.041) and ELN (p=0.01). In the tissue samples with a low WSS we also identified a significant over-expression of CCL2 (p=0.005) and COL1A1 (p=0.01). Conclusions Tissue samples from the slow WSS area with a proximal aortic diameter ≥50mm presented elevated levels of inflammatory response genes (i.e, CCL2). On the other hand, samples that were exposed to higher WSS demonstrated more relation to changes in the architecture of the connective fibres (i.e., elastin and collagen). Acknowledgement/Funding None


Medicine ◽  
2021 ◽  
Vol 100 (26) ◽  
pp. e26518
Author(s):  
Patrick Geeraert ◽  
Fatemehsadat Jamalidinan ◽  
Ali Fatehi Hassanabad ◽  
Alireza Sojoudi ◽  
Michael Bristow ◽  
...  

2019 ◽  
Vol 35 (10) ◽  
pp. 1925-1934 ◽  
Author(s):  
Ozair Rahman ◽  
Michael Scott ◽  
Emilie Bollache ◽  
Kenichiro Suwa ◽  
Jeremy Collins ◽  
...  

2018 ◽  
Vol 48 (2) ◽  
pp. 522-530 ◽  
Author(s):  
Emile S. Farag ◽  
Pim van Ooij ◽  
R. Nils Planken ◽  
Kayleigh C.P. Dukker ◽  
Frederiek de Heer ◽  
...  

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
H Yang ◽  
Y Song ◽  
Z Huang ◽  
J Qian ◽  
Z Pang ◽  
...  

Abstract Background Aortic valve disease is the most common valvular heart disease leading to valve replacement. The efficacy of pharmacological therapy for aortic valve disease is limited by the high mechanical stress at the aortic valves impairing the binding rate. We aimed to identify nanoparticle coating with entire platelet membranes to fully mimic their inherent multiple adhesion mechanisms and target the sclerotic aortic valve of apolipoprotein E-deficient (ApoE−/−) mice based on their multiple sites binding capacity under high shear stress. Methods Considering the potent interaction of platelet membrane glycoproteins with components present in sclerotic aortic valves, platelet membrane-coated nanoparticles (PNPs) were synthetized and the binding capacity under high shear stress was evaluated in vitro and in vivo. Results Compared with PNPs bound intensity in the static station, 161%, 59%, and 39% of attached PNPs remained adherent on VWF-, collagen-, and fibrin-coated surfaces under shear stress of 25dyn/cm2 respectively. PNPs demonstrated effectively adhering to von Willebrand factor, collagen and fibrin under shear stresses in vitro. In an aortic valve disease model established in ApoE−/− mice, PNPs group exhibited significant increase of accumulation in the aortic valves compared with PBS and control NP group. PNPs displayed high degrees of proximity or co-localization with vWF, collagen and fibrin, which exhibited good targeting to sclerotic aortic valves by mimicking platelet multiple adhesive mechanisms. Conclusion PNPs could provide a promising platform for the molecular diagnosis and targeting treatment of aortic valve disease. Targeting combination Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): National Natural Science Foundation of China


2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Carolyn M Roos ◽  
Bin Zhang ◽  
Grace Verzosa ◽  
Elise A Oehler ◽  
Michael A Hagler ◽  
...  

Increasing age is a major risk factor for calcific aortic valve disease (CAVD). Interestingly, SIRT6 knockout mice have a marked progeroid phenotype, and we recently reported that sirtuin enzyme expression is dramatically reduced with aging and that SIRT6 expression is reduced further in valves from patients with end-stage CAVD. It is unknown, however, whether experimentally reducing SIRT6 promotes osteogenic signaling in the valve and ultimately accelerates progression of CAVD. Thus, we used cultured mouse aortic valve interstitial cells and ldlr-deficient, apolipoprotein B100-only mice (LA) that were SIRT6 wild-type (LA-SIRT6 +/+ ) or heterozygous (LA-SIRT6 +/- ) and fed a Western diet for 3 or 12 months to determine the role of SIRT6 in valve calcification. In vitro , reduction of SIRT6 increased histone acetylation and significantly increased mRNA and protein levels of the osteogenic genes Runx2 and Sp7 in response to bone morphogenetic protein 2 (100ng/ml BMP2 for 18 hours), and siRNA knockdown of SIRT6 increased mRNA levels of Sp7 even in the absence of exogenous bone morphogens. Using high-resolution ultrasound to evaluate aortic valve function in vivo, we found that 3 month old LA-SIRT6 +/- mice did not have significant impairments in valve function compared to LA-SIRT6 +/+ mice. In contrast, 12 month old LA-SIRT6 +/- had dramatically worsened aortic valve dysfunction and stenosis compared to LA-SIRT6 +/+ mice, which was also associated with reductions in left ventricular ejection fraction. Collectively, our data strongly suggest SIRT6 plays a critical role in the tonic repression of osteogenic signaling in the aortic valve, and that age-related reductions in SIRT6 are likely to increase susceptibility to valve calcification in response to risk factors for CAVD such as hypercholesterolemia. Collectively, increasing activity of SIRT6 or reducing acetylation of its targets may serve as viable therapeutic strategies to slow progression of age-related valvular calcification and stenosis.


Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Christina V Theodoris ◽  
Mark P White ◽  
Molong Li ◽  
Lei Liu ◽  
Daniel He ◽  
...  

In humans, NOTCH1 mutations result in congenital heart defects including valve malformations and severe valve calcification in adults. Valve calcification typically occurs on the aortic side of the valve leaflets that is not exposed to laminar shear stress, suggesting a protective role of flow sensed by the endothelial lining. To understand the mechanisms by which NOTCH1 mutations in endothelial cells (ECs) cause disease, we generated induced pluripotent stem cell (iPSC) lines from fibroblasts of four individuals from two families affected with aortic valve disease due to heterozygous non-sense mutations in NOTCH1. We differentiated control and mutant iPSC lines into ECs and exposed the ECs to either static or fluid shear stress conditions. NOTCH1 mRNA levels were decreased by ~50% in the NOTCH1+/- ECs under static or shear stress conditions. RNA-seq revealed that 165 genes were differentially expressed in static conditions and 193 genes responded abnormally to shear stress in NOTCH1+/- ECs compared to NOTCH1+/+ ECs. Differentially expressed genes included canonical NOTCH1 targets HRT2 and EFNB2 as well as novel targets involved in vascular development, inflammation, and endochondral ossification. Anti-calcific genes uniquely upregulated in shear stress were dysregulated in NOTCH1+/- ECs, indicating that they were unable to mount the normal protective response induced by shear stress in the valve. Generating isogenic NOTCH1+/+ and NOTCH1+/- cell lines using TALEN genome editing identified genes specifically dysregulated due to NOTCH1 heterozygosity rather than differentially expressed due to genetic background and showed rescue of this dysregulation in TALEN-corrected NOTCH1+/+ ECs. We have mapped the gene networks dysregulated in NOTCH1+/- ECs as determined by NOTCH1 ChIP-seq, differentially methylated regions of DNA, and genome-wide differences in the progression of activating and repressive chromatin states that begin to explain the mechanisms by which heterozygosity of a transcription factor leads to disease-specific changes. Determining the consequence of NOTCH1 heterozygous mutations in human patient-specific ECs will reveal novel mechanisms underlying aortic valve disease, leading to potential targets for intervention.


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