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Plenary Session Presentation at the Vascular and Endovascular Surgical Society 28th Annual Winter Meeting; Sun Valley Resort, Sun Valley, ID January 18 - 21, 2024 OBJECTIVES: In 2021, Ferraresi et al. created a novel scoring system based on the impact of small artery disease (SAD) and medial arterial calcification (MAC) on wound healing. SAD and MAC scores functioned similar to WIfI but with minimal resource expenditure. Despite its potential, few studies have expanded on the original dataset. We aim to validate SAD and MAC's impact on wound healing outcomes and determine their utility in relation to current predictive models. METHODS: Single-institution retrospective review was used to identify amputations for chronic (>1mo) podiatric wounds between 2015-2020. Foot x-ray (MAC) or angiography (SAD) <6 months of index procedure was required. Primary outcomes included major amputation, wound healing, major adverse limb events (MALE), and amputation-free survival (AFS). Statistical analysis included chi-square, one-way ANOVA, non-parametric correlation, Kaplan-Meier, Cox regression, and Akaike (AIC)/ Bayesian Inclusion Criteria (BIC) model comparison. RESULTS: Of 136 limbs, 67 received SAD scores (0-2) and 128 received MAC scores (0-2). SAD cohorts exhibited similar comorbidity profiles with exception of coronary disease, heart failure, and chronic kidney disease. MAC cohorts were notably disparate in prevalence of multiple conditions. High mean SAD/MAC scores were seen in severe (3-vessel) below-ankle disease (p=.001* [SAD], p=.041* [MAC]). Both SAD and MAC correlated with lower mean toe pressure (p=.043* [SAD], p=<.001* [MAC]), while only MAC correlated with higher overall WIfI score (p=.029*). No significant procedural differences were noted. However, higher re-admission rates (73.9% [2] vs. 46.9% [0], p=.014*) and all-cause mortality (65.2% [2] vs. 26.0% [0], p=.002*) were noted with higher MAC. Survival analysis revealed higher one-year major amputation rates (p=.036*), impaired wound healing (p<.001*), and lower amputation-free survival (p=.001*) with increasing MAC severity. Additionally, MAC-2 patients underwent amputation at faster rates than MAC-0 patients (HR 5.25, 95% CI [1.82, 9.77]) with longer times to wound healing (HR 0.21, 95% CI [0.08, 0.53]). Model comparison suggested a combination of WIfI and MAC could improve accuracy of predicted time to major amputation, wound healing, and amputation-free survival. CONCLUSIONS: MAC scoring showed significant promise both as individual predictor and adjunct to current predictive models of long-term wound healing outcomes. Routine use of MAC scoring in CLTI evaluation, especially when non-invasive testing is unavailable, could promote timely referral for intervention and efficient resource utilization in limited-resource or critical care settings. Further investigation is necessary to determine MAC's impact on revascularization and how scoring can be used to guide surgical decision making.
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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.
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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.
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Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux.
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Cholesterol metabolism is paramount to cells. Aberrations to cholesterol metabolism affects cholesterol homeostasis, which may impact the risk of several diseases. Recent evidence has suggested that vascular smooth muscle cell (VSMC) cholesterol metabolism may play a role in atherosclerosis. However, there is scant in vitro mechanistic data involving primary VSMC that directly tests how VSMC cholesterol metabolism may impact atherosclerosis. One reason for this lack of data is due to the impracticality of gene manipulation studies in primary VSMC, as cultured primary VSMC become senescent and lose their morphology rapidly. However, there are no immortalized VSMC lines known to be suitable for studying VSMC cholesterol metabolism. The purpose of this study was to determine whether MOVAS cells, a commercially available VSMC line, are suitable to use for studying VSMC cholesterol metabolism. Using immunoblotting and immunofluorescence, we showed that MOVAS cells express ABCA1, ABCG1, and SREBP-2. We also determined that MOVAS cells efflux cholesterol to apoAI and HDL, which indicates functionality of ABCA1/ABCG1. In serum-starved MOVAS cells, SREBP-2 target gene expression was increased, confirming SREBP-2 functionality. We detected miR-33a expression in MOVAS cells and determined this microRNA can silence ABCA1 and ABCG1 via identifying conserved miR-33a binding sites within ABCA1/ABCG1 3'UTR in MOVAS cells. We showed that cholesterol-loading MOVAS cells results in this cell line to transdifferentiate into a macrophage-like cell, which also occurs when VSMC accumulate cholesterol. Our characterization of MOVAS cells sufficiently demonstrates that they are suitable to use for studying VSMC cholesterol metabolism in the context of atherosclerosis.
