Computational fluid dynamicaccuracy in mimicking changes in blood hemodynamics in patients with acute type IIIb aortic dissection treated with TEVAR

Background: We aimed to verify the accuracy of the Computational Fluid Dynamics (CFD) algorithm for blood flow reconstruction for type IIIb aortic dissection (TBAD) before and after thoracic endovascular aortic repair (TEVAR). Methods: We made 3D models of the aorta and its branches using pre- and post-operative CT data from five patients treated for TBAD. The CFD technique was used to quantify the displacement forces acting on the aortic wall in the areas of endograft, mass flow rate/velocity and wall shear stress (WSS). Calculated results were verified with ultrasonography (USG-Doppler) data. Results: CFD results indicated that the TEVAR procedure caused a 7-fold improvement in overall blood flow through the aorta (p = 0.0001), which is in line with USG-Doppler data. A comparison of CFD results and USG-Doppler data indicated no significant change in blood flow through the analysed arteries. CFD also showed a significant increase in flow rate for thoracic trunk and renal arteries, which was in accordance with USG-Doppler data (accuracy 90% and 99.9%). Moreover, we observed a significant decrease in WSS values within the whole aorta after TEVAR compared to pre-TEVAR (1.34 ± 0.20 Pa vs. 3.80 ± 0.59 Pa, respectively, p = 0.0001). This decrease was shown by a significant reduction in WSS and WSS contours in the thoracic aorta (from 3.10 ± 0.27 Pa to 1.34 ± 0.11Pa, p = 0.043) and renal arteries (from 4.40 ± 0.25 Pa to 1.50 ± 0.22 Pa p = 0.043). Conclusions: Post-operative remodelling of the aorta after TEVAR for TBAD improved hemodynamic patterns reflected by flow, velocity and WSS with an accuracy of 99%

Lower levels of Caveolin-1 and higher levels of endothelial nitric oxide synthase are observed in abdominal aortic aneurysm patients treated with simvastatin

This study was undertaken to verify whether simvastatin modulates Cav-1/eNOS expression, and if this modulation is associated with changes in pro- and anti-inflammatory cytokine and Toll-like receptor 4 (TLR4) level in abdominal aortic aneurysm (AAA). It is a 1:2 case-control study of non-statin (n=12) and simvastatin-treated patients (n=24) who underwent open AAA repair. Simvastatin treatment decreased Cav-1 (p0.05) and increased IL-10 concentration (p=0.055); however, TLR4 expression was unaffected, suggesting that simvastatin influences Cav-1 and eNOS in the AAA wall by other mechanisms. Simvastatin may modulate Cav-1 and eNOS expression in the aneurysmal wall, indicating a potentially beneficial role for statins in AAA patients

Simvastatin treatment upregulates HO-1 in patients with abdominal aortic aneurysm but independently of Nrf2

Heme oxygenase-1 (HO-1), encoded by HMOX1 gene and regulated by Nrf2 transcription factor, is a cytoprotective enzyme. Its deficiency may exacerbate abdominal aortic aneurysm (AAA) development, which is also often associated with hyperlipidemia. Beneficial effects of statins, the broadly used antilipidemic drugs, were attributed to modulation of Nrf2/HO-1 axis. However, the effect of statins on Nrf2/HO-1 pathway in patients with AAA has not been studied yet. We analyzed AAA tissue from patients treated with simvastatin (N = 28) or without statins (N = 14). Simvastatin treatment increased HO-1 protein level in AAA, both in endothelial cells (ECs) and in smooth muscle cells (SMCs), but increased Nrf2 localization was restricted only to vasa vasorum. Nrf2 target genes HMOX1, NQO1, and GCLM expression remained unchanged in AAA. In vitro studies showed that simvastatin raises HO-1 protein level slightly in ECs and to much higher extent in SMCs, which is not related to Nrf2/ARE activation, although HMOX1 expression is upregulated by simvastatin in both cell types. In conclusion, simvastatin-induced modulation of HO-1 level in ECs and SMCs in vitro is not related to Nrf2/ARE activity. Likewise, divergent HO-1 and Nrf2 localization together with stable expression of Nrf2 target genes, including HMOX1, in AAA tissue denotes Nrf2 independency

Computational fluid dynamic technique for assessment of how changing character of blood flow and different value of Hct influence blood hemodynamic in dissected aorta

Using computer tomography angiography (CTA) and computational structural analysis, we present a non-invasive method of mass flow rate/velocity and wall stress analysis in type B aortic dissection. Three-dimensional (3D) computer models of the aorta were calculated using pre-operative (baseline) and post-operative CT data from 12 male patients (aged from 51 to 64 years) who were treated for acute type B dissection. A computational fluid dynamics (CFD) technique was used to quantify the displacement forces acting on the aortic wall in the areas of endografts placement. The mass flow rate and wall stress were measured and quantified using the CFD technique. The CFD model indicated the places with a lower value of blood velocity and shear rate, which corelated with higher blood viscosity and a probability of thrombus appearance. Moreover, with the increase in Hct, blood viscosity also increased, while the intensity of blood flow provoked changing viscosity values in these areas. Furthermore, the velocity gradient near the tear surface caused high wall WSS; this could lead to a decreased resistance in the aorta's wall with further implications to a patient

Artificial Circulatory Model for Analysis of Human and Artificial Vessels

Background: Ex vivo computer controlled circulatory reactors are advantageous for the investigation of circulatory systems. So far, most of the models have dealt with laminar or pulsatile flow. This study aimed to monitor blood vessel and vessel graft compliance continuously under physiological flow in real time. Methods: Human common iliac arteries and silicon tubes served as interposition grafts. Changes in wall diameter and displacement were analyzed. The artificial circulatory system (ACM) presented an “artificial heart” able to simulate various ejection pressures, ejection volumes (EV), and frequencies of pulsation (FP). ACM was validated by comparing medical data reconstructed with the 2D-speckle-tracking-technique (2DSTT). Results: Silicon tubes were more rigid compared to iliac arteries, as changes in diameter were approximately 48% lower (0.56 ± 0.007 mm vs. 0.83 ± 0.016 mm, p < 0.0001, for EV = 70 mL and FP = 60 min−1). Wall displacement was 2.3-fold less pronounced in silicon tubes (1.45 ± 0.032 mm vs. 5.79 ± 0.043 mm for iliac arteries (p < 0.0001)). FP and EV did not further increase differences in wall displacement between both types of grafts. There were no significant changes between results gathered from ACM and 2DSTT. Conclusions: The ACM was successfully validated by 2DSTT with the use of selected grafts. It may become a useful tool to investigate different types of vascular grafts

Prostaglandin−J2Prostaglandin-J_{2} upregulates expression of matrix metalloproteinase-1 independently of activation of peroxisome proliferator-activated receptor−γreceptor-\gamma

Peroxisome proliferator-activated receptor-γ (PPARγ) is a ligand-inducible nuclear receptor that functions as a transcription factor involved in lipid metabolism, inflammatory response and angiogenesis. The most potent endogenous PPARγ activator is 15-deoxy-Δ12,14prostaglandin-J2 (15d-PGJ2), whereas synthetic ligands include the oral antidiabetic drugs thiazolidinediones (TZDs). Activation of PPARγ was reported to decrease the synthesis of matrix metalloproteinases (MMPs) in vascular smooth muscle cells and macrophages. We aimed to investigate the effect of PPARγ ligands on expression of MMP-1 and urokinase plasminogen activator (uPA) in human microvascular endothelial cells (HMEC-1). We found that treatment of HMEC-1 with 15d-PGJ2 increased the synthesis of MMP-1 protein up to 168% comparing to untreated cells. TZDs (ciglitazone and troglitazone), more potent activators of PPARγ in HMEC-1, did not influence MMP-1 production, arguing against the involvement of PPARγ in this process. Importantly, the stimulatory effect of 15d-PGJ2 was reversed by the antioxidant N-acetyl-cysteine (NAC), suggesting a contribution of oxidative stress. We demonstrated also that 15d-PGJ2 did not change the activity of MMP-1 promoter, but increased the stability of MMP-1 mRNA. In contrast, 15d-PGJ2 very potently inhibited the synthesis of uPA. This effect was in part mimicked by ciglitazone and troglitazone implying an involvement of PPARγ. Accordingly, NAC did not modify the inhibitory effect of 15d-PGJ2 on uPA expression. In conclusion, we postulate that 15d-PGJ2 may differently regulate the synthesis of proteases involved in angiogenesis : it upregulates MMP-1 expression in HMEC-1 through induction of oxidative stress, and inhibits uPA synthesis partly by activation of PPARγ

Expression of Proteolytic Enzymes by Small Cell Lung Cancer Circulating Tumor Cell Lines

Small cell lung cancer (SCLC) is an aggressive type of lung cancer which disseminates vigorously and has a dismal prognosis. Metastasis of SCLC is linked to an extremely high number of circulating tumor cells (CTCs), which form chemoresistant spheroids, termed tumorospheres. Intravasation and extravasation during tumor spread requires the activity of a number of proteases to disintegrate the stroma and vascular tissue. Generation of several permanent SCLC CTC lines allowed us to screen for the expression of 35 proteases using Western blot arrays. Cell culture supernatants of two CTC lines, namely BHGc7 and 10, were analyzed for secreted proteases, including matrix metalloproteinases (MMPs), ADAM/TS, cathepsins, kallikreins, and others, and compared to proteases expressed by SCLC cell lines (GLC14, GLC16, NCI-H526 and SCLC26A). In contrast to NCI-H526 and SCLC26A, MMP-9 was highly expressed in the two CTC lines and in GLC16 derived of a relapse. Furthermore, cathepsins (S, V, X/Z/P, A and D) were highly expressed in the CTC lines, whereas ADAM/TS and kallikreins were not detectable. In conclusion, SCLC CTCs express MMP-9 and a range of cathepsins for proteolysis and, aside from tissue degradation, these enzymes are involved in cell signaling, survival, and the chemoresistance of tumor cells