Aortic Wall Research Articles

Poisson function and volume ratio of soft anisotropic materials under large deformations

Accurate transverse deformation measurements are required for the estimation of the Poisson function and volume ratio. In this study, pure silicone and soft composite specimens were subjected to uniaxial tension, and the digital image correlation method was used to measure longitudinal and in- and out-of-plane transverse stretches. To minimize the effects of measurement errors on parameter estimation, the measured transverse stretches were defined in terms of the longitudinal stretch using a new formulation based on Poisson's ratios and two stretch-dependent parameters. From this formulation, Poisson functions and volume ratio for soft materials under large deformations were obtained. The results showed that pure silicone can be considered isotropic and nearly incompressible under large deformations, as expected. In contrast, Poisson's ratio of silicone reinforced with extensible fabric can exceed classical bounds, including negative value (auxetic behavior). The incompressibility assumption can be employed for describing the stress-stretch curve of pure silicone, while volume ratios are required for soft composites. Data of human skin, aortic wall, and annulus fibrosus from the literature were selected and analyzed. Except for the aortic wall, which can be considered nearly incompressible, the studied soft tissues must be regarded as compressible. All tissues presented anisotropic behavior.

Antibody to Endogenous Cardiotonic Steroid Reverses Vascular Fibrosis and Restores Vasorelaxation in Chronic Kidney Disease.

Marinobufagenin (MBG) is implicated in chronic kidney disease, where it removes Fli1-induced inhibition of the collagen-1. We hypothesized that (i) in nephrectomized rats, aortic fibrosis develops due to elevated plasma MBG and inhibited Fli1, and (ii) that the antibody to MBG reduces collagen-1 and improves vasodilatation. A partial nephrectomy was performed in male Sprague-Dawley rats. Sham-operated animals comprised the control group. At 5 weeks following nephrectomy, rats were administered the vehicle (n = 8), or the anti-MBG antibody (n = 8). Isolated aortic rings were tested for their responsiveness to sodium nitroprusside following endothelin-1-induced constriction. In nephrectomized rats, there was an increase in the intensity of collagen staining in the aortic wall vs. the controls. In antibody-treated rats, the structure of bundles of collagen fibers had ordered organization. Western blots of the aorta had lower levels of Fli1 (arbitrary units, 1 ± 0.05 vs. 0.2 ± 0.01; p < 0.001) and greater collagen-1 (arbitrary units, 1 ± 0.01 vs. 9 ± 0.4; p < 0.001) vs. the control group. Administration of the MBG antibody to rats reversed the effect of the nephrectomy on Fli1 and collagen-1 proteins. Aortic rings pretreated with endothelin-1 exhibited 50% relaxation following the addition of sodium nitroprusside (EC50 = 0.28 μmol/L). The responsiveness of the aortic rings obtained from nephrectomized rats was markedly reduced (EC50 = 3.5 mol/L) compared to the control rings. Treatment of rats with the antibody restored vasorelaxation. Thus, the anti-MBG antibody counteracts the Fli1-collagen-1 system and reduces aortic fibrosis.

Mineralocorticoid Receptor Antagonism Prevents Aortic Plaque Progression and Reduces Left Ventricular Mass and Fibrosis in Patients With Type 2 Diabetes and Chronic Kidney Disease: The MAGMA Trial.

Persistent mineralocorticoid receptor activation is a pathologic response in type 2 diabetes and chronic kidney disease. Whereas mineralocorticoid receptor antagonists are beneficial in reducing cardiovascular complications, direct mechanistic pathways for these effects in humans are lacking. The MAGMA trial (Mineralocorticoid Receptor Antagonism Clinical Evaluation in Atherosclerosis) was a randomized, double-blind, placebo-controlled trial in patients with high-risk type 2 diabetes with chronic kidney disease (not receiving dialysis) on maximum tolerated renin-angiotensin system blockade. The primary end point was change in thoracic aortic wall volume, expressed as absolute or percent value (ΔTWV or ΔPWV), using 3T magnetic resonance imaging at 12 months. Secondary end points were changes in left ventricle (LV) mass; LV fibrosis, measured as a change in myocardial native T1; and 24-hour ambulatory and central aortic blood pressures. Tertiary end points included plasma proteomic changes in 7596 plasma proteins using an aptamer-based assay. A total of 79 patients were randomized to placebo (n=42) or 25 mg of spironolactone daily (n=37). After a modified intent-to-treat, including available baseline data of study end points, patients who completed the trial protocol were included in the final analyses. At the 12-month follow-up, the average change in PWV was 7.1±10.7% in the placebo group and 0.87±10.0% in the spironolactone group (P=0.028), and ΔTWV was 1.2±1.7 cm3 in the placebo group and 0.037±1.9 cm3 in the spironolactone group (P=0.022). Change in LV mass was 3.1±8.4 g in the placebo group and -5.8±8.4 g in the spironolactone group (P=0.001). Changes in LV T1 values were significantly different between the placebo and spironolactone groups (26.0±41.9 ms in the placebo group versus a decrease of -10.1±36.3 ms in the spironolactone group; P=6.33×10-4). Mediation analysis revealed that the spironolactone effect on thoracic aortic wall volume and myocardial mass remained significant after adjustment for ambulatory and central blood pressures. Proteomic analysis revealed a dominant effect of spironolactone on pathways involving oxidative stress, inflammation, and leukocyte activation. Among patients with diabetes with moderate to severe chronic kidney disease at elevated cardiovascular risk, treatment with spironolactone prevented progression of aortic wall volume and resulted in regression of LV mass and favorable alterations in native T1, suggesting amelioration of left-ventricular fibrosis. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02169089.

Acute type B aortic dissection following transcatheter mitral valve edge-to-edge repair: a case report

Abstract Background Transoesophageal echocardiography is rarely reported as a possible cause of aortic dissection during the transcatheter edge-to-edge repair procedure. Herein, we present a case of type B aortic dissection following the transcatheter mitral valve edge-to-edge repair procedure, most likely related to the transoesophageal echocardiography probe. Case summary A 68-year-old Chinese man complained of exertional dyspnoea lasting over 2 years and had been diagnosed with severe mitral regurgitation. He was admitted to our hospital for the treatment of severe mitral regurgitation with transcatheter edge-to-edge repair. One MitraClip XTR (Abbott Vascular) was successfully implanted under the guidance of active transoesophageal echocardiography, and the mitral regurgitation became trace. However, the patient complained of persistent back pain after the treatment, and computed tomography angiography revealed a type B aortic dissection in the descending aorta. After 2 weeks of unsuccessful conservative treatment, he successfully underwent endovascular stenting and was discharged from the hospital. The patient recovered well and remained event free during the 6-month follow-up. Discussion Herein, we presented a rare complication following transcatheter mitral valve edge-to-edge repair that was most likely related to the transoesophageal echocardiography probe—type B aortic dissection. We postulated that repetitive flexion of the transoesophageal echocardiography probe led to compression-induced injury to the descending aorta wall at the mid-oesophageal level, which was the most probable aetiology of type B aortic dissection. Although this complication is rare, it is potentially fatal and therefore needs attention.

Abstract Tu021: Genome-wide CRISPR Screen In Vivo Decodes Monocyte Infiltration Associated With Abdominal Aortic Aneurysm

Introduction: Aortic aneurysm is the second most common aortic disease following atherosclerosis and accounts for the ninth-leading cause of death overall. The inflammatory response has a crucial role in the Abdominal Aortic Aneurysm (AAA) development. The infiltration of monocyte into aortic wall is a hallmark of aortic inflammation and it still requires further understanding of this complicated process. CRISPR screening is a powerful tool to investigate biological process, but it requires large pool of mutant cells and reliable selection procedure, which can usually only be performed in vitro or in xenograft models. To overcome this problem, we developed an unbiased genome-wide CRISPR-Cas Screen for Monocyte Infiltration in vivo (CRISPR-MI) and employed this new method in mouse AAA model to systematically study key genes regulating monocyte infiltration into aortic wall. Hypothesis: Monocyte infiltration is an important process in AAA development and CRISPR-MI could be utilized to study this process in vivo. Methods: To acquire enough monocytes for screen, we used the adoptive transfer method to transplant in vivo differentiated monocytes (bone marrow derived macrophage, BMDM) back into mouse circulation via tail vein injection. We optimized the lentivirus infection protocol, so that sgRNA library delivered by lentivirus can effectively knock out target genes in BMDMs. The BMDMs were infected with sgRNA library before adoptive transfer into AAA-model mice. After transfer, by comparing the sgRNA enrichment in different organs of receipt mice, we could identify key genes inhibiting monocyte infiltration. Results: CRISPR-MI identified novels genes regulating monocyte infiltration into aorta in AAA model, including Trem2 gene. In vitro experiments confirmed that Trem2 knockout increased adhesion molecules and chemokine receptors expression. Conclusions: CRISPR-MI can be used to identify new therapeutical targets for cardiovascular diseases.

Abstract Tu018: Integrin alpha 1 plays a critical role in angiotensin II-induced abdominal aortic aneurysm rupture

Background: Abdominal aortic aneurysm (AAA) is a life-threatening condition without an established specific therapy. This study aims to identify a new therapeutic target for preventing AAA rupture. Methods and Results: Angiotensin II (AngII)-infused ApoE-/- mice develop AAA, an established model of AAA. To identify molecular pathways contributing to AAA development, we conducted single-cell RNA sequence analysis using a dataset of aortic tissues harvested from mice infused with AngII for 4 weeks (GSE186865). Gene set enrichment analysis revealed upregulation of integrin- and TGFB-related pathways in AngII-stimulated smooth muscle cells (SMCs). Integrin α1 (Itga1) constitutes half of the α1β1 integrin duplex and serves as a major collagen receptor in SMCs. Male wild-type (n=37) and Itga1 knockout (n=36) mice with an ApoE-/- background received a continuous infusion of AngII for 4 weeks to develop AAA. Kaplan-Meier analysis indicated that ablating Itga1 significantly suppressed AAA rupture (p=0.009), without affecting the maximum diameter of the abdominal aorta. Considering extracellular matrix degradation as a critical hallmark of AAA rupture, we examined the abundance of major matrix metalloproteinases (MMPs) in the aortic wall, specifically MMP2 and MMP9, two major MMPs in the aorta. Gelatin zymography revealed that ablation of Itga1 suppressed AngII-induced MMP9 increase, without affecting MMP2 abundance. The expression of MMP9 is controlled by inflammation and proliferation signals; hence, we focused on these signals. qPCR analysis (n=8 per group) demonstrated that AngII-induced upregulation of Tnfa (p&lt;0.001) and Tgfb1 (p=0.026) was mitigated by Itga1 ablation in aortic tissues. Conclusion: The integrin pathway is activated in the tissue of AAA tissue and deletion of Itga1 suppresses AAA rupture. Here we showed that the Itga1-Tgfb1-MMP9 axis would be a novel molecular target to inhibit AAA rupture.

AT1b receptors contribute to regional disparities in angiotensin II mediated aortic remodelling in mice.

The renin-angiotensin system plays a key role in regulating blood pressure, which has motivated many investigations of associated mouse models of hypertensive arterial remodelling. Such studies typically focus on histological and cell biological changes, not wall mechanics. This study explores tissue-level ramifications of chronic angiotensin II infusion in wild-type (WT) and type 1b angiotensin II (AngII) receptor null (Agtr1b -/-) mice. Biaxial biomechanical and immunohistological changes were quantified and compared in the thoracic and abdominal aorta in these mice following 14 and 28 days of angiotensin II infusion. Preliminary results showed that changes were largely independent of sex. Associated thickening and stiffening of the aortic wall in male mice differed significantly between thoracic and abdominal regions and between genotypes. Notwithstanding multiple biomechanical changes in both WT and Agtr1b -/- mice, AngII infusion caused distinctive wall thickening and inflammation in the descending thoracic aorta of WT, but not Agtr1b -/-, mice. Our study underscores the importance of exploring differential roles of receptor-dependent angiotensin II signalling along the aorta and its influence on distinct cell types involved in regional histomechanical remodelling. Disrupting the AT1b receptor primarily affected inflammatory cell responses and smooth muscle contractility, suggesting potential therapeutic targets.

The proximal extension of acute type A aortic dissection is associated with ascending aortic wall degeneration.

Aortic root involvement during acute type A aortic dissection (ATAAD) may depend on ascending aortic wall degeneration. Surgical decision-making for extended resection of the aortic root is clinically made without histopathology. The aim of the study was to investigate whether the degree of degeneration of the ascending aortic wall found in patients with ATAAD is associated with the aortic root involvement. Collectively, 141 consecutive patients undergoing ATAAD surgery at Tampere University Heart Hospital were investigated. The ascending aortic wall resected in surgery was processed for 11 different variables that describe medial and adventitial degeneration. In addition, atherosclerosis and inflammation were separately evaluated. Patients undergoing aortic root replacement were compared with those with supracoronary reconstruction of the ascending aorta with/without aortic valve surgery (root-sparing surgery) during a mean 4.9-year follow-up. Aortic root replacement together with the ascending aortic replacement was performed in 39% of the patients (n=55). The mean age for all patients was 65 years [standard deviation (SD 13)]. Many patients with aortic root replacement had moderate to severe aortic valve regurgitation (85.5%). Most of the patients with aortic root-sparing surgery included a supracoronary tube prosthesis (89.5%), while nine patients also had aortic valve replacement. The degree of mucoid extracellular matrix accumulation was more prominent in patients with aortic root replacement compared to patients with root-sparing surgery (2.1 SD 0.4 vs. 1.9 SD 0.4, P=0.04, respectively). During follow-up, there were 52 deaths among patients (log rank P=0.79). Histopathology of the ascending aorta during ATAAD reveals distinctive aortic wall degeneration in patients with aortic root involvement vs. not. The degree of mucoid extracellular matrix accumulation assessed postoperatively is associated with the choice of surgical procedure in many patients.

Advanced Abdominal Aortic Aneurysm Modeling in Mice by Combination of Topical Elastase and Oral ß-aminopropionitrile.

The topical elastase murine model of abdominal aortic aneurysm (AAA) is enhanced when combined with ß-aminopropionitrile (BAPN)-supplemented drinking water to reliably produce true infrarenal aneurysms with behaviors that mimic human AAAs. Topically applying elastase to the adventitia of the infrarenal aorta causes structural damage to the elastic layers of the aortic wall and initiates aneurysmal dilation. Co-administering BAPN, a lysyl oxidase inhibitor, promotes sustained wall degeneration by reducing collagen and elastin crosslinking. This combination results in large AAAs that progressively expand, form intraluminal thrombus, and are capable of rupture. Refining surgical techniques, such as circumferentially isolating the entire infrarenal aortic segment, can help standardize the procedure for a consistent and thorough application of porcine pancreatic elastase despite different operators and anatomic variations between mice. Therefore, the elastase/BAPN model is a refined approach to surgically inducing AAA in mice, which may better recapitulate human aneurysms and provide additional opportunities to study aneurysm growth and rupture risk.

Genome-Wide Methylation Analysis Reveals a KCNK3-Prominent Causal Cascade on Hypertension.

Despite advances in understanding hypertension's genetic structure, how noncoding genetic variants influence it remains unclear. Studying their interaction with DNA methylation is crucial to deciphering this complex disease's genetic mechanisms. We investigated the genetic and epigenetic interplay in hypertension using whole-genome bisulfite sequencing. Methylation profiling in 918 males revealed allele-specific methylation and methylation quantitative trait loci. We engineered rs1275988T/C mutant mice using CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated protein 9), bred them for homozygosity, and subjected them to a high-salt diet. Telemetry captured their cardiovascular metrics. Protein-DNA interactions were elucidated using DNA pull-downs, mass spectrometry, and Western blots. A wire myograph assessed vascular function, and analysis of the Kcnk3 gene methylation highlighted the mutation's role in hypertension. We discovered that DNA methylation-associated genetic effects, especially in non-cytosine-phosphate-guanine (non-CpG) island and noncoding distal regulatory regions, significantly contribute to hypertension predisposition. We identified distinct methylation quantitative trait locus patterns in the hypertensive population and observed that the onset of hypertension is influenced by the transmission of genetic effects through the demethylation process. By evidence-driven prioritization and in vivo experiments, we unearthed rs1275988 in a cell type-specific enhancer as a notable hypertension causal variant, intensifying hypertension through the modulation of local DNA methylation and consequential alterations in Kcnk3 gene expression and vascular remodeling. When exposed to a high-salt diet, mice with the rs1275988C/C genotype exhibited exacerbated hypertension and significant vascular remodeling, underscored by increased aortic wall thickness. The C allele of rs1275988 was associated with elevated DNA methylation levels, driving down the expression of the Kcnk3 gene by attenuating Nr2f2 (nuclear receptor subfamily 2 group F member 2) binding at the enhancer locus. Our research reveals new insights into the complex interplay between genetic variations and DNA methylation in hypertension. We underscore hypomethylation's potential in hypertension onset and identify rs1275988 as a causal variant in vascular remodeling. This work advances our understanding of hypertension's molecular mechanisms and encourages personalized health care strategies.

PI3Kγ promotes neutrophil extracellular trap formation by noncanonical pyroptosis in abdominal aortic aneurysm.

Abdominal aortic aneurysm (AAA) is one of the most life-threatening cardiovascular diseases; however, effective drug treatments are still lacking. The formation of neutrophil extracellular traps (NETs) has been shown to be a crucial trigger of AAA, and identifying upstream regulatory targets is thus key to discovering therapeutic agents for AAA. We revealed that phosphoinositide-3-kinase γ (PI3Kγ) acted as an upstream regulatory molecule and that PI3Kγ inhibition reduced NET formation and aortic wall inflammation, thereby markedly ameliorating AAA. However, the mechanism of NET formation regulated by PI3Kγ remains unclear. In this study, we showed that PI3Kγ deficiency inactivated the noncanonical pyroptosis pathway, which suppressed downstream NET formation. In addition, PI3Kγ regulation of noncanonical pyroptosis was dependent on cyclic AMP/protein kinase A signaling. These results clarify the molecular mechanism and crosstalk between PI3Kγ and NETosis in the development of AAA, potentially facilitating the discovery of therapeutic options for AAA.

Finding peace in a new version of oneself- a qualitative study of post operative patients after aorta dissection and their experiences of cardiac rehabilitation

Abstract Background Aortic dissection, characterized by a sudden rupture in the carotid artery allowing blood to enter the aortic wall. The mortality rate is 1% per hour, and half of the patients die within 48 hours. Following surgery, patients are advised to limit arm lifting to 2 kg, maintain strict blood pressure control for life, and engage in physical activities that do not strain the aorta. Despite the limited evidence on optimal rehabilitation, our University Hospital in Denmark has established a team that secure patients with aortic dissection a structured post operative rehabilitation program. Aim This study aims to explore the experiences and importance of a specialized rehabilitation program for individuals post-surgery for aortic dissection. Method A qualitative interview study, analyzed using content analysis inspired by Graneheim &amp; Lundman. Interview participants were recruited through the physiotherapist at the hospital either at the end or shortly after their rehabilitation program. Interviews were conducted over the phone or in a private room at the hospital. Results Based on interviews with eight patients (three women and five men aged 43-73), an overarching theme emerged; "Finding peace in a new version of oneself." This theme encapsulates the journey of adapting to a new identity with a changed body that has limitations, combined with a sense of gratitude for being alive. Three subthemes describe the period from surgery to the end of the rehabilitation course: 1) Surviving the operation - the initial miracle and the subsequent uncertainties, 2) The rehabilitation course enhance a sense of security and well-being, and 3) Reclaiming wholeness. Conclusion A specialized rehabilitation program proves to be a crucial support in helping individuals with aortic dissection find peace in their altered selves after facing a life-threatening trauma. These patients require comprehensive physical and psychological support through cardiac rehabilitation provided by cardiac nurses, along with prompt initiation of specialized rehabilitation led by physiotherapists with expertise in aortic dissection.

Side Effects of Anthracycline Chemotherapy on the Heart of Laboratory Animals

Anthracycline is one of the chemical drugs commonly used worldwide for the treatment of various types of cancer. The high doses of it cause unwanted toxic side effects on the tissues. Our study designed to demonstrated the physiological and histopathological effect of the drug on the heart organ of experimental animals. For this purpose, twenty adults male rats were used in this study and were divided into four main groups. Control group, Azoxymethane treated group, Azoxymethane qrand anthracycline treated group, and anthracycline treated group only. Blood of the experimented animals was collected in order to measure biochemical parameters such as glutathione, lactate dehydrogenase, malondialdehyde, peroxynitrite, Creatinine Kinase, C-reactive protein Creatine kinase –myocardial band, and Myoglobin concentrations. In this study a significant increase and decrease was observed in biochemical parameters. Histological examination on the heart shown that rats treated with AOM have been revealed only hypertrophy of cardiac muscles, while other groups were observed hypertrophy of cardiac muscles furthermore. Aorta in AOM group have been revealed Adverse histological changes and transformation in the thickness aortic wall layers. The tissue sections of the groups treated with Anthracyclin showed a negative effect on the aortic wall layers, the endothelial layer and the middle layer, as well as the outer layer in the sections prepared from these groups.

An efficient procedure for the blood flow computer simulation of patient-specific aortic dissections

In this work we present a novel methodology for the numerical simulation of patient-specific aortic dissections. Our proposal, which targets the seamless virtual prototyping of customized scenarios, combines an innovative two-step segmentation procedure with a CutFEM technique capable of dealing with thin-walled bodies such as the intimal flap. First, we generate the fluid mesh from the outer aortic wall disregarding the intimal flap, similarly to what would be done in a healthy aorta. Second, we create a surface mesh from the approximate midline of the intimal flap. This approach allows us to decouple the segmentation of the fluid volume from that of the intimal flap, thereby bypassing the need to create a volumetric mesh around a thin-walled body, an operation widely known to be complex and error-prone. Once the two meshes are obtained, the original configuration of the dissection into true and false lumen is recovered by embedding the surface mesh into the volumetric one and calculating a level set function that implicitly represents the intimal flap in terms of the volumetric mesh entities. We then leverage the capabilities of unfitted mesh methods, specifically relying on a CutFEM technique tailored for thin-walled bodies, to impose the wall boundary conditions over the embedded intimal flap. We tested the method by simulating the flow in four patient-specific aortic dissections, all involving intricate geometrical patterns. In all cases, the preprocess is greatly simplified with no impact on the computational times. Additionally, the obtained results are consistent with clinical evidence and previous research.

Administration of an antibody against apoptosis inhibitor of macrophage prevents aortic aneurysm progression in mice

Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.

Traction-separation law parameters for the description of age-related changes in the delamination strength of the human descending thoracic aorta.

Aortic dissection is a life-threatening disease that consists in the development of a tear in the wall of the aorta. The initial tear propagates as a discontinuity leading to separation within the aortic wall, which can result in the creation of a so-called false lumen. A fatal threat occurs if the rupture extends through the whole thickness of the aortic wall, as blood may then leak. It is generally accepted that the dissection, which can sometime extend along the entire length of the aorta, propagates via a delamination mechanism. The aim of the present paper is to provide experimentally validated parameters of a mathematical model for the description of the wall's cohesion. A model of the peeling experiment was built in Abaqus. The delamination interface was described by a piecewise linear traction-separation law. The bulk behavior of the aorta was assumed to be nonlinearly elastic, anisotropic, and incompressible. Our simulations resulted in estimates of the material parameters for the traction-separation law of the human descending thoracic aorta, which were obtained by minimizing the differences between the FEM predictions and the delamination force given by the regression of the peeling experiments. The results show that the stress at damage initiation, Tc, should be understood as an age-dependent quantity, and under the assumptions of our model this dependence can be expressed by linear regression as Tc = - 13.03·10-4·Age + 0.2485 if the crack front advances in the axial direction, and Tc = - 7.58·10-4·Age + 0.1897 if the crack front advances in the direction of the aortic circumference (Tc [MPa], Age [years]). Other model parameters were the stiffness K and the separation at failure, δf-δc (K = 0.5MPa/mm, δf-δc = 0.1mm). The material parameters provided by our study can be used in numerical simulations of the biomechanics of dissection propagation through the aorta especially when age-associated phenomena are studied.

Expression of MMP2, MMP9, TIMP2 and TIMP3 genes in aortic dissection.

Thoracic aortic dissection (TAD) is a highly lethal disease occurring inside the aortic wall and is characterized by matrix degradation. Matrix metalloproteinases (MMPs) are members of a large endopeptidase family that function in the degradation of the extracellular matrix (ECM) proteins, the maintenance of the ECM, and the regulation of signaling in the aorta. MMPs are found in tissue with their natural inhibitors. Tissue inhibitors of metalloproteinases (TIMPs) are actively involved in both the activation and inhibition of MMPs. The present study was designed to determine the mRNA level gene expression differences of MMP2, MMP9, TIMP2 and TIMP3, which are considered to have an essential role in TAD, in aortic tissue and circulating monocyte cells. For the purpose of the present study, aortic vascular tissue and peripheral blood-derived monocyte cells were obtained from 10 patients with TAD and 10 control individuals. The gene expression levels of targeted genes (MMP2, MMP9, TIMP2 and TIMP3) were examined by droplet digital PCR. In research results, decreased expression of MMP9, TIMP2 and TIMP3 genes (P=0.043, P=0.009 and P=0.028, respectively) and increased ratio of MMP2/TIMP3 (P=0.012) were obtained in the aortic tissue. No changes were observed in terms of gene expression in monocyte cells. When the results obtained were evaluated within the framework of TAD pathogenesis, it was concluded that expression changes in MMP9, TIMP2 and TIMP3 genes may provide a sensitive environment in aortic tissue and may be associated with TAD formation. In addition, since the expression ratios of MMPs and TIMPs may reflect disease development, it was considered that the evaluation of MMPs along with TIMPs may be an appropriate and informative approach for future studies.

L-Wnk1 Deletion in Smooth Muscle Cells Causes Aortitis and Inflammatory Shift.

The long isoform of the Wnk1 (with-no-lysine [K] kinase 1) is a ubiquitous serine/threonine kinase, but its role in vascular smooth muscle cells (VSMCs) pathophysiology remains unknown. AngII (angiotensin II) was infused in Apoe-/- to induce experimental aortic aneurysm. Mice carrying an Sm22-Cre allele were cross-bred with mice carrying a floxed Wnk1 allele to specifically investigate the functional role of Wnk1 in VSMCs. Single-cell RNA-sequencing of the aneurysmal abdominal aorta from AngII-infused Apoe-/- mice revealed that VSMCs that did not express Wnk1 showed lower expression of contractile phenotype markers and increased inflammatory activity. Interestingly, WNK1 gene expression in VSMCs was decreased in human abdominal aortic aneurysm. Wnk1-deficient VSMCs lost their contractile function and exhibited a proinflammatory phenotype, characterized by the production of matrix metalloproteases, as well as cytokines and chemokines, which contributed to local accumulation of inflammatory macrophages, Ly6Chi monocytes, and γδ T cells. Sm22Cre+Wnk1lox/lox mice spontaneously developed aortitis in the infrarenal abdominal aorta, which extended to the thoracic area over time without any negative effect on long-term survival. AngII infusion in Sm22Cre+Wnk1lox/lox mice aggravated the aortic disease, with the formation of lethal abdominal aortic aneurysms. Pharmacological blockade of γδ T-cell recruitment using neutralizing anti-CXCL9 (anti-CXC motif chemokine ligand 9) antibody treatment, or of monocyte/macrophage using Ki20227, a selective inhibitor of CSF1 receptor, attenuated aortitis. Wnk1 deletion in VSMCs led to aortic wall remodeling with destruction of elastin layers, increased collagen content, and enhanced local TGF-β (transforming growth factor-beta) 1 expression. Finally, in vivo TGF-β blockade using neutralizing anti-TGF-β antibody promoted saccular aneurysm formation and aorta rupture in Sm22 Cre+ Wnk1lox/lox mice but not in control animals. Wnk1 is a key regulator of VSMC function. Wnk1 deletion promotes VSMC phenotype switch toward a pathogenic proinflammatory phenotype, orchestrating deleterious vascular remodeling and spontaneous severe aortitis in mice.

Look Past the Bleed! A Case of Non-Traumatic Thoracic Aortic Pseudoaneurysm Presenting as Haemoptysis.

Aortic pseudoaneurysms are a type of contained rupture where most of the aortic wall is breached, leaving only a thin rim of the remaining wall or adventitia to hold the blood. This condition carries a high risk of rupture and potentially fatal complications. Typically, patients present with chest pain; haemoptysis can also occur, though rarely. A 64-year-old male who presented with two episodes of haemoptysis, with no history of cardiovascular surgery or trauma. A chest computerized tomography (CT) followed by an aortogram revealed a thoracic aortic pseudoaneurysm and the patient underwent surgical aortic repair without any complications. This case underscores the rare presentation of thoracic aortic pseudoaneurysm. Haemoptysis is a rare manifestation of thoracic aorta pseudoaneurysm and can be a warning sign of impending rupture. Haemoptysis may occur due to formation of aortopulmonary fistula or direct erosion of pseudoaneurysm into lung parenchyma. It is imperative for clinicians to recognise such manifestations early for prompt diagnosis and prevention of complications. Recognise haemoptysis as the manifestation of thoracic aortic pseudoaneurysm.Early diagnosis and treatment are crucial due to high rate of complications and mortality.Trauma and cardiovascular surgery are the most common cause for thoracic aortic pseudoaneurysm; however, sometimes it can occur due to atherosclerosis.

Biomechanical effects of hemin and sildenafil treatments on the aortic wall of chronic-hypoxic lambs.

Introduction: Gestation under chronic hypoxia causes pulmonary hypertension, cardiovascular remodeling, and increased aortic stiffness in the offspring. To mitigate the neonatal cardiovascular risk, pharmacological treatments (such as hemin and sildenafil) have been proposed to improve pulmonary vasodilation. However, little is known about the effects of these treatments on the aorta. Therefore, we studied the effect of hemin and sildenafil treatments in the aorta of lambs gestated and raised at highlands, thereby subjected to chronic hypoxia. Methods: Several biomechanical tests were conducted in the descending thoracic aorta (DTA) and the distal abdominal aorta (DAA), assessing 3 groups of study of hypoxic animals: non-treated (Control) and treated either with hemin or sildenafil. Based on them, the stiffness level has been quantified in both zones, along with the physiological strain in the unloaded aortic duct. Furthermore, a morphological study by histology was conducted in the DTA. Results: Biomechanical results indicate that treatments trigger an increment of axial pre-stress and circumferential residual stress levels in DTA and DAA of lambs exposed to high-altitude chronic hypoxia, which reveals a vasodilatation improvement along with an anti-hypertensive response under this characteristic environmental condition. In addition, histological findings do not reveal significant differences in either structure or microstructural content. Discussion: The biomechanics approach emerges as a valuable study perspective, providing insights to explain the physiological mechanisms of vascular function. According to established results, alterations in the function of the aortic wall may not necessarily be explained by morphostructural changes, but rather by the characteristic mechanical state of the microstructural components that are part of the studied tissue. In this sense, the reported biomechanical changes are beneficial in mitigating the adverse effects of hypobaric hypoxia exposure during gestation and early postnatal life.