Biomechanical dysregulation of SGK-1 dependent aortic pathologic markers in hypertension.

Introduction: In hypertension (HTN), biomechanical stress may drive matrix remodeling through dysfunctional VSMC activity. Prior evidence has indicated VSMC tension-induced signaling through the serum and glucocorticoid inducible kinase-1 (SGK-1) can impact cytokine abundance. Here, we hypothesize that SGK-1 impacts production of additional aortic pathologic markers (APMs) representing VSMC dysfunction in HTN. Methods: Aortic VSMC expression of APMs was quantified by QPCR in cyclic biaxial stretch (Stretch) +/- AngiotensinII (AngII). APMs were selected to represent VSMC dedifferentiated transcriptional activity, specifically Interleukin-6 (IL-6), Cathepsin S (CtsS), Cystatin C (CysC), Osteoprotegerin (OPG), and Tenascin C (TNC). To further assess the effect of tension alone, abdominal aortic rings from C57Bl/6 WT mice were held in a myograph at experimentally derived optimal tension (OT) or OT + 30% +/-AngII. Dependence on SGK-1 was assessed by treating with EMD638683 (SGK-1 inhibitor) and APMs were measured by QPCR. Then, WT and smooth muscle cell specific SGK-1 heterozygous knockout (SMC-SGK-1KO+/-) mice had AngII-induced HTN. Systolic blood pressure and mechanical stress parameters were assessed on Day 0 and Day 21. Plasma was analyzed by ELISA to quantify APMs. Statistical analysis was performed by ANOVA. Results: In cultured aortic VSMCs, expression of all APMs was increased in response to biomechanical stimuli (Stretch +/-AngII,). Integrating the matrix contribution to signal transduction in the aortic rings led to IL-6 and CysC demonstrating SGK-1 dependence in response to elevated tension and interactive effect with concurrent AngII stimulation. CtsS and TNC, on the other hand, primarily responded to AngII, and OPG expression was unaffected in aortic ring experimentation. Both mouse strains had >30% increase in blood pressure with AngII infusion, reduced aortic distensibility and increased PPV, indicating increased aortic stiffness. In WT + AngII mice, IL-6, CtsS, CysC, and TNC plasma levels were significantly elevated, but these APMs were unaffected by HTN in the SMC-SGK-1KO+/- +AngII mice, suggesting SGK-1 plays a major role in VSMC biomechanical signaling to promote dysfunctional production of selected APMs. Conclusion: In HTN, changes in the plasma levels of markers associated with aortic matrix homeostasis can reflect remodeling driven by mechanobiologic signaling in dysfunctional VSMCs, potentially through the activity of SGK-1. Further defining these pathways may identify therapeutic targets to reduce cardiovascular morbidity and mortality.

Submitting a successful National Institutes of Health career development award for the vascular surgeon scientist.

Obtaining a career development award from the National Institutes of Health (K award) is often an important step in establishing a career as a vascular surgeon scientist. The application and review process is competitive, involves many steps, and may be confusing to the prospective applicant. Further, there are requirements involving mentors and the applicant's institution. This article, authored completely by vascular surgeons with active K awards, is intended for potential applicants and personnel at their institution and reviews relevant information including strategies for a successful application.

Hostile neck anatomy contributes to higher rates of reintervention following endovascular aortic repair for ruptured infrarenal abdominal aortic aneurysm.

INTRODUCTION: Ruptured abdominal aortic aneurysms (AAA) presenting with hostile neck anatomy can represent a challenge in surgical decision-making. We hypothesized that, patients who require reinterventions have higher rates of compromised neck anatomy at initial presentation and may indicate a need for altered surveillance paradigm. METHODS: Patients presenting with ruptured AAA to a single tertiary care institution from 2014 to 2021 were retrospectively reviewed. Those treated with infrarenal EVAR, with no prior aortic surgeries, and with available pre-operative computed tomography (CT) scans were included. Demographics, timing and type of reintervention, follow-up, and survival were collected. CT scans were assessed for hostile neck anatomy via measurements of diameter, length, angle, taper, bulge, calcification, and thrombus. Demographics, comorbidities, and neck anatomy of those with and without reintervention were compared using Fischer's Exact and Student's T-test. Survival was analyzed via Kaplan-Meier and log-rank test. RESULTS: Eighty-nine patients were available for analysis, 37 of which met inclusion criteria. Intraoperative death occurred in 3 patients (8.1%) and 1 patient (2.7%) was intraoperatively converted to an open repair. Thirty-day and 1-year survival were 97% and 91%, respectively. The reintervention rate was 30% (n = 10), occurring at a median of 200 days (18-2053 days) after the index operation. All patients requiring reintervention met hostile neck criteria (p = .002) and had a statistically higher number of hostile neck criteria (1.80 vs 0.87, p = .03). Thirty percent (n = 3) of patients that received a reintervention had neck diameter greater than 3 cm, compared to zero patients in the non-reintervention group (p = .022). Proximal reinterventions (n = 5) had statistically higher neck diameters and neck angle compared to the non-reintervention group. CONCLUSION: Infrarenal rEVAR is effective at preventing acute mortality despite specific anatomic considerations that may contribute to the higher reintervention rates, and therefore those parameters ought to be considered when following patients in the post-intervention period.

Addressing Barriers to Entry and Retention of Women in Interventional Vascular Specialties With Proposed Solutions: A Scientific Statement From the American Heart Association.

Representation of women in interventional vascular fields (interventional cardiology, interventional radiology, and vascular surgery) lags behind that in other specialties. With women representing half of all medical school graduates, encouraging parity of women in these fields needs to start in medical school. Barriers to pursuing careers in vascular intervention include insufficient exposure during core clerkships, early mentorship, visibility of women in the field, length of training, lifestyle considerations, work culture and environment, and concerns about radiation exposure. This scientific statement highlights potential solutions for both the real and perceived barriers that women may face in pursuing careers in vascular intervention, including streamlining of training (as both interventional radiology and vascular surgery have done with a resultant increase in percentage of women trainees), standardization of institutional promotion of women in leadership, and professional and industry partnerships for the retention and advancement of women.

Highly accelerated free-breathing real-time 2D flow imaging using compressed sensing and shared velocity encoding.

OBJECTIVES: 2D real-time (RT) phase-contrast (PC) MRI is a promising alternative to conventional PC MRI, which overcomes problems due to irregular heartbeats or poor respiratory control. This study aims to evaluate a prototype compressed sensing (CS)-accelerated 2D RT-PC MRI technique with shared velocity encoding (SVE) for accurate beat-to-beat flow measurements. METHODS: The CS RT-PC technique was implemented using a single-shot fast RF-spoiled gradient echo with SVE by symmetric velocity encoding, and acquired with a temporal resolution of 51-56.5 ms in 1-5 heartbeats. Both aortic dissection phantom (n = 8) and volunteer (n = 7) studies were conducted using the prototype CS RT (CS, R = 8), the conventional (GRAPPA, R = 2), and the fully sampled PC sequences on a 3T clinical system. Flow parameters including peak velocity, peak flow rate, net flow rate, and maximum velocity were calculated to compare the performance between different methods using linear regression, intraclass correlation (ICC), and Bland-Altman analyses. RESULTS: Comparisons of the flow measurements at all locations in the phantoms demonstrated an excellent correlation (all R2 ≥ 0.93) and agreement (all ICC ≥ 0.97) with negligible means of differences. In healthy volunteers, a similarly good correlation (all R2 ≥ 0.80) and agreement (all ICC ≥ 0.90) were observed; however, CS RT slightly underestimated the maximum velocities and flow rates (~ 12%). CONCLUSION: The highly accelerated CS RT-PC technique is feasible for the evaluation of flow patterns without requiring breath-holding, and it allows for rapid flow assessment in patients with arrhythmia or poor breath-hold capacity. CLINICAL RELEVANCE STATEMENT: The free-breathing real-time flow MRI technique offers improved spatial and temporal resolutions, as well as the ability to image individual cardiac cycles, resulting in superior image quality compared to the conventional PC technique when imaging patients with arrhythmias, especially those with atrial fibrillation. KEY POINTS: • The highly accelerated prototype CS RT-PC MRI technique with improved temporal resolution by the concept of SVE is feasible for beat-to-beat flow evaluation without requiring breath-holding. • The results of the phantom and in vivo quantitative flow evaluation show the ability of the prototype CS RT-PC technique to obtain reliable flow measurements similarly to the conventional PC MRI. • With less than 12% underestimation, excellent agreements between the two techniques were shown for the measurements of peak velocities and flow rates.

Vascular smooth muscle cell mechanotransduction through serum and glucocorticoid inducible kinase-1 promotes interleukin-6 production and macrophage accumulation in murine hypertension.

Objective: The objective of this investigation was to demonstrate that in vivo induction of hypertension (HTN) and in vitro cyclic stretch of aortic vascular smooth muscle cells (VSMCs) can cause serum and glucocorticoid-inducible kinase (SGK-1)-dependent production of cytokines to promote macrophage accumulation that may promote vascular pathology. Methods: HTN was induced in C57Bl/6 mice with angiotensin II infusion (1.46 mg/kg/day × 21 days) with or without systemic infusion of EMD638683 (2.5 mg/kg/day × 21 days), a selective SGK-1 inhibitor. Systolic blood pressure was recorded. Abdominal aortas were harvested to quantify SGK-1 activity (pSGK-1/SGK-1) by immunoblot. Flow cytometry quantified the abundance of CD11b+/F480+ cells (macrophages). Plasma interleukin (IL)-6 and monocyte chemoattractant protein-1 (MCP-1) was assessed by enzyme-linked immunosorbent assay. Aortic VSMCs from wild-type mice were subjected to 12% biaxial cyclic stretch (Stretch) for 3 or 12 hours with or without EMD638683 (10 µM) and with or without SGK-1 small interfering RNA with subsequent quantitative polymerase chain reaction for IL-6 and MCP-1 expression. IL-6 and MCP-1 in culture media were analyzed by enzyme-linked immunosorbent assay. Aortic VSMCs from SGK-1flox+/+ mice were transfected with Cre-Adenovirus to knockdown SGK-1 (SGK-1KD VSMCs) and underwent parallel tension experimentation. Computational modeling was used to simulate VSMC signaling. Statistical analysis included analysis of variance with significance at a P value of <.05. Results: SGK-1 activity, abundance of CD11b+/F4-80+ cells, and plasma IL-6 were increased in the abdominal aorta of mice with HTN and significantly reduced by treatment with EMD638683. This outcome mirrored the increased abundance of IL-6 in media from Stretch C57Bl/6 VSMCs and attenuation of the effect with EMD638683 or SGK-1 small interfering RNA. C57Bl/6 VSMCs also responded to Stretch with increased MCP-1 expression and secretion into the culture media. Further supporting the integral role of mechanical signaling through SGK-1, target gene expression and cytokine secretion was unchanged in SGK-1KD VSMCs with Stretch, and computer modeling confirmed SGK-1 as an intersecting node of signaling owing to mechanical strain and angiotensin II. Conclusions: Mechanical activation of SGK-1 in aortic VSMCs can promote inflammatory signaling and increased macrophage abundance, therefore this kinase warrants further exploration as a pharmacotherapeutic target to abrogate hypertensive vascular pathology.

Extra-anatomic bypass can treat renovascular hypertension due to atherosclerotic atypical aortic coarctation.

Atypical aortic coarctation causing high-grade descending thoracic aortic stenosis secondary to calcified atherosclerosis is rare. We have described the case of a 75-year old man with uncontrolled renovascular hypertension secondary to this etiology. His unique anatomy meant he was not a candidate for endovascular management and his multiple comorbidities meant he was high risk for open thoracoabdominal surgery. He successfully underwent extra-anatomic bypass. Postoperatively, his renovascular hypertension improved, and he was weaned off multiple intravenous and oral antihypertensive medications. The findings from the present case suggest that extra-anatomic bypass can be a good option for treating selected patients with renovascular hypertension due to atypical aortic coarctation.

Signaling through the IL-6-STAT3 Pathway Promotes Proteolytically-Active Macrophage Accumulation Necessary for Development of Small AAA.

INTRODUCTION: Elevated interleukin-6 (IL-6) plasma levels have been associated with abdominal aortic aneurysm (AAA), but whether this cytokine plays a causative role in the degenerative remodeling or represents an effect from the inflammatory cascades initiated by infiltrating leukocytes remained unclear. This project aims to demonstrate that within the aortic wall, signaling from IL-6 through the STAT3 transcription factor is necessary for infiltration of proteolytically-active macrophages and development of small AAA. METHODS: Following measurement of baseline infrarenal aortic diameter (AoD, digital microscopy), C57Bl/6 and IL-6 knockout (IL-6KO) mice underwent AAA induction by application of peri-adventitial CaCl2 (0.5 M) +/- implantation of an osmotic mini-pump delivering IL-6 (4.36 µg/kg/day over 21 days). At the terminal procedure, AoDs were measured by digital microscopy and aortas harvested for immunoblot (pSTAT3/STAT3), matrix metalloproteinase (MMP) quantification, or flow cytometric analysis of macrophage content. Plasma was collected for cytokine analysis. RESULTS: IL-6 infusion significantly increased the plasma IL-6 levels in C57Bl/6 and IL-6KO animals. The C57Bl/6 + CaCl2 group developed AAA (AoD >50% above baseline) but IL-6KO + CaCl2 did not. In the IL-6KO + IL-6+CaCl2 group, AAA developed to match that of C57Bl/6 + CaCl2 mice. STAT3 activity was significantly increased in animals with advanced stages of dilation (>40% from baseline), compared to those with ectasia (≤25%). Although cytokine profiles did not support T-cells or neutrophils as being active contributors in this stage of aortic remodeling, changes in the profile of elaborated MMPs suggested macrophage activity with a trend toward alternatively activated pathways. Flow cytometry confirmed significantly increased macrophage abundance specifically in animals with upregulated STAT3 activity and advanced aortic dilation. CONCLUSION: In this murine model of AAA, progressive dilation to development of true AAA was only accomplished when IL-6 signaling upregulated STAT3 activity to effect accumulation of proteolytically-active macrophages. This pathway warrants further investigation to identify potential therapeutic avenues to abrogate growth of small AAA.

Integrating Ultrasound-Derived Carotid Artery Stiffness in the Assessment of Cardiovascular Risk.

Historically, pulse wave velocity (PWV) has been used to measure vascular stiffness, but is limited in its utility when certain vascular disease states are present, such as aneurysm or iliac stenosis. PWV can therefore only provide reliable assessment of global vascular stiffness in limited vascular pathology. Speckle tracking is a method of post-hoc ultrasound image analysis that can measure vascular stiffness in a more comprehensive manner. Evidence from in vitro as well as in vivo studies has validated these techniques in the assessment of strain, distensibility, modulus, and stiffness index (ß) in the carotid arterial system. Unfortunately, despite the well-established correlation between vascular stiffness and cardiovascular morbidity and mortality, standard vascular laboratory ultrasound protocols do not include stiffness assessment. Herein, we present evidence in favor of integrating speckle tracking into carotid artery duplex protocols to measure vascular stiffness that can be utilized in medical management to modulate cardiovascular risk.

Mechanical activation of the angiotensin II type 1 receptor contributes to abdominal aortic aneurysm formation.

OBJECTIVE: The angiotensin II type 1 receptor (AT1R) can be activated under conditions of mechanical stretch in some cellular systems. Whether this activity influences signaling within the abdominal aorta to promote to abdominal aortic aneurysm (AAA) development remains unknown. We evaluated the hypothesis that mechanical AT1R activation can occur under conditions of hypertension (HTN) and contribute to AAA formation. METHODS: BPH/2 mice, which demonstrate spontaneous neurogenic, low-renin HTN, and normotensive BPN/3 mice underwent AAA induction via the calcium chloride model, with or without an osmotic minipump delivering 30 mg/kg/d of the AT1R blocker Losartan. Systolic blood pressure (SBP) was measured at baseline and weekly via a tail cuff. The aortic diameter (AoD) was measured at baseline and terminal surgery at 21 days by digital microscopy. Aortic tissue was harvested for immunoblotting (phosphorylated extracellular signal-regulated kinase-1 and -2 [pERK1/2] to ERK1/2 ratio) and expressed as the fold-change from the BPN/3 control mice. Aortic vascular smooth muscle cells (VSMCs) underwent stretch with or without Losartan (1 µM) treatment to assess the mechanical stimulation of ERK1/2 activity. Statistical analysis of the blood pressure, AoD, and VSMC ERK1/2 activity was performed using analysis of variance. However, the data distribution was determined to be log-normal (Shapiro-Wilk test) for ERK1/2 activity. Therefore, it was logarithmically transformed before analysis of variance. RESULTS: At baseline, the SBP was elevated in the BPH/2 mice relative to the BPN/3 mice (P < .05). Losartan treatment significantly reduced the SBP in both mouse strains (P < .05). AAA induction did not affect the SBP. At 21 days after induction, the percentage of increase in the AoD from baseline was significantly greater in the BPH/2 mice than in the BPN/3 mice (101.28% ± 4.19% vs 75.59% ± 1.67% above baseline; P < .05). Losartan treatment significantly attenuated AAA growth in both BPH/2 and BPN/3 mice (33.88% ± 2.97% and 43.96% ± 3.05% above baseline, respectively; P < .05). ERK1/2 activity was increased approximately fivefold in the BPH/2 control mice relative to the BPN/3 control mice (P < .05). In the BPH/2 and BPN/3 mice with AAA, ERK1/2 activity was significantly increased relative to the respective baseline control (P < .05) and effectively reduced by concomitant Losartan therapy (P < .05). Biaxial stretch of the VSMCs in the absence of angiotensin II demonstrated increased ERK1/2 activation (P < .05 vs static control), which was significantly inhibited by Losartan. CONCLUSIONS: In BPH/2 mice with spontaneous neurogenic, low-renin HTN, AAA growth was amplified compared with the normotensive control and was effectively attenuated using Losartan. ERK1/2 activity was significantly elevated in the BPH/2 mice and after AAA induction in the normotensive and hypertensive mice but was attenuated by Losartan treatment. These data suggest that AT1R activation contributes to AAA development. Therefore, further investigation into this signaling pathway could establish targets for pharmacotherapeutic engineering to slow AAA growth. (JVS-Vascular Science 2021;2:194-206.). CLINICAL RELEVANCE: Hypertension (HTN) and abdominal aortic aneurysm (AAA) have been epidemiologically linked for decades; however, a biomechanical link has not yet been identified. Using a murine model of spontaneous neurogenic HTN experimentally demonstrated to have low circulating renin, mechanical activation of the angiotensin II type 1 receptor (AT1R) was identified with elevated blood pressure and AAA induction. HTN amplified AAA growth. However, more importantly, blocking the activation of AT1R with the angiotensin receptor blocker Losartan effectively abrogated AAA development. Although inhibiting the production of angiotensin II has previously been unsuccessful in altering AAA growth, the results from the present study suggest that blocking the activation of AT1R through direct ligand binding or mechanical stimulation might alter aortic wall signaling and warrants further investigation.

Response by Sex in Patient-Centered Outcomes With Baroreflex Activation Therapy in Systolic Heart Failure.

OBJECTIVES: The aim of this study was to assess sex differences in the efficacy and safety of baroreflex activation therapy (BAT) in the BeAT-HF (Baroreflex Activation Therapy for Heart Failure) trial. BACKGROUND: Patients were randomized 1:1 to receive guideline-directed medical therapy (GDMT) alone (control group) or BAT plus GDMT. METHODS: Pre-specified subgroup analyses including change from baseline to 6 months in 6-min walk distance (6MWD), quality of life (QoL) assessed using the Minnesota Living With Heart Failure Questionnaire (MLWHQ), New York Heart Association (NYHA) functional class, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) were conducted in men versus women. RESULTS: Fifty-three women and 211 men were evaluated. Women had similar baseline NT-proBNP levels, 6MWDs, and percentage of subjects with NYHA functional class III symptoms but poorer MLWHQ scores (mean 62 ± 22 vs. 50 ± 24; p = 0.01) compared with men. Women experienced significant improvement from baseline to 6 months with BAT plus GDMT relative to GDMT alone in MLWHQ score (-34 ± 27 vs. -9 ± 23, respectively; p < 0.01), 6MWD (44 ± 45 m vs. -32 ± 118 m; p < 0.01), and improvement in NYHA functional class (70% vs. 27%; p < 0.01), similar to the responses seen in men, with no significant difference in safety. Women receiving BAT plus GDMT had a significant decrease in NT-proBNP (-43% vs. 7% with GDMT alone; difference -48%; p < 0.01), while in men this decrease was -15% versus 2%, respectively (difference -17%; p = 0.08), with an interaction p value of 0.05. CONCLUSIONS: Women in BeAT-HF had poorer baseline QoL than men but demonstrated similar improvements with BAT in 6MWD, QoL, and NYHA functional class. Women had a significant improvement in NT-proBNP, whereas men did not. (Baroreflex Activation Therapy for Heart Failure [BeAT-HF]; NCT02627196).

Elevated Cardiopulmonary Complications after Revascularization in Patients with Severe Mental Health Disorders.

Introduction: Mental health disorders (MHD) are prevalent within surgical patient populations and can be associated with poorer postoperative outcomes, particularly in those with more severe MHD (schizophrenia and bipolar disorder). However, these associations have not been examined in vascular surgery patients. This study investigated patients undergoing lower extremity revascularization, hypothesizing that those with severe MHD would experience worse health and postoperative outcomes. Methods: A retrospective chart review of patients from 2010-2015 with peripheral arterial disease (PAD) requiring revascularization was conducted, with subsequent narrowing to those with concurrent MHD diagnoses, including severe MHD (sMHD) defined as bipolar disorder or schizophrenia and non-severe MHD (nsMHD), defined as anxiety or depression. The primary endpoints were 30-day mortality; Major Adverse Limb Events (MALE) including amputation at the above or below knee level; and Major Adverse Cardiac Events (MACE) including myocardial infarction (MI), congestive heart failure (CHF) exacerbation, and arrhythmia. Secondary endpoints were readmission within 30 days, pulmonary complications, and wound infection. Statistical analyses included Fisher Exact Test and Student's T-test. Results: Eighteen patients with MHD (sMHD, n=10; nsMHD, n=8) were identified and stratified. Twenty-four limbs were revascularized (sMHD, n=13; nsMHD, n=11). Overall incidence of 30-day mortality, MALE, and MACE were 4.2%, 33.3%, and 50.0%, respectively. Readmission rate, pneumonia, and wound infection occurred in 41.7%, 20.8%, and 16.7% of the population. Stratifying by MHD severity, no significant differences were observed for medical comorbidities, MALE, intervention type (open vs. endovascular), or treatment indication (claudication vs. critical limb ischemia). Patients with sMHD had significantly higher rates of MACE compared to patients with nsMHD (30.8% vs. 18.2%, p<.05). Pneumonia was also more prevalent in this group (38.5% vs. 0.0%, p<.05). Conclusion: While patients with concurrent diagnoses of MHD and PAD presented with similar comorbidities, comparable disease severity, and were equally treated by open versus endovascular techniques, those with severe MHD suffered significantly elevated rates of cardiopulmonary complications, specifically MACE and pneumonia. Further investigation is warranted to identify opportunities to optimize post-operative care for these complex patients.

Occlusion of the Celiac Artery during Endovascular Thoracoabdominal Aortic Aneurysm Repair Is associated with Increased Perioperative Morbidity and Mortality.

BACKGROUND: Some studies suggest that celiac artery coverage during elective endovascular thoracoabdominal aortic aneurysm (TAAA) repair is safe given sufficient collateralization of visceral organ perfusion from the superior mesenteric artery. However, there is concern that celiac artery coverage may lead to increased risk of foregut or spinal cord ischemia with an attendant increased risk of mortality. We sought to investigate rates of bowel ischemia, spinal cord ischemia, and 30-day mortality associated with celiac artery coverage during TEVAR and complex EVAR. METHODS: The Society for Vascular Surgery Vascular Quality Initiative database was queried for TEVAR and complex EVAR cases from 2012 to 2018. Inclusion criteria included TAAA pathology and endograft extension to aortic zone 6. Patients with aortic rupture, trauma, prior thoracic aortic surgery, known preoperative occlusion of the left subclavian superior mesenteric, or celiac arteries were excluded. Cases with intraoperative celiac artery occlusion (CAO) were compared retrospectively to cases with celiac artery preservation (CAP). Primary outcomes included 30-day mortality and a composite end point of 30-day mortality, spinal cord ischemia (transient or permanent lower extremity neurologic deficit), and bowel ischemia (colonoscopic evidence of ischemia, bloody stools in a patient who dies prior to colonoscopy or laparotomy, or other documented clinical diagnosis). Univariable comparisons were performed using chi-squared tests and Student's t-tests, as appropriate. Multivariable logistic regression analyses were employed to identify independent predictors of outcome. RESULTS: There were 628 cases identified for inclusion in the study. Patients undergoing CAO (n = 44) were more likely to be female or to have higher rates of preoperative spinal drain use, American Society of Anesthesiologists score ≥3, low preop hemoglobin, and/or symptomatic presentation, but fewer mean number of aortic zones covered. CAO was associated with higher 30-day mortality (5 of 44, 11%) compared to CAP (23 of 584, 4%), P = 0.039. The composite end point occurred at a significantly greater proportion for those who had CAO (10 of 44, 23%) compared to CAP (53 of 584, 9%, P = 0.008), driven by higher rates of 30-day mortality and bowel ischemia (9% vs. 2%, P = 0.026). By multivariate analysis, CAO was predictive of 30-day mortality (odds ratio [OR] = 3.9, 95% confidence interval [CI] = 1.1-13.8, P = 0.04) and the composite endpoint (OR = 3.0, 95% CI = 1.1-8.5, P = 0.03). Increasing procedure time was also associated with 30-day mortality (OR = 1.4, 95% CI = 1.1-1.7, P < 0.001) and the composite end point (OR = 1.4, 95% CI = 1.1-1.6, P < 0.001). CONCLUSIONS: For those treated for TAAAs, CAO was independently predictive of increased 30-day mortality and a composite end point of perioperative mortality, spinal cord ischemia, and bowel ischemia. When treating patients with extensive aortic aneurysmal disease, physicians should attempt to preserve the celiac artery, by revascularization or avoiding ostium coverage, whenever feasible.

Discharge to a Post-Acute Care Facility after Emergent Femoral Artery Repair is Not Protective Against Wound Complications.

BACKGROUND: Access site complication is the most common adverse event after endovascular intervention, and when emergent operative repair of the common femoral artery (CFA) is needed, patient morbidity can be significantly increased. The intent of this project was to identify predictors of wound events after emergent operative repair of the CFA due to an access site complication. It was hypothesized that patients discharged to a facility would benefit from an ongoing relationship with healthcare professionals as evidenced by more consistent follow-up and lower wound complication rates. METHODS: Patients who had a percutaneous CFA access complication and required emergent open CFA repair at an academic medical institution between 2015 and 2018 were included, and the charts were reviewed retrospectively. Primary outcomes included wound complication and outpatient compliance with vascular surgery clinic visit. Dichotomous groups were evaluated by the chi-squared test, and continuous variables were evaluated by Student's t-test. Univariate and multivariate regression analyses were completed to assess risk factors contributing to wound event or failure of clinic follow-up. RESULTS: Forty-four patients were identified with emergent CFA repair due to an access complication between July 2015 and June 2018. Among this population, 33% of patients had wound complications and 27% were discharged to a facility. Among those discharged to a facility, the rate of follow-up to the vascular surgeon's clinic was significantly lower than those discharged to home (40% vs. 85%, P < 0.05), and the incidence of wound complications appeared greater but did not reach statistical significance (50% vs. 27%, P = 0.11). Univariate analysis indicated that kidney disease, albumin <3 g/dL, and current smoking were predictive of wound complication, whereas on multivariate analysis, only kidney disease remained predictive (P < 0.05, odds ratio = 22). The modified frailty index (mFI) was not predictive of wound complications or compliance with follow-up. However, mFI did approach statistical significance when predicting discharge to a facility. CONCLUSIONS: Despite the availability of medical personnel to arrange transportation and provide wound care in post-acute care facilities, patients who were discharged to a facility after CFA injury requiring emergent repair experienced lower compliance with clinic follow-up and may have suffered more wound complications. Strategies to improve compliance with patient follow-up and wound healing in patients sent to post-acute care facilities are warranted.

Racial and Gender Disparity in Achieving Optimal Medical Therapy for Inpatients with Peripheral Artery Disease.

Best medical therapy for peripheral artery disease (PAD) includes statin and anti-platelet agents, a combination shown to decrease rates of major cardiovascular events. Despite these findings, many patients remain undertreated and the objective of this project was to investigate the rate of initiating anti-platelet and statin therapy for inpatients newly diagnosed with PAD with a focus on disparities by race and sex. A retrospective chart review of inpatients with newly diagnosed PAD was performed between January 1, 2016 to December 31, 2016 at a single institution. Demographics and comorbid conditions were collected. Primary outcomes included antiplatelet and statin prescription at discharge. The 44 patients included in this study were predominantly male (59% vs. 41%) and African American (61% vs. 39%). Between admission and discharge, prescriptions rose from 70% to 82% for statin and 82% to 91% for anti-platelet agents. Vascular specialists were more successful than non-vascular specialists at initiating medical therapy, with statin prescriptions increasing 22% and anti-platelet prescriptions climbing 23% for those admitted to a vascular specialist. Interestingly, when the ABI was reported in the normal range, rates of statin initiation were particularly compromised at only 40%. For the total patient sample, those discharged without a statin were more commonly African American (63%) and the majority were female (67%). All patients discharged without an antiplatelet were African American and 50% were females. Despite national guidelines, patients with PAD continue to be discharged without optimal medical therapy. This study suggests that obstacles to initiation may include race, sex, admitting service, or presence of a normal ABI. Further investigation is warranted to determine effective avenues for provider education and system-wide initiatives.

Elevated Wall Tension Leads to Reduced miR-133a in the Thoracic Aorta by Exosome Release.

Background Reduced miR-133a was previously found to be associated with thoracic aortic ( TA ) dilation, as seen in aneurysm disease. Because wall tension increases with vessel diameter (Law of Laplace), this study tested the hypothesis that elevated tension led to the reduction of miR-133a in the TA . Methods and Results Elevated tension (1.5 g; 150 mm Hg) applied to murine TA ex vivo reduced miR-133a tissue abundance compared with TA held at normotension (0.7 g; 70 mm Hg). Cellular miR-133a levels were reduced with biaxial stretch of isolated murine TA fibroblasts, whereas smooth muscle cells were not affected. Mechanisms contributing to the loss of miR-133a abundance were further investigated in TA fibroblasts. Biaxial stretch did not reduce primary miR-133a transcription and had no effect on the expression/abundance of 3 micro RNA -specific exoribonucleases. Remarkably, biaxial stretch increased exosome secretion, and exosomes isolated from TA fibroblasts contained more miR-133a. Inhibition of exosome secretion prevented the biaxial stretch-induced reduction of miR-133a. Subsequently, 2 in vivo models of hypertension were used to determine the effect of elevated wall tension on miR-133a abundance in the TA : wild-type mice with osmotic pump-mediated angiotensin II infusion and angiotensin II -independent spontaneously hypertensive mice. Interestingly, the abundance of miR-133a was decreased in TA tissue and increased in the plasma in both models of hypertension compared with a normotensive control group. Furthermore, miR-133a was elevated in the plasma of hypertensive human subjects, compared with normotensive patients. Conclusions Taken together, these results identified exosome secretion as a tension-sensitive mechanism by which miR-133a abundance was reduced in TA fibroblasts.

Elevated Wall Tension Initiates Interleukin-6 Expression and Abdominal Aortic Dilation.

BACKGROUND: Hypertension (HTN) has long been associated with abdominal aortic aneurysm (AAA) development, and these cardiovascular pathologies are biochemically characterized by elevated plasma levels of angiotensin II (AngII) as well as interleukin-6 (IL-6). A biologic relationship between HTN and AAA has not been established, however. Accordingly, the objective of this study was to evaluate whether elevated tension may initiate IL-6 production to accumulate monocyte/macrophages and promote dilation of the abdominal aorta (AA). METHODS: An IL-6 infusion model (4.36 µg/kg/day) was created utilizing an osmotic infusion pump, and after 4 weeks, AA diameter was measured by digital microscopy. The AA was then excised for CD68 immunostaining and flow cytometric analysis with CD11b and F4/80 to identify macrophages. Aortic segments from wild-type mice were suspended on parallel wires in an ex vivo tissue myograph at experimentally derived optimal tension (1.2 g) and in the presence of elevated tension (ET, 1.7 g) for 3 hr, and expression of IL-6 and monocyte chemoattractant protein-1 (MCP-1) was evaluated by quantitative polymerase chain reaction (QPCR). Isolated aortic vascular smooth muscle cells (VSMCs) were subjected to 12% biaxial cyclic stretch or held static (control) for 3 hr (n = 7), and IL-6 and MCP-1 expressions were evaluated by QPCR. RESULTS: Four-week IL-6 infusion resulted in an AA outer diameter that was 72.5 ± 5.6% (P < 0.05) greater than that of control mice, and aortic dilation was accompanied by an accumulation of macrophages in the AA medial layer as defined by an increase in CD68 + staining as well as an increase by flow cytometric quantification of CD11b+/F4/80+ cells. Wild-type AA segments did not respond to ex vivo application of ET but cyclic stretch of isolated VSMCs increased IL-6 (2.03 ± 0.3 fold) and MCP-1 (1.51 ± 0.11 fold) expression compared to static control (P < 0.05). Pretreatment with the selective STAT3 inhibitor WP1066 blunted the response in both cases. Interestingly, AngII did not stimulate expression of IL-6 and MCP-1 above that initiated by tension and again, the response was inhibited by WP1066, supporting an integral role of STAT3 in this pathway. CONCLUSIONS: An IL-6 infusion model can initiate macrophage accumulation as well as aortic dilation, and under conditions of elevated tension, this proinflammatory cytokine can be produced by aortic VSMCs. By activation of STAT3, MCP-1 is expressed to increase media macrophage abundance and create an environment susceptible to dilation. This biomechanical association between HTN and aortic dilation may allow for the identification of novel therapeutic strategies.

Differential hypertensive protease expression in the thoracic versus abdominal aorta.

BACKGROUND: Hypertension (HTN), which is a major risk factor for cardiovascular morbidity and mortality, can drive pathologic remodeling of the macro- and microcirculation. Patterns of aortic pathology differ, however, suggesting regional heterogeneity of the pressure-sensitive protease systems triggering extracellular matrix remodeling in the thoracic (TA) and abdominal aortas (AA). This study tested the hypothesis that the expression of two major protease systems (matrix metalloproteinases [MMPs] and cathepsins) in the TA and AA would be differentially affected with HTN. METHODS: Normotensive (BPN3) mice at 14-16 weeks of age underwent implantation of osmotic infusion pumps for 28-day angiotensin II (AngII) delivery (1.46 mg/kg/day; BPN3+AngII; n = 8) to induce HTN. The TA and AA were harvested to determine levels of MMP-2, MMP-9, and membrane type 1-MMP, and cathepsins S, K, and L were evaluated in age-matched BPN3 (n = 8) control and BPH2 spontaneously hypertensive mice (non-AngII pathway; n = 7). Blood pressure was monitored via CODA tail cuff plethysmography (Kent Scientific Corporation, Torrington, Conn). Quantitative real-time polymerase chain reaction and immunoblotting/zymography were used to measure MMP and cathepsin messenger RNA expression and protein abundance, respectively. Target protease values were compared within each aortic region via analysis of variance. RESULTS: Following 28 days infusion, the BPN3+AngII mice had a 17% increase in systolic blood pressure, matching that of the BPH2 spontaneously hypertensive mice (both P < .05 vs BPN3). MMP-2 gene expression demonstrated an AngII-dependent increase in the TA (P < .05), but MMP-9 was not altered with HTN. Expression of tissue inhibitor of metalloproteinases-1 was markedly increased in TA of BPN3+AngII mice, but tissue inhibitor of metalloproteinases-2 demonstrated decreased expression in the AA of both hypertensive groups (P < .05). Only cathepsin K responded to AngII-induced HTN with significant elevation in the TA of those mice, but expression of cathepsin L and cystatin C was inhibited in AA of both hypertensive groups (P < .05). Apoptotic markers were not significantly elevated in any experimental group. CONCLUSIONS: By using two different models of HTN, this study has identified pressure-dependent as well as AngII-dependent regional alterations in aortic gene expression of MMPs and cathepsins that may lead to differential remodeling responses in each of the aortic regions. Further studies will delineate mechanisms and may provide targeted therapies to attenuate down-stream aortic pathology based on demonstrated regional heterogeneity.