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.

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.

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.

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.

Multidimensional Contribution of Matrix Metalloproteinases to Atherosclerotic Plaque Vulnerability: Multiple Mechanisms of Inhibition to Promote Stability.

The prevalence of atherosclerotic disease continues to increase, and despite significant reductions in major cardiovascular events with current medical interventions, an additional therapeutic window exists. Atherosclerotic plaque growth is a complex integration of cholesterol penetration, inflammatory cell infiltration, vascular smooth muscle cell (VSMC) migration, and neovascular invasion. A family of matrix-degrading proteases, the matrix metalloproteinases (MMPs), contributes to all phases of vascular remodeling. The contribution of specific MMPs to endothelial cell integrity and VSMC migration in atherosclerotic lesion initiation and progression has been confirmed by the increased expression of these proteases in plasma and plaque specimens. Endogenous blockade of MMPs by the tissue inhibitors of metalloproteinases (TIMPs) may attenuate proteolysis in some regions, but the progression of matrix degeneration suggests that MMPs predominate in atherosclerotic plaque, precipitating vulnerability. Plaque neovascularization also contributes to instability and, coupling the known role of MMPs in angiogenesis to that of atherosclerotic plaque growth, interest in targeting MMPs to facilitate plaque stabilization continues to accumulate. This article aims to review the contributions of MMPs and TIMPs to atherosclerotic plaque expansion, neovascularization, and rupture vulnerability with an interest in promoting targeted therapies to improve plaque stabilization and decrease the risk of major cardiovascular events.

Development and testing of a silicone in vitro model of descending aortic dissection.

BACKGROUND: Stanford type B dissection of the descending aorta is a potentially fatal condition that is poorly understood. Limited scientific understanding of the role of current interventional techniques, as well as heterogeneity in the condition, contributes to lack of consensus as to the most effective treatment strategy. This study introduces an anatomically accurate model for investigating aortic dissection in a laboratory setting. MATERIALS AND METHODS: A silicone model was fabricated and filled with fluid to mimic human blood. Flow was established, and the model was scanned using a four-dimensional flow magnetic resonance imaging protocol. On analysis, luminal flow rates were quantified by multiplying local velocity by included area. RESULTS: The upstream total flow was compared with the sum of the flow in the true and false lumens. The two values were within the margin of error. Furthermore, flow rates matched with the relative areas of each compartment. CONCLUSIONS: These results validate our model as a novel and unique system that mimics a type B aortic dissection and will allow for more sophisticated analysis of dissection physiology in future studies.

Open repair of superior mesenteric artery mycotic aneurysm in an adolescent girl.

Aneurysmal degeneration of the superior mesenteric artery (SMA) is rare, particularly in the pediatric population. We report the case of a 16-year-old female who presented with abdominal discomfort, back pain, fever, and vomiting. Extensive work-up revealed a 3-cm SMA aneurysm (SMAA) with surrounding inflammation. No bacterial growth was identified on current cultures, but a mycotic etiology was suspected due to recent episodes of suppurative hidradenitis. In addition to broad-spectrum antibiotics, she underwent transabdominal surgical intervention, including proximal and distal aneurysm ligation with aortomesenteric bypass, utilizing the reversed saphenous vein. Although endovascular intervention in the mesenteric arterial system has increased in utilization, patient-specific considerations, such as age and potential for infectious etiology, must drive therapeutic decision-making, with open surgical bypass being liberally employed.

Stent graft therapy for false lumen aneurysmal degeneration in established type B aortic dissection (FADED) results in differential volumetric remodeling of the thoracic versus abdominal aortic segments.

BACKGROUND: Despite optimal medical therapy of type B aortic dissections, false lumen aneurysmal degeneration of these established dissections (FADED) occur over long term (>6 months). The efficacy of thoracic stent grafts (thoracic endovascular aortic repair [TEVAR]) in promoting aortic remodeling when placed at late time points remains controversial and was the focus of this investigation. METHODS: Utilizing tomographic scans, the volume of 6 distinct aortic compartments were calculated including the stented true lumen and stented false lumen (STL and SFL), below-stent true and false lumens (BSTL and BSFL), and the infrarenal aorta true and false lumens (IRA TL and IRA FL) when applicable. Cross-sectional areas were calculated at 1-cm intervals, collated, and volumetric ratios were derived from preoperative values. RESULTS: From 2004 to 2011, 21 patients met inclusion criteria. Complete false lumen (FL) thrombosis was achieved in 85.7% of SFL and 26.3% of BSFL. Volumetric analysis demonstrated that 71% of patients had increased STL volume and 71% had decreased SFL. In the below-stent region, 75% of patients had increased true lumen (TL) with 59% concurrently decreased FL volume. The IRA TL volume increased in 85% of patients and the IRA FL also expanded in 75% of this cohort. At the latest time point, overall growth was noted in the infrarenal aortic segment. CONCLUSIONS: Utilization of TEVAR in patients suffering from FADED can promote TL expansion with concurrent FL regression; however, progressive dilation in the total infrarenal aorta volume may occur and warrants close surveillance.

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.

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.

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.

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.

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.

Long-term localized high-frequency electric stimulation within the myocardial infarct: effects on matrix metalloproteinases and regional remodeling.

BACKGROUND: Disruption of the balance between matrix metalloproteinases (MMP) and MMP inhibitors (TIMPs) within a myocardial infarct (MI) contributes to left ventricular wall thinning and changes in regional stiffness at the MI region. This study tested the hypothesis that a targeted regional approach through localized high-frequency stimulation (LHFS) using low-amplitude electric pulses instituted within a formed MI scar would alter MMP/TIMP levels and prevent MI thinning. METHODS AND RESULTS: At 3 weeks after MI, pigs were randomized for LHFS (n=7; 240 bpm, 0.8 V, 0.05-ms pulses) or were left unstimulated (UNSTIM; n=10). At 4 weeks after MI, left ventricular wall thickness (echocardiography; 0.89+/-0.07 versus 0.67+/-0.08 cm; P<0.05) and regional stiffness (piezoelectric crystals; 14.70+/-2.08 versus 9.11+/-1.24; P<0.05) were higher with LHFS than in UNSTIM. In vivo interstitial MMP activity (fluorescent substrate cleavage; 943+/-59 versus 1210+/-72 U; P<0.05) in the MI region was lower with LHFS than in UNSTIM. In the MI region, MMP-2 levels were lower and TIMP-1 and collagen levels were higher with LHFS than in UNSTIM (all P<0.05). Transforming growth factor-beta receptor 1 and phosphorylated SMAD-2/3 levels within the MI region were higher with LHFS than in UNSTIM. Electric stimulation (4 Hz) of isolated fibroblasts resulted in reduced MMP-2 and MT1-MMP levels but increased TIMP-1 levels compared with unstimulated fibroblasts. CONCLUSIONS: These unique findings demonstrate that LHFS of the MI region altered left ventricular wall thickness and material properties, likely as a result of reduced regional MMP activity. Thus, LHFS may provide a novel means to favorably modify left ventricular remodeling after MI.