Aortic Segments Research Articles

High Prevalence of Thoracic Aortic Dilatation in Men with Previous Inguinal Hernia Repair

Identifying a useful marker for thoracic aortic dilatation (TAD) could help improve informed clinical decisions, enhance diagnosis, and develop TAD screening programs. Inguinal hernia could be such a marker. This study tested the hypothesis that the thoracic aorta is larger and more often dilated in men with previous inguinal hernia repair versus nonhernia controls. Four hundred men each with either previous inguinal hernia repair or cholecystectomy (controls) were identified to undergo chest computed tomography to measure the diameter of the thoracic aorta in the aortic root, ascending, isthmic, and descending aorta and to provide self-reported health data. Presence of TAD (root or ascending diameter > 45 mm; isthmic or descending diameter > 35 mm) and thoracic aortic diameters were compared between groups and associations explored using uni- and multivariable statistical methods. Complete data were obtained from 470/718 (65%) eligible participants. TAD prevalence was significantly higher in the inguinal hernia group: 21 (10%) versus 6 (2.4%), p = 0.001 for proximal TAD, 29 (13%) versus 21 (8.3%), p = 0.049 for distal TAD, and 50 (23%) versus 27 (11%), p < 0.001 for all aortic segments combined. In multivariable analysis, previous inguinal hernia repair was independently associated with dilatation of the proximal aorta (odds ratio 5.3, 95% confidence interval 1.8-15, p = 0.003). Contrarily, mean thoracic aortic diameters were similar (root and ascending aorta) or showed clinically irrelevant differences (isthmus and descending aorta). TAD, but not increased aortic diameters on average, was common and significantly more prevalent in men with previous inguinal hernia repair. Hernia could be a marker condition associated with increased prevalence of TAD. Ultimately, TAD screening could consider hernia as a possible selection criterion.

Downstream thoracic endovascular aortic repair following the frozen elephant trunk procedure.

The frozen elephant trunk technique has become a well-established treatment option for patients presenting all thoracic aortic pathologies including acute and chronic dissection, aortic aneurysms and even penetrating aortic ulcers involving the aortic arch and descending aorta. Nevertheless, there is a significant incidence of and risk for distal aortic reinterventions after the frozen elephant trunk. Indications mainly include a planned staged approach, diameter progression of downstream aortic segments and the development of distal stent-graft induced new entries (dSINEs). Endovascular stent-graft extension through conventional thoracic endovascular aortic repair (TEVAR) is a relatively simple and safe method to address any pathologies in the remaining descending thoracic aorta up to the level of the coeliac trunk. In fact, the frozen elephant trunk stent-graft provides an ideal proximal landing zone for any endovascular stent-graft extension. Postoperative outcomes are very promising with very low reported in-hospital mortality and morbidity. In case this 2-staged-approach fails to stabilize the remaining aorta, a 3-step procedure, namely open thoracoabdominal aortic replacement, is simplified because the anastomosis site has moved distally. Follow-up of all patients, following frozen elephant trunk implantation or distal stent-graft extension, is mandatory, ideally in an outpatient clinic dedicated to the aorta in order to identify disease progression or to detect any complications as soon as possible.

Long-term outcome of patients treated by TEVAR for type B aortic dissection or intramural hematoma depending on a healthy vs non-healthy proximal landing zone

Abstract Objective Thoracic endovascular aortic repair (TEVAR) is the first-line therapy for complicated type B aortic dissection (TBAD) or intramural hematoma (IMH). However, depending on the location of the primary entry tear, there is paucity of data as to whether the proximal landing zone (PLZ) of the stent prosthesis must be in a non-dissected healthy part (healthy landing zone = HLZ) or in the dissected aorta (non-healthy landing zone= non-HLZ). Methods Retrospective analysis of patients who underwent TEVAR for acute (&amp;lt;14 days) or subacute (&amp;lt;3 months) TBAD or IMH from 2003–2020 at a single center. A HLZ was defined as a non-dissected aortic segment (length ≥2 cm). Primary endpoints were freedom from aortic reintervention and -growth (≥5 mm). Secondary endpoints involved stroke, retrograde type A aortic dissection, proximal stent graft induced new entry (pSINE), debranching failure, 30-day and overall mortality. Results 94 patients (age 70 years (interquartile-range (IQR): 59 to 78) were included. 84 (89%) presented with a TBAD and only ten (11%) with an IMH. CTA analysis revealed a HLZ in 62 (66%) patients. Debranching of the left subclavian artery was performed in 21 (22%) patients to extend the PLZ. The median follow-up time was 20 (IQR: 4.6 to 72.9) months. The overall aortic reintervention rate was 22%. Estimated re-intervention rate at 12 months was 13.1% for HLZ vs. 16.1% for non-HLZ and at 5 years 16.8% for HLZ 29.9% vs. for non-HLZ (P=0.187). Aortic growth was observed in 12 patients after 2.2 years (IQR: 0.8 to 5.9), with no significant difference in patients with HLZ vs. non-HLZ (11% vs 16%,P=0.535). No significant differences were observed for the secondary endpoints. 30-day mortality was 10% in both groups, P=1.0. Overall survival was 47% in the HLZ group vs. 41% in the non-HLZ group, P=0.663. A Cox proportional hazard model for reintervention with mortality as a competing risk showed a trend towards better long-term outcome for patients with a HLZ, hazard ratio 0.451 (95%-CI: 0.186–1.09, P=0.078). Conclusion In the majority of patients, it was possible to land in a HLZ. Consistently, reintervention rates, aortic growth, and mortality were higher in patients with non-HLZ compared with HLZ over the mid- and long-term. However, these differences were not statistically significant. Therefore, larger studies are urgently needed.

Simultaneous Endovascular Repair Is Not Associated With Increased Risk for Thoracic and Abdominal Aortic Pathologies: Early and Midterm Outcomes.

Coexisting multilevel aortic pathologies were caused by atherosclerosis and hypertension and presented in a small subgroup of patients. Endovascular repair is a safe and effective treatment for a variety of aortic pathologies. However, fewer small series and cases were reported using simultaneous thoracic endovascular repair (TEVAR) and endovascular aneurysm repair (EVAR) for both aortic segments. To determine the outcomes of simultaneous and separately TEVAR and EVAR treating for multilevel aortic pathologies. Between 2010 and 2020, 31 patients and 22 patients were treated by one-staged and two-staged repair, respectively at a single center. All patients had the concomitant thoracic and abdominal aortic disease (aortic dissection, aneurysms, and penetrating aortic ulcers). Compared with the patients with two-staged aortic repair, the one-staged repair patients were older (mean age, 68 vs. 57 years; P < 0.001) and had a larger preoperative maximal aortic diameter (67.03 ± 10.65 vs. 57.45 ± 10.36 mm; p = 0.002). The intraoperative and postoperative outcomes show that the procedure times and length of hospital stay (LOS) were longer in the two-staged group. There is no significant difference in postoperative complications between the two groups. In the follow up, the freedom from re–intervention and the mean survival rate for the one-staged group were 100 vs. 100%, 92.4 vs. 95%, and 88 vs. 88% at one, two, and 5 years, respectively, whereas the mean survival rate for the two-staged group was 86.4 vs. 90.5%, 87 vs. 90.5%, and 76 vs. 84% at one, two, and 5 years, respectively, all with no statistical difference. Combined TEVAR and EVAR can be performed successfully with minimal morbidity and mortality. The one-staged repair was not associated with the increased risk for multilevel aortic pathologies treatment.

Treatment of Abdominal Aortic Aneurysm Utilizing Adipose-Derived Mesenchymal Stem Cells in a Porcine Model

IntroductionThe current treatment paradigm of abdominal aortic aneurysms (AAA) focuses on observing patients until their disease reaches certain thresholds for intervention, with no preceding treatment available. There is an opportunity to develop novel therapies to prevent further aneurysmal growth and decrease the risk of a highly morbid rupture. We used a porcine model of aortic dilation to assess the ability of human adipose-derived mesenchymal stem cells (MSCs) to attenuate aortic dilation. Materials and methodsTwelve Yorkshire pigs received periadventitial injections (collagenase and elastase) into a 4-cm segment of infrarenal aorta. Animals were treated with either 1 × 106 MSCs placed onto Gelfoam or treated with media as a control. Aortic diameters were measured at the time of surgery and monitored at postoperative day (POD) 7 and 14 with ultrasound. Animals were sacrificed on POD 21. Aortic tissue was harvested for histopathological analyses and immunohistochemistry. Groups were compared with paired t-tests or Mann–Whitney U-tests. ResultsAll animals survived until POD 21. The mean aortic diameter was reduced in the aortic dilation + MSC treatment group compared to aortic dilation control animals (1.10 ± 0.126 versus 1.48 cm ± 0.151, P < 0.001). Aortic media thickness was reduced in the aortic dilation group compared to the aortic dilation + MSC group (609.14 IQR 445.21-692.93 μm versus 643.55 IQR 560.91-733.88 μm, P = 0.0048). There was a significant decrease in the content of collagen and alpha-smooth muscle actin and elastin perturbation in the aortic dilation group as compared to the aortic dilation + MSC group. Immunohistochemistry demonstrated an increased level of vascular endothelial growth factor, tissue inhibitor of matrix metalloproteinase 1, and tissue inhibitor of matrix metalloproteinase 3 expression in the aorta of aortic dilation + MSC animals. ConclusionsStem cell therapy suppressed the aortic dilation in a porcine model. Animals from the aortic dilation group showed more diseased gross features, histologic changes, and biochemical properties of the aorta compared to that of the aortic dilation + MSC treated animals. This novel finding should prompt further investigation into translatable drug and cell therapies for aneurysmal disease.

A Comparison of Thoracoabdominal Aortic Aneurysms Open Repair in Patients With or Without “Shaggy Aorta”

Shaggy aorta (SA) syndrome is an independent risk factor for mortality, spinal cord ischemia, and acute renal failure in patients submitted to open thoracoabdominal aortic aneurysm (TAAA) repair. The aim of this paper is to report the results of a single-center large cohort of patients treated with open surgical repair (OSR) for TAAA with SA, comparing the outcomes with patients affected by TAAA without SA, and analyzing the impact of the actual scores for SA on the outcomes. All consecutive patients receiving OSR for TAAA between 2012 and 2021 were retrospectively analyzed. Clinical data from patients with degenerative TAAA were included and analyzed for preoperative characteristics and postoperative outcomes; patients with ruptured TAAA and patients with aortic dissection were excluded from the analysis. Patients with degenerative aortic aneurysm, thrombus measurement in nonaneurysmal aortic segments (≤40 mm), atheroma thickness ≥5 mm, and finger-like thrombus projection were included in the “SA group,” whereas the others were included in the “non-shaggy aorta group” (NSA group). The SA group and NSA group were compared using a propensity-matched comparison. Preoperative computed tomography scans of patients in the SA group were also classified according to the actual SA grading scores. A total of 58 patients with SA were identified (male 43 [74.1%], mean age 70.1 ± 7.8 years). After propensity matching, there were 48 patients in the SA group and 48 in the NSA group with correction of all differences in baseline characteristics. Patients in the SA group presented significantly higher in-hospital mortality (SA group: 10.4% vs NSA group: 2.1%, P < .001), postoperative acute renal failure (RIFLE 4-5) (SA group: 16.7% vs NSA group: 0%, P < .002), and embolization rate (SA group: 25.0% vs NSA group: 8.3%, P < .02). Spinal cord ischemia and stroke rate were not significantly influenced by the presence of SA. In the SA group, 16 (27.6%) patients with end-organ embolization were compared with 42 (72.4%) patients without a documented embolization considering the grade of aortic “shagginess,” and no significant difference was identified (P = .0546). Despite several intraoperative adjuncts, TAAA patients with SA treated with OSR still have worse postoperative outcomes if compared with “non-shaggy” patients. The presence of SA is a risk factor itself, whereas the grade of “shagginess” seems not to impact on postoperative outcomes.

Aortic dilatation using cardiac magnetic resonance in asymptomatic ELITE athletes

Abstract Funding Acknowledgements Type of funding sources: None. Purpose Aortic dilatation is associated with acute aortic pathology. Cardiac magnetic resonance (CMR) data in asymptomatic elite athletes is lacking. Therefore, we investigated the prevalence of aortic dilatation in a cohort of elite-level athletes using CMR. Methods We performed a cross-sectional study of aortic dimensions among elite-level (national-, international-, Olympic-, Paralympic-level or comparable) athletes. All athletes were asymptomatic and examined during pre-participation screening. Each underwent CMR with 3D whole heart in diastole (1.5 mm voxel) for aortic measurements, next to cine imaging, late gadolinium enhancement (LGE), and T1-mapping. We defined dilatation as 38 and 40 mm at the aortic root (sinus of Valsalva cusp-cusp), 27 and 31 mm at the sinotubular junction, and 23 and 26 mm at the level of the diaphragm, in male- and female athletes, respectively. Athletes were grouped for having 0- (normal), 1-, 2- or 3 measurements above cut-off values. Results We screened 156 athletes, 41% female, with a mean age (±SD) of 28±7 and body surface area (BSA) of 2.0±0.2 m2. Mean aortic dimensions were 33±4 mm for the sinus of Valsalva, 28±3 mm for the sinotubular junction, 20±3 mm for the aorta at diaphragm. We observed indexed end-diastolic volumes (EDVi) of 122±20 and 123±20 ml/m2, indexed end-systolic volumes (ESVi) of 53±13 and 54±16 ml/m2, stroke volumes (SV) of 129±36 and 126±39 ml, and ejection fractions (EF) of 56±5 and 55±6 %, in the left- (LV) and right ventricle (RV), respectively Fifty-three (34%) athletes, of which 45% female, had 1 or 2 aortic measurements above conventional cut-off values (Table 1). Eleven (7%), 18% female, had 2 aortic measurements above cut-off values. No athlete had all 3 measurements above cut-offs values. Athletes with 2 dilated measurements compared to athletes with 1 or 0 dilated measurements, had greater LV EDVi (145±19 vs. 119±18 vs. 120±19 ml/m2, p&amp;lt;0.001), greater RV EDVi (142±18 vs. 119±17 vs. and 122±20 ml/m2, p=0.002), greater LV ESVi (66±10 vs. 51±13 vs. 52±13 ml/m2, p=0.002), greater RV ESVi (66±10 vs. 53±13 vs. 53±17 ml/m2, p=0.039), greater LV SV (156±26 vs. 132±35 vs. 125±36 ml, p=0.020), and greater RV SV (152±25 vs. 130±34 vs. 121±41 ml, p=0.031), 2- vs, 1- vs. 0 dilated segments, respectively (Table 1, Figure 1). Athletes with dilated measurements had no LGE (excluding the hinge point), no difference in T1-mapping times, or LV- and RV EF, compared to athletes without dilated measurements. Conclusion One in three elite-athletes has dilatation in one or more aortic segments, including the sinus of Valsalva, sinotubular junction, or the aorta at diaphragm. Athletes with 2 dilated measurements (7%) had greater LV- and RV EDVi, ESVi, and SV, suggesting an association with ventricular volumes. Our findings in asymptomatic elite athletes, with normal EF and no LGE and comparable T1-mapping times, could be a sign of an outspoken physiological sports adaptation, instead of pathology.

Time-related aortic inflammatory response, as assessed with 18F-FDG PET/CT, in patients hospitalized with severely or critical COVID-19: the COVAIR study

AimArterial involvement has been implicated in the coronavirus disease of 2019 (COVID-19). Fluorine 18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) imaging is a valuable tool for the assessment of aortic inflammation and is a predictor of outcome. We sought to prospectively assess the presence of aortic inflammation and its time-dependent trend in patients with COVID-19. MethodsBetween November 2020 and May 2021, in this pilot, case-control study, we recruited 20 patients with severe or critical COVID-19 (mean age of 59 ± 12 years), while 10 age and sex-matched individuals served as the control group. Aortic inflammation was assessed by measuring 18F-FDG uptake in PET/CT performed 20-120 days post-admission. Global aortic target to background ratio (GLA-TBR) was calculated as the sum of TBRs of ascending and descending aorta, aortic arch, and abdominal aorta divided by 4. Index aortic segment TBR (IAS-TBR) was designated as the aortic segment with the highest TBR. ResultsThere was no significant difference in aortic 18F-FDG PET/CT uptake between patients and controls (GLA-TBR: 1.46 [1.40-1.57] vs. 1.43 [1.32-1.70], respectively, P = 0.422 and IAS-TBR: 1.60 [1.50-1.67] vs. 1.50 [1.42-1.61], respectively, P = 0.155). There was a moderate correlation between aortic TBR values (both GLA and IAS) and time distance from admission to 18F-FDG PET-CT scan (Spearman’s rho = − 0.528, P = 0.017 and Spearman’s rho = − 0.480, p = 0.032, respectively). Patients who were scanned less than or equal to 60 days from admission (n = 11) had significantly higher GLA-TBR values compared to patients that were examined more than 60 days post-admission (GLA-TBR: 1.53 [1.42-1.60] vs. 1.40 [1.33-1.45], respectively, P = 0.016 and IAS-TBR: 1.64 [1.51-1.74] vs. 1.52 [1.46-1.60], respectively, P = 0.038). There was a significant difference in IAS- TBR between patients scanned ≤ 60 days and controls (1.64 [1.51-1.74] vs. 1.50 [1.41-1.61], P = 0.036). ConclusionThis is the first study suggesting that aortic inflammation, as assessed by 18F-FDG PET/CT imaging, is increased in the early post COVID phase in patients with severe or critical COVID-19 and largely resolves over time. Our findings may have important implications for the understanding of the course of the disease and for improving our preventive and therapeutic strategies.

Electronic Cigarette Exposure Induces Vascular Endothelial Dysfunction with NADPH Oxidase Activation and eNOS Uncoupling

BackgroundWe recently reported a mouse model of chronic electronic cigarette (e‐cig) exposure‐induced cardiovascular pathology, where long‐term exposure to e‐cig vape (ECV) induces cardiac abnormalities, impairment of endothelial function, and systemic hypertension. Using this model, we performed studies to delineate the underlying mechanisms of ECV‐induced vascular endothelial dysfunction (VED), which is a central trigger of cardiovascular disease.MethodsC57/BL6 male mice were exposed 2 hours/day, 5 days/week to ECV generated from e‐cig liquid containing 0, 6, or 24 mg/ml nicotine for 16 and 60 weeks. Blood pressure was measured by tail cuff and endothelial‐dependent and independent relaxation was measured on aortic segments using wire myography. Western blotting, immunofluorescence and ELISA were used to analyze the pathways involved in the mechanism of ECV‐induced VED.ResultsTime‐dependent elevation in blood pressure and systemic vascular resistance were observed, along with an impairment of acetylcholine‐induced aortic relaxation in ECV‐exposed mice, compared to air‐exposed control. Decreased intravascular nitric oxide (NO) levels and increased superoxide generation with elevated 3‐nitrotyrosine levels in the aorta of ECV‐exposed mice were observed, indicating that ECV‐induced superoxide reacts with NO to generate cytotoxic peroxynitrite. Exposure increased NADPH oxidase expression, supporting its role in ECV‐induced superoxide generation. Downregulation of endothelial nitric oxide synthase (eNOS) expression and Akt‐dependent eNOS phosphorylation occurred in the aorta of ECV‐exposed mice, indicating that exposure inhibited de novo NO synthesis. Following ECV exposure, the critical NOS cofactor tetrahydrobiopterin was decreased, with a concomitant loss of its salvage enzyme, dihydrofolate reductase. NADPH oxidase and NOS inhibitors abrogated ECV‐induced superoxide generation in the aorta of ECV exposed mice.ConclusionOur data demonstrate that ECV exposure activates NADPH oxidase and uncouples eNOS, causing a vicious cycle of superoxide generation and vascular oxidant stress that triggers VED and hypertension with predisposition to other cardiovascular disease.

Location of Aortic Enlargement and Risk of Type A Dissection at Smaller Diameters

BackgroundPrevious work has demonstrated that more than one-half of acute type A aortic dissections (ATADs) occur at a maximal aortic diameter (MAD) of <5.5 cm. However, no analysis has investigated whether ATAD risk at smaller MADs is more common with modest dilation of the aortic root (AR) or supracoronary ascending aorta (AA) in patients without genetically triggered aortopathy. ObjectivesThis study sought to determine if the segment of modest aortic dilation affects risk of ATAD. MethodsUsing the International Registry of Acute Aortic Dissection (IRAD) database from May 1996 to October 2016, we identified 667 ATAD patients with MAD <5.5 cm. Patients were stratified by location of the largest proximal aortic segment (AR or AA). Patients with known genetically triggered aortopathy were excluded. MADs at time of dissection were compared between AR and AA groups. Secondary outcomes included operation, postoperative outcomes, and long-term survival. ResultsOf patients with ATAD at an MAD <5.5 cm, 79.5% (n = 530) were in the AA group and 20.5% (n = 137) in the AR group. Modestly dilated ARs (median MAD 4.6 cm [IQR: 4.1-5.0 cm]) dissected at a significantly smaller diameter than modestly dilated AAs (median MAD 4.8 cm [IQR: 4.4-5.1 cm]) (P < 0.01). AR patients were significantly younger than AA patients (58.5 ± 13.0 years vs 63.2 ± 13.3 years; P < 0.01) and more commonly male (78% vs 65%; P < 0.01). Postoperative and long-term outcomes did not differ between groups. ConclusionsATAD appears to occur at smaller diameters in patients with modest dilation in the AR vs the AA (4.6 vs 4.8 cm). These findings may have implications for future consensus guidelines regarding the management of patients with aortic disease.

Evaluation of the effects of mild aerobic exercise and Losartan treatment on aortic endothelial function in a mouse model of Marfan syndrome

Marfan Syndrome (MFS) is an autosomal dominant disorder in a family of connective tissue disorders. It is well established that vascular complications in MFS is associated with endothelial dysfunction, leading to a whole host of phenotypic abnormalities. A predominant clinical concern is the development of aortic aneurysm with possible subsequent dissection and rupture.In the present study, we have utilized the ex‐vivo isometric myograph technique to examine the reactivity of isolated aortic segments from control and MFS mice in the presence or absence of different in‐vivo treatments and pharmacological agents. More specifically, we assessed the impact of mild aerobic exercise on endothelial function, aortic root growth, and aortic wall elasticity in a well‐established mouse model of MFS‐associated aortic aneurysm with special focus on nitric oxide production. Nitric oxide, as frequently demonstrated in the literature, plays a crucial role in maintaining normal vascular structure and function. In the current study, we examine the potential effects of mild aerobic exercise in the absence or presence of a potent general inhibitor of nitric oxide synthase (NOS), N5‐[imino(nitroamino)methyl]‐L‐ornithine, methyl ester, monohydrochloride (L‐NAME) on aortic contraction and endothelium‐mediated vasorelaxation in 6‐month‐old MFS mice carrying Fbn1 mutation and age‐ and sex‐matched C57BL/6J wildtype (WT) controls (male and females).At 4‐6 weeks of age, MFS mice were subjected to daily treadmill exercise (at 55% of VO2max, 8m/min, 30min/day, 5days/week) and/or drug treatment for a duration of 5 months. At 6 months of age, 2mm descending aortic rings were collected and mounted onto a small chamber myograph in order to measure the vascular reactivity in response to different vasoconstricting and vasodilating agents.Our study shows marked reduction in the phenylephrine (PE)‐induced contraction [50 µmol] and aortic wall rupture point in MFS mice aorta as compared to healthy controls. Treatment with either aerobic exercise or Losartan, an angiotensin II type 1 receptor blocker (ARB), rescued rupture point closer to WT control, but led to further decrease in PE contraction compared to MFS sedentary mice, mainly due to further increase in NO production within the aortic wall. In addition, direct inhibition of NO production via L‐Name, a nitric oxide synthase (NOS) inhibitor, effectively reduced PE‐induced contraction in MFS mice aorta that were subjected to exercise or Losartan treatment, further confirming that both exercise and Losartan treatment cause an increase in NO production.This study highlights the importance of endothelial function in improving the function and structure of aortic wall during the progression of aortic aneurysm in MFS mice and establish the notion that the protective effects of aerobic exercise and Losartan treatments are potentially through improving endothelium‐mediated nitric oxide production.

Abstract 489: Glutathione Regulates Endothelial Cell Function And Vegfr2 Signaling

Under physiological and pathological conditions angiogenesis progresses in an idealized redox window. Mice heterozygous for the Glutamate cysteine ligase modifier (GCLm) subunit knockout have augmented ischemic remodeling. During occlusion, the ensuing ischemic milieu and accompanying vascular changes regulate the activity of vascular endothelial receptor 2 (VEGFR2). We hypothesized that the cellular GSH concentration regulates endothelial cell function via altered VEGFR2 signaling. To test this hypothesis, we first performed mouse aortic endothelial cell (MAEC) outgrowth assays on aortic segments dissected from mice homozygous (KO) and heterozygous (Het) for GCLm knockout as well as wildtype control (WT). Outgrowth area in the Het group was significantly higher than WT and KO at day 7 of outgrowth (2.15 fold, n=4, P&lt;0.001). MAECs were isolated and relative migration rates were determined using under-agarose migration assays. Het MAECs were 1.25 fold faster than WT (n=4 p&lt;0.001) while KO MAECs were slower, 0.90 fold (n=3, p&lt;0.05). Cell proliferation assays are currently underway. Concurrently, we inhibited glutathione reductase in primary human aortic endothelial cells using 2-AAPA. 2-AAPA (75 μm) alone didn’t activate VEGFR2 (determined by western blot for pY1175 VEGFR2). 2-AAPA in combination with H 2 O 2 (100 μM) induced a 5.5 fold (p&lt;0.01, n=4) increase in the relative amount of active VEGFR2 compared to vehicle treated HAECs. 2-AAPA with H 2 O 2 induced a significant increase in pY416 proto-oncogene c-Src (Src) 9.5 fold (p&lt;0.01, n=6), This effect was attenuated by the addition of DTT. Furthermore, Src kinase inhibitor 1 (SKI) (200 nM) attenuated the effect of 2-AAPA + H 2 O 2 on VEGFR2. While the VEGFR2 kinase inhibitor SU1948 inhibited activation of VEGFR2, it had no significant effect on the 2-AAPA + H 2 O 2 mediated activation of Src. Combined these data suggest Src mediates the 2-AAPA + H 2 O 2 activation of VEGFR2. Glutathione S-transferase P1 (GSTP1) catalyzes the enzymatic glutathionylation of proteins, The GSTP1 inhibitor TLK199 (50 μM) abrogated the effects of 2-AAPA + H 2 O 2 on VEGFR2 and experiments are underway to determine the glutathionylation status of Src in our system and its effect on the interaction of Src and VEGFR2.

Glutathione Regulates Endothelial Cell Function and VEGFR2 Signaling

Under physiological and pathological conditions angiogenesis progresses in an idealized window of reactive oxygen species. Mice heterozygous for the Glutamate cysteine ligase modifier subunit knockout have augmented ischemic remodeling. During occlusion the ensuing ischemic milieu and accompanying vascular changes regulate the activity of vascular endothelial receptor 2 (VEGFR2). We hypothesized that cellular GSH concentration regulates endothelial cell function via altered VEGFR2 signaling.MethodsTo test this hypothesis, we first preformed mouse aortic endothelial cell (MAEC) outgrowth assays on aortic segments dissected from mice homozygous (KO) and heterozygous (Het) for GCLm knockout as well as wildtype controls (WT). VEGF stimulated chemotaxis was determined using the under‐agarose migration assay. Primary human aortic endothelial cells (HAEC) were purchased from Lonza and cultured following suppliers’ recomendations. Phospho‐Y1175 VEGFR2/total VEGFR2 and phospho‐Y416 proto‐oncogene c‐Src (Src)/total Src were determined by western blotting.ResultsOutgrowth area in the Het group was significantly larger than WT and KO at day 7 (2.15 fold, n=4, P&lt;0.001). Het MAECs were 1.25 fold faster (n=4 p&lt;0.001) while KO MAECs were 0.90 fold slower than WT (n=3, p&lt;0.05) migrating towards VEGF‐A. Concurrently, we inhibited glutathione reductase in HAECs using 2‐acetylamino‐3‐[4‐(2‐acetylamino‐2‐carboxyethylsulfanylthiocarbonylamino)phenylthiocarbamoylsulfanyl]propionic acid (2‐AAPA). 2‐AAPA (75 µM) alone didn’t significantly activate VEGFR2. However, 2‐AAPA (75 µM) in combination with H2O2 (100 µM) induced a 5.5 fold (p&lt;0.01, n=4) increase in the relative amount of active VEGFR2 compared to vehicle treated HAECs. 2‐AAPA both with and without H2O2 induced a significant increase in active Src, 5.3 and 9.0 fold (p&lt;0.05, p&lt;0.01, n=6) respectively. This effect was attenuated by the addition of Dithiothreitol (1mM). Furthermore, Src kinase inhibitor 1 (SKI) (200 nM) attenuated the effect of 2‐AAPA + H2O2 on VEGFR2. While the VEGFR2 kinase inhibitor SU1948 inhibited activation of VEGFR2, it had no significant effect on the 2‐AAPA + H2O2 mediated activation of Src. Glutathione S‐transferase P1 (GSTP1) catalyzes the enzymatic glutathionylation of proteins, The GSTP1 inhibitor TLK199 (50 µM) abrogated the effects of 2‐AAPA + H2O2 on VEGFR2.ConclusionCombined these data suggest Src mediates the 2‐AAPA + H2O2 activation of VEGFR2. And that glutathionylation is necessary for this effect, co‐immunoprecipitation experiments are underway to determine the glutathionylation status of Src in our system and its effect on the interaction of Src and VEGFR2.

Material parameter identification of the proximal and distal segments of the porcine thoracic aorta based on ECG-gated CT angiography

Vessel wall material parameters are important in biomechanical research. The purpose of this study was to identify the material parameters of two porcine thoracic aortic segments and verify the accuracy of the identification results with uniaxial tensile testing. Principal component analysis (PCA) was used to reduce the dimensionality of the stress matrix. Data points in PCA space were initially screened by K-means cluster analysis, and connection networks of two levels were constructed based on the distance between the data points. The material parameters corresponding to the data points were substituted, and pressure was applied to convert the diastolic models to systolic models to match those reconstructed from electrocardiographic (ECG) gated computed tomography angiography (CTA), and determine the optimal material parameters. The proximal and distal segments of the thoracic aorta were selected for uniaxial tensile testing, and the stress–strain curves obtained from numerical simulations and experiments were compared. The average distances between the simulated systolic proximal and distal segments and their corresponding systolic models reconstructed from the ECG-gated-CTA were 0.388 mm and 0.257 mm, respectively. The fit goodness of the stress–strain data obtained by two methods was 0.9953 and 0.9750, respectively, with equivalent elastic moduli differences of 1.08% and 0.36%. Thus, a material parameter screening method for different aortic segments was proposed and its accuracy was verified experimentally with good consistency. This method is expected to provide a theoretical basis for biomechanical studies of aortic diseases.

An intersegmental single-cell profile reveals aortic heterogeneity and identifies a novel Malat1+ vascular smooth muscle subtype involved in abdominal aortic aneurysm formation

The developmental origin, anatomical location, and other factors contribute to aortic heterogeneity in a physiological state. On this basis, vascular diseases occur at different ratios based on position specificity, even with the same risk factor. However, the continuous intersegmental aortic profile has been rarely reported at the single-cell level. To reveal aortic heterogeneity, we identified 15 cell subtypes from five continuous aortic segments by marker genes and functional definitions. The EC1 subtype highly expressed Vcam1 and Scarb2 genes in the aortic arch, which were reported to be associated with atherosclerosis. The newly identified Fbn1+ fibroblasts were found highly expressed in thoracic segments. More importantly, vascular smooth muscle cells (VSMCs) demonstrated a novel composition in which VSMC 4 marked with the gene Malat1 were mainly distributed in the abdominal segment. Malat1 knockout reduced MMPs and inflammatory factor production induced by Ang II in smooth muscle cells, and the Malat1 inhibitor exerted preventive, inhibitory, and reversing effects on AngII-induced abdominal aortic aneurysm (AAA) in vivo revealed by a series of animal experiments. Single-cell analysis of AngII-induced AAA tissues treated with or without the inhibitor further clarified the key role of Malat1+VSMC in the occurrence and progression of AAA. In summary, segmental gene expression and cell subtype features in normal aorta associated with different vascular diseases might provide potential therapeutic targets.

A dissection … of the Dacron?

A dissection … of the Dacron?

AIM2 Inflammasome Activation Contributes to Aortic Dissection in a Sporadic Aortic Disease Mouse Model.

The absent in melanoma 2 (AIM2) inflammasome induces pyroptosis, tissue inflammation, and extracellular matrix destruction. We tested the hypothesis that the AIM2 inflammasome contributes to aortic aneurysm and dissection (AAD) development by promoting pyroptosis in smooth muscle cells (SMCs). We examined AIM2 expression in aortic tissues from patients with ascending thoracic aortic aneurysm (ATAA) and aortic dissection (ATAD) and from organ donor controls. AIM2's role in AAD development was evaluated in AIM2-deficient mice in a sporadic AAD model induced by challenging mice with a high-fat diet and angiotensin II infusion. The direct effects of dsDNA on SMC death in vitro were studied. Western blot analyses showed that AIM2 was increased in ATAD compared to ATAA and control tissue. Immunofluorescence demonstrated increased AIM2 in SMCs and macrophages in the aortic media and adventitia of dissected tissue. Increased AIM2 abundance was associated with increased cleavage of caspase-1 and cleavage of gasdermin-D, indicating activation of pyroptosis. In a mouse model of sporadic AAD induced by high-fat diet and angiotensin II infusion, AIM2-deficient mice showed significant reduction in aortic dissection, but not aneurysm formation in all aortic segments, versus wild-type mice. Finally, treating cultured human aortic SMCs with double-stranded DNA induced AIM2 expression, caspase-1 cleavage, and gasdermin-D cleavage; these effects were reduced by silencing AIM2 and caspase-1 genes, suggesting involvement of the AIM2 inflammasome in cytosolic DNA-induced activation of SMC pyroptosis. Activation of the AIM2 inflammasome cascade contributes to aortic degeneration and dissection, in part, by activating pyroptosis.

Viscoelasticity of human descending thoracic aorta in a mock circulatory loop

Healthy human descending thoracic aortas, obtained during organ donation for transplant and research, were tested in a mock circulatory loop to measure the mechanical response to physiological pulsatile pressure and flow. The viscoelastic properties of the aortic segments were investigated at three different pulse rates. The same aortic segments were also subjected to quasi-static pressure tests in order to identify the aortic dynamic stiffness ratio, which is defined as the ratio between the stiffness in case of pulsatile pressure and the stiffness measured for static pressurization, both at the same value of pressure. The loss factor was also identified. The shape of the deformed aorta under static and dynamic pressure was measured by image processing to verify the compatibility of the end supports with the natural deformation of the aorta in the human body. In addition, layer-specific experiments on 10 human descending thoracic aortas allowed to precisely identify the mass density of the aortic tissue, which is an important parameter in cardiovascular dynamic models.

An observational assessment of aortic deformation during infrarenal and complex endovascular aortic aneurysm repair

ObjectiveReal-time aortic deformation during endovascular aortic aneurysm repair (EVAR) has not been reported. Successful EVAR relies on predicting intraoperative aortic-endograft deformation from preoperative imaging. Correct prediction is essential, because malalignment of endografts decreases patient survival. We describe intraoperative aortic deformation during infrarenal EVAR and complex fenestrated/branched EVAR (F/BEVAR), relating deformation to preoperative anatomy and follow-up outcomes. MethodsA multicenter, retrospective cohort of aortic aneurysm patients undergoing operation between January 2019 and February 2021, substratified by repair, infrarenal EVAR (n = 50), F/BEVAR (n = 80), and iliac branch graft with F/B/EVAR (IBG + F/B/EVAR; n = 27), were compared using software-based nonrigid two- and three-dimensional aortic deformational intraoperative assessment (CYDAR). Preoperative computed tomography reconstructions of aortic and iliac tortuosities were assessed against intraoperative deformation, the primary outcome, and related to perioperative and follow-up adverse outcomes. ResultsAll treatment groups had low preoperative visceral aortic tortuosity; the EVAR group had higher iliac tortuosity (1.43 ± 0.05; P = .018). Intraoperative aortic visceral deformation was consistently cranial and anterior; IBG + F/B/EVAR patients had the largest magnitude deformation (superior mesenteric artery, EVAR 5.1 ± 0.9 mm; F/BEVAR 4.4 ± 0.4 mm; IBG 8.3 ± 1.2 mm; P = .004). Celiac artery, superior mesenteric artery, and bilateral renal artery deformations were correlated (R = 0.923-0.983). Iliac deformation was variable in magnitude and direction. Preoperative tortuosity was not correlated with the magnitude of intraoperative deformation nor was deformation magnitude related to endograft instability during follow-up, including endoleak development, reinterventions, or visceral vessel complications. ConclusionsThe aorta deforms consistently during EVAR at the visceral aortic segment but unpredictably at the iliac bifurcation. Aortoiliac deformation is unrelated to adverse perioperative outcomes, branch instability, or reinterventions during short-term follow-up.

The Nutraceutical Antihypertensive Action of C-Phycocyanin in Chronic Kidney Disease Is Related to the Prevention of Endothelial Dysfunction.

C-phycocyanin (CPC) is an antihypertensive that is not still wholly pharmacologically described. The aim of this study was to evaluate whether CPC counteracts endothelial dysfunction as an antihypertensive mechanism in rats with 5/6 nephrectomy (NFx) as a chronic kidney disease (CKD) model. Twenty-four male Wistar rats were divided into four groups: sham control, sham-treated with CPC (100 mg/Kg/d), NFx, and NFx treated with CPC. Blood pressure was measured each week, and renal function evaluated at the end of the treatment. Afterward, animals were euthanized, and their thoracic aortas were analyzed for endothelium functional test, oxidative stress, and NO production. 5/6 Nephrectomy caused hypertension increasing lipid peroxidation and ROS production, overexpression of inducible nitric oxide synthase (iNOS), reduction in the first-line antioxidant enzymes activities, and reduced-glutathione (GSH) with a down-expression of eNOS. The vasomotor response reduced endothelium-dependent vasodilation in aorta segments exposed to acetylcholine and sodium nitroprusside. However, the treatment with CPC prevented hypertension by reducing oxidative stress, NO system disturbance, and endothelial dysfunction. The CPC treatment did not prevent CKD-caused disturbance in the antioxidant enzymes activities. Therefore, CPC exhibited an antihypertensive activity while avoiding endothelial dysfunction.