Aortic Dissection Model Research Articles

The expression of Nesprin-1 increased in aortic dissection: why?

To detect the expression of Nesprin-1 in aortic dissection (AD) in patients and to investigate the role of Nesprin-1 in the pathogenesis of AD in a mouse model. Blood and tissue specimens from AD patients were collected. The expression of Nesprin-1 in tissues from AD patients and non-AD patients with heart disease was studied by western blotting and quantitative real-time polymerase chain reaction (qRT-PCR). In addition, the expression and distribution of Nesprin-1 in AD and sham mice were compared in an induced AD mouse model, and detected by immunohistochemistry and qRT-PCR. Immunoblotting and qRT-PCR both showed that the expression of Nesprin-1 was significantly higher in AD versus control patients. An animal model of AD was established by continuous injection of Ang II into ApoE-/- mice. The expression of Nesprin-1 in aortic tissue of AD mice was higher than that of sham-operated mice as determined by immunohistochemistry. qRT-PCR showed that Nesprin-1 gene expression in aorta of AD mice was higher than that of sham-operated mice. An increased expression of Nesprin-1 was associated with AD, and hence Nesprin-1 may be involved in the pathogenesis of ADs. Preliminary findings suggest that Nesprin-1 may be a therapeutic target for the treatment of AD.

Febuxostat Pretreatment Attenuates Experimental Aortic Dissection in Mice

Introduction - Acute aortic dissection (AAD) is a life-threatening disease among the elderly. AAD is caused by excessive smooth muscle cell loss, extracellular matrix degradation, and inflammation. Although it was recently reported that reactive oxygen species (ROS), which are generated by various pathways such as through the action of xanthine oxidoreductase (XOR), is associated with AAD pathogenesis,1 the mechanisms underlying AAD are not yet understood. XOR is a molybdopterin-containing enzyme that oxidizes hypoxanthine to xanthine, and subsequently, to uric acid. XOR exists in two interconvertible forms, xanthine oxidase (XO) and xanthine dehydrogenase (XDH), and has been linked to the pathogenesis of cardiovascular disease.2 The objective of this study was to investigate the role of XOR in the pathogenesis of AAD and to evaluate whether ROS inhibition by febuxostat, a highly potent inhibitor of XOR, attenuates the development of AAD. Methods - We used fluorescence immunohistochemistry to assess XOR expression in aortic tissues resected from ten AAD patients and in normal aortic tissues from five autopsy samples. In an experimental aortic dissection model based on spontaneously hyperlipidemic Apobec-1−/−/LDLR−/−mice, the mice were treated with drinking water containing 0.027 mg/mL of febuxostat for seven days before angiotensin II (1000 ng/kg/min) was infused. Results - We revealed enhanced XOR expression in atherosclerotic plaques and the degenerated tunica media in AAD tissues compared to that in control tissues, suggesting that XOR-inhibition is associated with the pathogenesis of AAD. In experimental animal study, febuxostat suppressed significantly mortality caused by aortic dissection and ruptured bleeding. (Fig. 1) Furthermore, aortic architecture was preserved, (Fig. 2A) and ROS activity in the aortic wall and macrophage infiltration to the wall was decreased by febuxostat administration compared to mice that received no treatment (Fig. 2B). Conclusion - Our findings suggest that XOR expression in aortic tissues may promote AAD. These results demonstrate that in the aortic wall, XO-mediated ROS formation is pro-inflammatory and XO inhibition by febuxostat is a potential therapy for AAD.

High Salt Intake Worsens Aortic Dissection in Mice: Involvement of IL (Interleukin)-17A-Dependent ECM (Extracellular Matrix) Metabolism.

Aortic dissection (AD) is a fatal disease that occurs suddenly without preceding clinical signs or symptoms. Although high salt intake is a proposed risk factor for cardiovascular diseases, the relationship between AD and high salt intake has not been clarified. We examined the effect of high-salt challenge on a mouse AD model. Approach and Results: AD was induced in male mice by continuous infusion of β-aminopropionitrile and Ang II (angiotensin II). High-salt challenge exacerbated aortic wall destruction in AD. Deletion of Il17a (IL-17KO [IL (interleukin)-17A knockout]) did not affect the AD phenotype at baseline, but it abolished the high salt-induced worsening of the aortic destruction. Unexpectedly, aortas of IL-17KO mice exhibited global changes in ECM (extracellular matrix)-related genes without alteration of proinflammatory genes, altered architecture of collagen fibers, and reduced stiffness before AD induction. The aortas of IL-17KO mice were less sensitive to AD-inducing stimuli, as shown by the induction of phenotypic modulation markers SMemb and vimentin, suggesting a reduced stress response. The aortas of IL-17KO mice had a higher population of smooth muscle cells with nuclear-localized phosphorylated Smad2, indicative of TGFβ (transforming growth factor-beta) signal activation. Consistently, pretreatment of smooth muscle cells in culture with IL-17A blunted the activation of Smad2 by TGFβ1. These findings indicate that high salt intake has a worsening effect on AD in the context of high aortic wall stiffness, which is under the control of IL-17A through ECM metabolism. Therefore, salt restriction may represent a low-cost and practical way to reduce AD risk.

Macrophage metabolic reprogramming aggravates aortic dissection through the HIF1α-ADAM17 pathway✰.

BackgroundAortic dissection is a severe inflammatory vascular disease with high mortality and limited therapeutic options. The hallmarks of aortic dissection comprise aortic inflammatory cell infiltration and elastic fiber disruption, highlighting the involvement of macrophage. Here a role for macrophage hypoxia-inducible factor 1-alpha (HIF-1α) in aortic dissection was uncovered.MethodsImmunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1α in two kinds of aortic dissection models and human tissues. Metabolomics and Seahorse extracellular flux analysis were used to detect the metabolic state of macrophages involved in the development of aortic dissection. Chromatin Immunoprecipitation (ChIP), enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were employed for mechanistic studies.FindingsMacrophages involved underwent distinct metabolic reprogramming, especially fumarate accumulation, thus inducing HIF-1α activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1α activation triggered vascular inflammation, extracellular matrix degradation and elastic plate breakage through increased a disintegrin and metallopeptidase domain 17 (ADAM17), identified as a novel target gene of HIF-1α. A HIF-1α specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1α.InterpretationThis study reveals that macrophage metabolic reprogramming activates HIF-1α and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1α inhibition might be a potential therapeutic target for treating aortic dissection.

P6493Syk activation is a defense mechanism in murine model of aortic dissection

Abstract Background Aortic dissection (AD) is a serious clinical condition with unknown etiology that frequently results in fatal outcome. Recent studies showed essential role of inflammatory response both in promoting AD and aortic aneurysm (AA). However, the difference of the molecular pathogenesis between AD and AA is unclear. Previously, we reported that Syk, a tyrosine kinase that regulates differentiation and activation of inflammatory cells, promotes AA formation in a mouse model. Objective In the current study, we investigated the role of Syk in AD. Methods and results A mouse AD model was created by continuous infusion of beta-aminopropionitrile (125 mg/kg/day) and angiotensin II (1,000 ng/min/kg) (BAPN+AngII), which caused AD in approximately 80% of mice within 14 days. Immunohistochemical staining for activated (phosphorylated) Syk (pSyk) revealed that Syk was inactive in normal mouse aorta, but was activated in the aortic walls after AD development. Double immunofluorescence staining for pSyk and smooth muscle alpha actin showed that Syk was active not only in the infiltrating inflammatory cells, but also in smooth muscle cells in AD tissue. Western blot analysis revealed that BAPN+AngII treatment caused Syk activation at 3 days before AD development, followed by transient suppression, and reactivation at 14 days after AD development. We examined the significance of Syk activation in AD by treating mice with fostamatinib, a specific Syk inhibitor, before and during BAPN+AngII infusion. Notably, fostamatinib-treated group developed more severe AD compared to the vehicle-treated group. The AD lesion length was 3.80±0.86 mm for vehicle group and 8.87±1.69 mm for fostamatinib group (P<0.05, n=12 for each group). In addition, fostamatinib significantly worsened the mortality of mice due to the rupture of the aorta from 0% to 42% (P<0.05, n=12 for each group). Transcriptome analysis revealed that fostamatinib suppressed both positive and negative regulators of immune response, defense response and inflammatory response. Conclusions These findings uncovered the previously unrecognized role of Syk for protecting the aortic tissue in AD pathogenesis, and suggested fundamentally different disease mechanisms of AD and AA.

MicroRNA-22 Promotes Apoptosis of Human Aortic Smooth Muscle Cells by Targeting p38MAPK Alpha in Vascular Remodeling of Aortic Dissection

Background: Post-transcriptional mechanisms, including microRNA-mediated inhibition of gene expression, participates in vascular remodeling by modulating the biological functions of VSMCs. Methods: We explored the miR-22 expression in aortic tissues from normal and thoracic aortic dissection patients respectively. In addition, we noticed that the apoptosis of VSMCs was regulated by miR-22 in vitro, and in vivo aortic dissection models. Findings: The miR-22 expression of aortic tissues in AD patients is lower than NA patients (P < 0.05). Apoptosis of VSMCs accelerates in human aorta with aortic dissection. In the meanwhile, downregulation of miR-22 increases the apoptosis of VSMCs, vice versa. Bioinformatics and luciferase analyses reveals that p38MAPKα is a novel target of miR-22. Inhibiting p38MAPKα expression could reverse the apoptosis of VSMCs, which is induced by downregulation of miR-22. Moreover, p38MAPKα expression is significantly positively correlated with the rate of apoptosis of VSMCs in aortic dissection tissues. Knockdown of miR-22 in a murine AD model significantly promotes the incidence rate of aortic dissection by enhancing the degradation of elastin and collagen. Finally, in-situ TUNEL staining shows that downregulation of miR-22 increases the apoptosis of VSMCs in mice aorta as well as p38MAPKα expression. Interpretation: Our study underscores the importance of vascular remodeling and VSMC function in controlling the development of aortic dissection. Funding Statement: This study was financed by the National Natural Science Foundation of China (81570425 and 91739110). Declaration of Interests: The authors declare they have no conflicts of interest. Ethics Approval Statement: All animal experiments were performed in accordance with the animal protocols approved by the Institutional Animal Care and Use Committee of Anti-Cancer Biotech (Beijing, China). Prior written informed consents from all patients inaccordance with the Declaration of Helsinki and the approval from the Ethics Committee of The Second Military Medical University Changhai Hospital were obtained.

Activation of Bone Marrow–Derived Cells and Resident Aortic Cells During Aortic Injury

BackgroundThe process of aortic injury, repair, and remodeling during aortic aneurysm and dissection is poorly understood. We examined the activation of bone marrow (BM)-derived and resident aortic cells in response to aortic injury in a mouse model of sporadic aortic aneurysm and dissection. Materials and methodsWild-type C57BL/6 mice were transplanted with green fluorescent protein (GFP)+ BM cells. For 4 wk, these mice were either unchallenged with chow diet and saline infusion or challenged with high-fat diet and angiotensin II infusion. We then examined the aortic recruitment of GFP+ BM-derived cells, growth factor production, and the differentiation potential of GFP+ BM-derived and GFP− resident aortic cells. ResultsAortic challenge induced recruitment of GFP+ BM cells and activation of GFP− resident aortic cells, both of which produced growth factors. Although BM cells and resident aortic cells equally contributed to the fibroblast populations, we did not detect the differentiation of BM cells into smooth muscle cells. Interestingly, aortic macrophages were both of BM-derived (45%) and of non−BM-derived (55%) origin. We also observed a significant increase in stem cell antigen-1 (Sca-1)+ stem/progenitor cells and neural/glial antigen 2 (NG2+) cells in the aortic wall of challenged mice. Although some of the Sca-1+ cells and NG2+ cells were BM derived, most of these cells were resident aortic cells. Sca-1+ cells produced growth factors and differentiated into fibroblasts and NG2+ cells. ConclusionsBM-derived and resident aortic cells are activated in response to aortic injury and contribute to aortic inflammation, repair, and remodeling by producing growth factors and differentiating into fibroblasts and inflammatory cells.

Scavenger receptor A1 attenuates aortic dissection via promoting efferocytosis in macrophages

Macrophage class A1 scavenger receptor (SR-A1) is a pattern recognition receptor with an anti-inflammatory feature in cardiovascular diseases. However, its role in acute aortic dissection (AD) is not known yet. Using an aortic dissection model in SR-A1-deficient mice and their wild type littermates, we found that SR-A1 deficiency aggravated beta-aminopropionitrile monofumarate induced thoracic aortic dilation, false lumen formation, extracellular matrix degradation, vascular inflammation and accumulation of apoptotic cells. These pathological changes were associated with an impaired macrophage efferocytosis mediated by tyrosine-protein kinase receptor Tyro3 in vitro and in vivo. SR-A1 could directly interact with Tyro3 and was required for Tyro3 phosphorylation to activate its downstream PI3K/Akt signaling pathway. Importantly, co-culture of SR-A1−/− macrophages with apoptotic Jurkat cells resulted in less devoured apoptotic cells accompanied by swelling mitochondria and damaged ATP generation, following poor IL-10 and robust TNF-α production. Deficiency of SR-A1 did not influence phagolysosome formation during the efferocytosis. Lentiviral overexpression of Tyro3 in SR-A1−/− macrophages induced restorative phagocytosis in vitro. Administration of Tyro3 agonist protein S could restore SR-A1−/− macrophages phagocytosis in vitro and in vivo. These findings suggest that SR-A1-Tyro3 axis in macrophages mitigate AD damage by promoting efferocytosis and inhibiting inflammation.

Effect of bilateral superior cervical sympathetic ganglion occlusion on pathological process of aortic dissection and its mechanism

To investigate the effect of bilateral superior cervical sympathetic ganglion occlusion (SCG) on aortic dissection and its possible mechanism. Forty-five SD rats were randomly divided into three groups with 15 in each:blank control group, sham operation group and SCG group. β-aminopropione (666 mg·kg-1·d-1) was given by subcutaneous injection for 4 weeks to establish the aortic dissection model. Rats in SCG group were given SCG before the injection of β-aminopropione. Blood pressure and heart rate of the rats were monitored using noninvasive tail artery blood pressure measuring instrument; sympathetic activity was monitored using drug block method; the structure of aortic wall was observed using HE staining; collagen fibers in aortic wall was observed using Sirius red staining; protein expression of Apelin was detected by immunohistochemistry; and the protein expression of matrix metalloproteinase (MMP)-2, 9 was detected by Western blotting. During the experiment, the body mass of the sham operation group and SCG group was smaller than that of the blank control group (all P<0.05), and the body mass of the SCG group was larger than that of the sham operation group (all P<0.05). The heart rate and sympathetic activity of the sham operation group were higher than those of the blank control group (all P<0.05), while the SCG group were lower (all P<0.05). Compared with the blank control group, the aortic wall in the sham operation group was thickening, while that in the SCG group was improved. A large number of collagen-1 in the aortic wall of the blank control group was stained brown by Sirius red, which was lighter in SCG group, and the staining in the sham operation group was the lightest. Compared with the blank control group, the expression of Apelin, MMP-2 and MMP-9 protein in the sham operation group increased (all P<0.05), while those in the SCG group decreased (all P<0.05). SCG can effectively reduce the incidence and mortality of aortic dissection in rats, which may be related to the inhibition of sympathetic activity and the decrease of collagen-1, Apelin, MMP-2 and MMP-9 expression.

A swine aortic dissection model applying to the hemodynamic and endovascular aortic repair study

Objective To construct an aortic dissection (AD) model in swine applying to the hemodynamic and endovascular aortic repair study. Methods Ten swine of AD were created using open surgical procedures under general anesthesia. The healthy aorta and dissection propagation were evaluated using digital subtraction angiography (DSA) before and after the procedure. The hemodynamic measurements were performed during the follow up. Animals were scanned with computed tomography scan during the 12 months of follow-up and subjected to post-experimental autopsy. Three models underwent endovascular stent-graft implantation through abdominal aorta access. Results All models were successfully created. The mean time for establishing the model was 44.1 min (range 27.4-65.0 min), while the duration of total aortic occlusion was 21.2 min (range 14.3-34.5 min). At the first day post-procedures, two animals died of anesthesia related complications and aortic rupture, respectively. The average follow-up was 8.4 months. The mean diameter of the aorta at the primary entry tear was 18.9 mm. The total propagation length was observed in the models during the follow-up was 147.6 mm, with the maximum diameter of the dissection aorta of 24.1 mm. Most of the distal tears were found around the branches fed by the aorta according to the CT images and autopsy. Histopathological examination demonstrated the fibers were stretched linearly at the outside of the false lumen. The signals of Doppler measurements of velocity and pressure in the models were acceptable. No complication was observed after stent-graft repair in the three models. Conclusion This model in swine can be applied in hemodynamic and endovascular aortic repair study for AD. Key words: Aortic dissection; Swine; Model; Hemodynamics; Endovascular repair

Involvement of DHX9/YB-1 complex induced alternative splicing of Krüppel-like factor 5 mRNA in phenotypic transformation of vascular smooth muscle cells.

Phenotypic transformation of vascular smooth muscle cells is a key phenomenon in the development of aortic dissection disease. However, the molecular mechanisms underlying this phenomenon have not been fully understood. We used β-BAPN combined with ANG II treatment to establish a disease model of acute aortic dissection (AAD) in mice. We first examined the gene expression profile of aortic tissue in mice with AAD using a gene chip, followed by confirmation of DExH-box helicase 9 (DHX9) expression using RT-PCR, Western blot, and immunofluorescence analysis. We further developed vascular smooth muscle cell-specific DHX9 conditional knockout mice and conducted differential and functional analysis of gene expression and alternative splicing in mouse vascular smooth muscle cells. Finally, we examined the involvement of DHX9 in Krüppel-like factor 5 (KLF5) mRNA alternative splicing. Our study reported a significant decrease in the expression of DHX9 in the vascular smooth muscle cells (VSMCs) of mice with AAD. The smooth muscle cell-specific knockout of DHX9 exacerbated the development of AAD and altered the transcriptional level expression of many smooth muscle cell phenotype-related genes. Finally, we reported that DHX9 may induce alternative splicing of KLF5 mRNA by bridging YB-1. These results together suggested a new pathogenic mechanism underlying the development of AAD, and future research of this mechanism may help identify effective therapeutic intervention for AAD.

Abnormal Ribosome Biogenesis Partly Induced p53-Dependent Aortic Medial Smooth Muscle Cell Apoptosis and Oxidative Stress.

Ribosome biogenesis is a crucial biological process related to cell proliferation, redox balance, and muscle contractility. Aortic smooth muscle cells (ASMCs) show inhibition of proliferation and apoptosis, along with high levels of oxidative stress in aortic dissection (AD). Theoretically, ribosome biogenesis should be enhanced in the ASMCs at its proliferative state but suppressed during apoptosis and oxidative stress. However, the exact status and role of ribosome biogenesis in AD are unknown. We therefore analyzed the expression levels of BOP1, a component of the PeBoW complex which is crucial to ribosome biogenesis, in AD patients and a murine AD model and its influence on the ASMCs. BOP1 was downregulated in the aortic tissues of AD patients compared to healthy donors. In addition, overexpression of BOP1 in human aortic smooth muscle cells (HASMCs) inhibited apoptosis and accumulation of p53 under hypoxic conditions, while knockdown of BOP1 decreased the protein synthesis rate and motility of HASMCs. The RNA polymerase I inhibitor cx-5461 induced apoptosis, ROS production, and proliferative inhibition in the HASMCs, which was partly attenuated by p53 knockout. Furthermore, cx-5461 aggravated the severity of AD in vivo, but a p53-/- background extended the life-span and lowered AD incidence in the mice. Taken together, decreased ribosome biogenesis in ASMCs resulting in p53-dependent proliferative inhibition, oxidative stress, and apoptosis is one of the underlying mechanisms of AD.

In Vivo Detection and Measurement of Aortic Aneurysm and Dissection in Mouse Models Using Microcomputed Tomography with Contrast Agent.

Objectives The aim of this study was to evaluate the potential of microcomputed tomography (micro-CT) using the intravascular contrast agent ExiTron nano 12000 for aorta imaging and monitoring the dynamic changing process of the aorta in mouse models with aortic aneurysm and dissection. Materials and Methods Experiments were performed on healthy mice and mice with aortic dissection. Mice that were developing aortic dissection and healthy mice underwent micro-CT imaging after injection of ExiTron nano 12000. Time-dependent signal enhancement (at 1, 2, 3, 6, and 12 hours after intravenous injection of the contrast agent, respectively) in the aorta of healthy mice was measured to confirm the optimal imaging time of aorta. Various contrast agent doses (70, 100, and 150 μl per 25 g mouse, respectively) were investigated to determine the optimal required dose for imaging of the aorta. The mice were scanned with micro-CT at 1, 14, and 28 days after onset of aneurysm and dissection to monitor the dynamic changing process of the aorta. Mouse aortas were stained with hematoxylin and eosin staining, and the diameter of the aorta was measured and compared with those obtained by micro-CT. Results Time-dependent signal enhancement in the aorta shows that the contrast agent has a long blood half-life of 6 hours, with a peak enhancement at 2 hours after injection. Injection of 100 μl ExiTron nano 12000 per 25 g mouse allows for effective visualization of the aorta. Micro-CT combined with contrast agent can monitor the changing process of the aorta in the mouse model of aortic aneurysm and dissection dynamically. The values of the diameter of the aortas obtained from the in vivo micro-CT imaging were compared with those obtained from histology and showed a significant correlation (R2 = 0.96). Conclusions These data demonstrate that in vivo micro-CT is an accurate and feasible technique to detect aortic aneurysm or dissection in a mouse model, and the micro-CT technique using the innovative contrast agent ExiTron nano 12000 allows for monitoring various processes dynamically such as aortic remodeling in longitudinal studies.

Numerical simulation study of type B aortic dissection using patient-specific reverse engineering and fluid-structure interaction

Objective: To construct computational fluid model of type B aortic dissection using patient-specific reverse engineering and fluid-structure interaction, and evaluate the application of computational fluid model on aortic remodeling of type B aortic dissection. Methods: Consecutive computed tomographic angiograph data was acquired from a patient with type B aortic dissection at initial diagnosis, 1 week and 6 years after endovascular repair of primary tear entry and 3 months after endovascular repair of distal tear erosion. Three-dimensional model of aortic dissection was reversely reconstructed by Mimics, and then the model was smoothened by Geomagic. Computational fluid dynamic numerical simulation was performed in ANSYS by the means of two-way fluid-structure interaction, and the relation between blood dynamic characteristic and thrombosed remodeling of type B aortic dissection was evaluated. Results: The computational fluid model of type B aortic dissection using patient-specific reverse engineering and fluid-structure interaction method was successfully constructed. Local peak of blood pressure on the convex surface of junction at aortic arch and descending aorta was found. The wall stress was much higher at the false lumen than that at the true lumen, and the peak of wall stress converged on the edge and tear entry of false lumen. After the exclusion of proximal tear entry, the blood streamline was decreased significantly and flowed reversely. Blood flow in the remaining false lumen was retrograded from the entry at left iliac artery and formed turbulence at the top of false lumen, which was benefit for dissection thrombus remodeling. The higher pressure at the false lumen was associated with the new formation of aortic aneurysm at the distal tear. Conclusion: The computational fluid model of aortic dissection based on patient-specific reverse engineering and fluid-structure interaction method can successfully reveal the relatively truly blood dynamic and wall pressure characteristic of type B aortic dissection.

Development of a novel aortic dissection mouse model and evaluation of drug efficacy using in-vivo assays and database analyses.

Aortic dissection is a life-threatening disease. At present, the only therapeutic strategies available are surgery and antihypertensive drugs. Moreover, the molecular mechanisms underlying the onset of aortic dissection are still unclear. We established a novel aortic dissection model in mice using pharmacologically induced endothelial dysfunction. We then used the Japanese Adverse Drug Event Report database to investigate the role of pitavastatin in preventing the onset of aortic dissection. To induce endothelial dysfunction, Nω-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, was administered to C57BL/6 mice. Three weeks later, angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, were administered with osmotic mini-pumps. False lumen formation was used as the pathological determinant of aortic dissection. The incidences of aortic dissection and death from aneurysmal rupture were significantly higher in the Nω-nitro-L-arginine methyl ester, Ang II, and BAPN (LAB) group than they were in the Ang II and BAPN (AB) group.Pitavastatin was administered orally to LAB mice. It significantly lowered the incidences of dissection and rupture. It also decreased inflammation and medial degradation, both of which were exacerbated in the LAB group. The Japanese Adverse Drug Event Report database analysis indicated that there were 113 cases of aortic dissection out of 95 090 patients (0.12%) not receiving statins but only six cases out of 16 668 patients receiving statins (0.04%) (odds ratio: 0.30; P = 0.0043). Our results suggest that endothelial dysfunction is associated with the onset of aortic dissection and pitavastatin can help prevent this condition.

Yes-associated protein 1 up-regulation inhibits apoptosis of aortic dissection vascular smooth muscle cells

Objective To investigate the role of Yes-associated protein 1 (YAP1) expression in apoptosis of vascular smooth muscle cells (VSMCs) and pathogenesis of aortic dissection (AD). Methods AD rat model was established to compare apoptosis and the expression of YAP1 within vascular tissues against normal controlled rats.In vitro cultured rat thoracic VSMCs were divided into control, cyclic stretch, cyclic stretch + pIRES2-blank and cyclic stretch + pIRES2-YAP1 groups. Cell apoptosis rate, YAP1 and Survivin expression were measured. AD rats were divided into model, Ad-NC injection, and Ad-YAP1 injection groups for comparing VSMCs apoptosis, AD formation rate, diameter and length. Results The AD rats of AD modle groupe is 43.1% [AD diameter is (6.21±1.13) mm, AD length is (9.25±1.77) mm]; The AD rats of Ad-NC-injecting groupe is 43.1% [AD diameter is (6.21±1.13) mm, AD length is (9.25±1.77) mm]; The AD rats of Ad-YAP1-injecting groupe is 43.1% [AD diameter is (6.21±1.13) mm, AD length is (9.25±1.77) mm]. Compared to control group, AD rats had elevated vascular cell apoptosis, and down-regulated YAP1 expression. Cyclic stretch significantly induced VSMCs apoptosis. YAP1 over-expression up-regulated Survivin and antagonized cyclic stretch-induced cell apoptosis. Injection of Ad-YAP1 via the tail vein significantly up-regulated YAP1 and Survivin expression, and decreased apoptosis, AD formation rate and AD diameter/length in vascular tissues of rat AD models. Conclusion YAP1 down-regulation plays a role in facilitating VSMCs apoptosis and AD pathogenesis. Up-regulation of YAP1 decreases VSMCs apoptosis and AD formation. Key words: Yes-associated protein 1; Hippo-Yes-associated protein; Vascular smooth muscle cells; Aortic dissection; Apoptosis

Mechanical stretch aggravates aortic dissection by regulating MAPK pathway and the expression of MMP-9 and inflammation factors.

This study aimed to explore whether mechanical stretch aggravated aortic dissection through regulating MAPK pathway, MMP-9, and inflammation factors. We first established aortic dissection model rats. Mechanical stretch (3 g) was exerted on vascular ring of aortic dissection which was also treated by inhibitors of MAPK pathway (SB203580, SP600125, and U0126). HE and Masson staining showed that aortic dissection severity with 3 g tension was worse than that without tension (0 g); after the treatments of diverse inhibitors, the fracture and breakage of the elastic fibers decreased. The expression of MMP-9, TNF-α, IL-1β) p38/p-p38, JNK1/p-JNK1, and ERK1/2/p-ERK1/2 were determined by immunohistochemical analysis, RT-PCR, and western blot. No matter whether tension was exerted or inhibitors were added, there was no change in the expression of p38, JNK1, and ERK1/2. However, compared to the 0 g group, the expression of MMP-9, TNF-α, IL-1β, p-p38, p-JNK1, and p-ERK1/2 was significantly upregulated in the 3 g group (P < 0.05). In both 0 g and 3 g groups, the expression of MMP-9, TNF-α, IL-1β, p-p38, p-JNK1, and p-ERK1/2 was remarkably downregulated after inhibitors treatment (P < 0.05). In conclusion, mechanical stretch aggravated aortic dissection by regulating the MAPK pathway and the consequent expression of MMP-9 and inflammation factors.

When Surgeons Create Their Own Tools!

In their paper, El Batti et al. proposed an experimental evaluation of endovascular fenestration scissors in an ovine model of aortic dissection.1El Batti S. Ben Abdallah I. Dufetelle E. Julia P. Menasche P. Alsac J.M. Experimental evaluation of endovascular fenestration scissors in an ovine model of aortic dissection.Eur J Vasc Endovasc Surg. 2018; 56: 373-380Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar This is a really interesting study that opens the doors to a new technique for treating patients and also for involving surgeons in creating the tools they actually need. The authors proposed a new device that may allow easier and safer endovascular fenestration than the usual technique that uses a sheath over two stiff wires to create a “scissor/fork” effect.2Alomran F. Alsac J.M. Distal endovascular fenestration inside thoracic exclusion: the DEFINITE technique for complicated acute type B dissections.Eur J Vasc Endovasc Surg. 2017; 53: 103Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar Contrary to this “sheath over two wires,” they proposed a new innovative device consisting of “endo-scissors” comparable with those used in open surgery. Theoretically, endo-scissors should provide sharp cuts and avoid folding and tearing of the flap. It appears logical to compare both methods and prove the efficiency of the new device. More in depth preliminary in vitro tests could have been performed to evaluate the capabilities of the new device to cut materials of different thicknesses or densities and focus in vivo on the optimal device prototype. Moreover, it would have been very interesting to know the differences the authors may have noticed concerning ease of cutting, quality of cutting such as torn area or regular cut, as well as the ability to control the quality of the procedure under X-ray. The authors included in their study a haemodynamic evaluation of flap resection in the ovine dissection model they developed. Several models of aortic dissection have already been developed, but haemodynamic evaluation has been doubtful: dissection flaps were often unpredictable and inconsistent, either being very short in length or with undefined propagation and low reproducibility, in subsequent experiments.3Qing K.X. Chang Y.C. Lau S.F. Yiu W.K. Ting A.C. Cheng S.W. Ex-vivo haemodynamic models for the study of Stanford type B aortic dissection in isolated porcine aorta.Eur J Vasc Endovasc Surg. 2012; 44: 399-405Abstract Full Text Full Text PDF PubMed Scopus (25) Google Scholar In their paper, El Batti et al. assessed the validity of the model using haemodynamic criteria, giving pressure values in both lumens and their change after fenestration. It may be criticised that the relatively short and small channel of dissection did not include visceral artery ostia, however, the model appeared to allow testing of endovascular fenestration scissors, even if it is unlike human pathology and does not allow valid conclusions concerning haemodynamic evaluation. In conclusion, this study is the perfect example of what should be a surgeon driven device to answer a clinical issue. The paper demonstrates how translational research and surgeon's involvement can lead to advances in our daily practice.4Vega de Ceniga M. Chakfé N. Back to the future.Eur J Vasc Endovasc Surg. 2018; 55: 453-454Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar Experimental Evaluation of Endovascular Fenestration Scissors in an Ovine Model of Aortic DissectionEuropean Journal of Vascular and Endovascular SurgeryVol. 56Issue 3PreviewTo evaluate the experimental feasibility of endovascular fenestration using specific endovascular scissor prototypes in an ovine model of acute aortic dissection (AD). Full-Text PDF Open Archive

Experimental Evaluation of Endovascular Fenestration Scissors in an Ovine Model of Aortic Dissection

To evaluate the experimental feasibility of endovascular fenestration using specific endovascular scissor prototypes in an ovine model of acute aortic dissection (AD). A previously described endovascular technique was used to create a model of acute type B AD in sheep. Endovascular fenestrations using either endovascular scissor prototypes or a long sheath were compared. Four prototypes of endovascular fenestration scissors were evaluated. Both validity of the experimental model of AD and technical success of endovascular fenestration were assessed by haemodynamic criteria, completion angiography, transesophageal echocardiography, and post-procedural analysis of harvested aortas. Experimental acute AD was created by endovascular means in 17 sheep, with a technical success rate of 82%. Systolic blood pressure was lower in the false lumen than in the true lumen (58±5 vs. 79±3mmHg, respectively; p<.001). Endovascular fenestration was performed in 11 models (endovascular scissors n=8; long sheath n=3). Controlled endovascular fenestration was obtained by the use of endovascular scissors (n=5/8), resulting in a significant rise in false lumen systolic blood pressure after fenestration (60±2 vs. 67±9mmHg before and after fenestration, respectively; p<.047). Long sheath fenestration resulted in an uncontrolled flap motion, leading to either pseudo-coarctation syndrome or aortic rupture (58±6 vs. 40±2mmHg before and after fenestration, respectively; p<.001). In this experimental study, a reproducible AD model has been developed in sheep using endovascular procedures exclusively to evaluate endovascular fenestration techniques. Endovascular fenestration using a long sheath appeared hazardous and risky invivo. Endovascular scissors constitute a dedicated and suitable tool to perform a safe controlled and effective endovascular fenestration in an ovine model.

Four-dimensional flow cardiovascular magnetic resonance in aortic dissection: Assessment in an ex vivo model and preliminary clinical experience

ObjectiveFour-dimensional flow cardiovascular magnetic resonance may improve assessment of hemodynamics in patients with aortic dissection. The purpose of this study was to evaluate the feasibility and accuracy of 4-dimensional flow cardiovascular magnetic resonance assessment of true and false lumens flow. MethodsThirteen ex vivo porcine aortic dissection models were mounted to a flow loop. Four-dimensional flow cardiovascular magnetic resonance and 2-dimensional phase-contrast cardiovascular magnetic resonance measurements were performed, assessed for intraobserver and interobserver variability, and compared with a reference standard of sonotransducer flow volume measurements. Intraobserver and interobserver variability of 4-dimensional flow cardiovascular magnetic resonance were also assessed in 14 patients with aortic dissection and compared with 2-dimensional phase-contrast cardiovascular magnetic resonance. ResultsIn the ex vivo model, the intraobserver and interobserver measurements had Lin's correlation coefficients of 0.98 and 0.96 and mean differences of 0.17 (±3.65) mL/beat and −0.59 (±5.33) mL/beat, respectively; 4-dimensional and sonotransducer measurements had a Lin's concordance correlation coefficient of 0.95 with a mean difference of 0.35 (±4.92) mL/beat, respectively. In patients with aortic dissection, the intraobserver and interobserver measurements had Lin's concordance correlation coefficients of 0.98 and 0.97 and mean differences of −0.95 (±8.24) mL/beat and 0.62 (±10.05) mL/beat, respectively; 4-dimensional and 2-dimensional flow had a Lin's concordance correlation coefficient of 0.91 with a mean difference of −9.27 (±17.79) mL/beat because of consistently higher flow measured with 4-dimensional flow cardiovascular magnetic resonance in the ascending aorta. ConclusionsFour-dimensional flow cardiovascular magnetic resonance is feasible in patients with aortic dissection and can reliably assess flow in the true and false lumens of the aorta. This promotes potential future work on functional assessment of aortic dissection hemodynamics.