Publications by authors named "Luke P Brewster"

61 Publications

COVID-19-associated venous thromboembolism portends worse survival.

Semin Vasc Surg 2021 Sep 9;34(3):117-124. Epub 2021 Aug 9.

Emory University, 1364 E Clifton Road NE, Atlanta, GA 30322; Atlanta Veterans Affairs Medical Center, 1670 Clairmont Road, Decatur, GA 30033.

Patients with coronavirus disease 2019 (COVID-19) seem to be at high risk for venous thromboembolism (VTE) development, but there is a paucity of data exploring both the natural history of COVID-19-associated VTE and the risk for poor outcomes after VTE development. This investigation aims to explore the relationship between COVID-19-associated VTE development and mortality. A prospectively maintained registry of patients older than 18 years admitted for COVID-19-related illnesses within an academic health care network between March and September 2020 was reviewed. Codes from the tenth revision of the International Classification of Diseases for VTE were collected. The charts of those patients with a code for VTE were manually reviewed to confirm VTE diagnosis. There were 2,552 patients admitted with COVID-19-related illnesses. One hundred and twenty-six patients (4.9%) developed a VTE. A disproportionate percentage of patients of Black race developed a VTE (70.9% VTE v 57.8% non-VTE; P = .012). A higher proportion of patients with VTE expired during their index hospitalization (22.8% VTE v 8.4% non-VTE; P < .001). On multivariable logistic regression analysis, VTE was independently associated with mortality (odds ratio = 3.17; 95% confidence interval, 1.9-5.2; P < .001). Hispanic/Latinx ethnicity was associated with decreased mortality (odds ratio = 0.45; 95% confidence interval, 0.21-1.00; P = .049). Hospitalized patients of Black race with COVID-19 were more prone to VTE development, and patients with COVID-19 who developed in-hospital VTE had roughly nearly threefold higher odds of mortality. Further emphasis should be placed on optimizing COVID-19 anticoagulation protocols to reduce mortality in this high-risk cohort.
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http://dx.doi.org/10.1053/j.semvascsurg.2021.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8351078PMC
September 2021

Vascular calcification: a left-handed compliment for aging.

Authors:
Luke P Brewster

Am J Physiol Heart Circ Physiol 2021 08 23;321(2):H422-H423. Epub 2021 Jul 23.

Department of Surgery, Emory University, Atlanta, Georgia.

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http://dx.doi.org/10.1152/ajpheart.00300.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8410121PMC
August 2021

The Nitric Oxide System in Peripheral Artery Disease: Connection with Oxidative Stress and Biopterins.

Antioxidants (Basel) 2020 Jul 6;9(7). Epub 2020 Jul 6.

Department of Nutrition, Food and Exercise Sciences, Florida State University, Tallahassee, FL 32304, USA.

Peripheral artery disease (PAD) pathophysiology extends beyond hemodynamics to include other operating mechanisms, including endothelial dysfunction. Oxidative stress may be linked to endothelial dysfunction by reducing nitric oxide (NO) bioavailability. We aimed to investigate whether the NO system and its regulators are altered in the setting of PAD and to assess the relationship between NO bioavailability and oxidative stress. Sera from 35 patients with intermittent claudication (IC), 26 patients with critical limb ischemia (CLI), and 35 non-PAD controls were analyzed to determine levels of tetrahydrobiopterin (BH4), dihydrobiopterin (BH2), nitrate/nitrite (nitric oxides, or NOx), arginine, citrulline, asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA), and the oxidative stress markers 8-Oxo-2'-deoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), advanced glycation end products (AGEs), and protein carbonyls. NOx was significantly lower in IC and CLI patients compared to controls in association with elevated oxidative stress, with the greatest NOx reductions observed in CLI. Compared with controls, IC and CLI patients had reduced BH4, elevated BH2, and a reduced BH4/BH2 ratio. SDMA, the arginine/SDMA ratio, and the arginine/ADMA ratio were significantly higher in CLI patients. The NO system and its regulators are significantly compromised in PAD. This dysregulation appears to be driven by increased oxidative stress and worsens as the disease progresses from claudication to CLI.
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http://dx.doi.org/10.3390/antiox9070590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402092PMC
July 2020

Rationale and design of the granulocyte-macrophage colony stimulating factor in peripheral arterial disease (GPAD-3) study.

Contemp Clin Trials 2020 04 4;91:105975. Epub 2020 Mar 4.

Emory Clinical Cardiovascular Research Institute, Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

Background: Lower extremity peripheral arterial disease (PAD) is a public health problem and many patients with PAD experience claudication despite adequate medical and/or surgical management. Mobilization of endogenous progenitor cells using Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) is a novel therapeutic option that has shown promising results in experimental models and phase I/IIA clinical trials. The GPAD-3 trial will study the effect of two successive administrations of GM-CSF at 3-month interval for improving claudication among patients with lower extremity PAD.

Methods: We plan to recruit 176 patients in this ongoing randomized, double-blind, placebo-controlled Phase IIB trial. After screening for inclusion and exclusion criteria, eligible subjects undergo a 4-week screening phase where they perform subcutaneous placebo injections thrice weekly and walk at least three times a day until they develop claudication. After the screening phase, eligible subjects undergo baseline testing and are randomized 2:1 to receive 500 μg/day of GM-CSF subcutaneously thrice weekly for three weeks or placebo injections. After 3 months, follow-up endpoint testing is performed and subjects in the GM-CSF group receive the second administration of the drug for three weeks while subjects in placebo group receive matching placebo injections. All participants undergo endpoint testing at six-month and nine-month follow-up. The primary endpoint is change in 6-min walk distance between baseline and 6-month follow-up.

Conclusion: GPAD-3 explores a novel approach to address the need for alternative therapies that can alleviate symptoms among patients with lower extremity PAD. If successful, this study will pave the way for a pivotal Phase III trial.
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http://dx.doi.org/10.1016/j.cct.2020.105975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7263983PMC
April 2020

Perfusion Assessment in Critical Limb Ischemia: Principles for Understanding and the Development of Evidence and Evaluation of Devices: A Scientific Statement From the American Heart Association.

Circulation 2019 09 12;140(12):e657-e672. Epub 2019 Aug 12.

There are >12 million patients with peripheral artery disease in the United States. The most severe form of peripheral artery disease is critical limb ischemia (CLI). The diagnosis and management of CLI is often challenging. Ethnic differences in comorbidities and presentation of CLI exist. Compared with white patients, black and Hispanic patients have higher prevalence rates of diabetes mellitus and chronic renal disease and are more likely to present with gangrene, whereas white patients are more likely to present with ulcers and rest pain. A thorough evaluation of limb perfusion is important in the diagnosis of CLI because it can not only enable timely diagnosis but also reduce unnecessary invasive procedures in patients with adequate blood flow or among those with other causes for ulcers, including venous, neuropathic, or pressure changes. This scientific statement discusses the current tests and technologies for noninvasive assessment of limb perfusion, including the ankle-brachial index, toe-brachial index, and other perfusion technologies. In addition, limitations of the current technologies along with opportunities for improvement, research, and reducing disparities in health care for patients with CLI are discussed.
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http://dx.doi.org/10.1161/CIR.0000000000000708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7372288PMC
September 2019

Poor glycemic control is a strong predictor of postoperative morbidity and mortality in patients undergoing vascular surgery.

J Vasc Surg 2019 Apr 17;69(4):1219-1226. Epub 2018 Nov 17.

Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Emory University School of Medicine, Atlanta, Ga.

Objective: Hyperglycemia is a common occurrence in patients undergoing cardiovascular surgery. It has been identified in several surgical cohorts that improved perioperative glycemic control reduced postoperative morbidity and mortality. A significant portion of the population with peripheral arterial disease suffers from the sequelae of diabetes or metabolic syndrome. A paucity of data exists regarding the relationship between perioperative glycemic control and postoperative outcomes in vascular surgery patients. The objective of this study was to better understand this relationship and to determine which negative perioperative outcomes could be abated with improved glycemic control.

Methods: This is a retrospective review of a vascular patient database at a large academic center from 2009 to 2013. Eligible procedures included carotid endarterectomy and stenting, endovascular and open aortic aneurysm repair, and all open bypass revascularization procedures. Data collected included standard demographics, outcome parameters, and glucose levels in the perioperative period. Perioperative hyperglycemia was defined as at least one glucose value >180 mg/dL within 72 hours of surgery. The primary outcome was 30-day mortality, with secondary outcomes of complications, need to return to the operating room, and readmission.

Results: Of the total 1051 patients reviewed, 366 (34.8%) were found to have perioperative hyperglycemia. Hyperglycemic patients had a higher 30-day mortality (5.7% vs 0.7%; P < .01) and increased rates of acute renal failure (4.9% vs 0.9%; P < .01), postoperative stroke (3.0% vs 0.7%; P < .01), and surgical site infections (5.7% vs 2.6%; P = .01). In addition, these patients were also more likely to undergo readmission (12.3% vs 7.9%; P = .02) and reoperation (6.3% vs 1.8%; P < .01). Furthermore, multivariable logistic regression demonstrated that perioperative hyperglycemia had a strong association with increased 30-day mortality and multiple negative postoperative outcomes, including myocardial infarction, stroke, renal failure, and wound complications.

Conclusions: This study demonstrates a strong association between perioperative glucose control and 30-day mortality in addition to multiple other postoperative outcomes after vascular surgery.
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http://dx.doi.org/10.1016/j.jvs.2018.06.212DOI Listing
April 2019

The small heat shock protein HSPB1 protects mice from sepsis.

Sci Rep 2018 08 21;8(1):12493. Epub 2018 Aug 21.

Department of Surgery and Emory Critical Care Center, Emory University School of Medicine, Atlanta, GA, Georgia.

In vitro studies have implicated the small heat shock protein HSPB1 in a range of physiological functions. However, its in vivo relevance is unclear as the phenotype of unstressed HSPB1 mice is unremarkable. To determine the impact of HSPB1 in injury, HSPB1 and wild type (WT) mice were subjected to cecal ligation and puncture, a model of polymicrobial sepsis. Ten-day mortality was significantly higher in HSPB1 mice following the onset of sepsis (65% vs. 35%). Ex vivo mechanical testing revealed that common carotid arteries from HSPB1 mice were more compliant than those in WT mice over pressures of 50-120 mm Hg. Septic HSPB1 mice also had increased peritoneal levels of IFN-γ and decreased systemic levels of IL-6 and KC. There were no differences in frequency of either splenic CD4 or CD8 T cells, nor were there differences in apoptosis in either cell type. However, splenic CD4 T cells and CD8 T cells from HSPB1 mice produced significantly less TNF and IL-2 following ex vivo stimulation. Systemic and local bacterial burden was similar in HSPB1 and WT mice. Thus while HSPB1 mice are uncompromised under basal conditions, HSPB1 has a critical function in vivo in sepsis, potentially mediated through alterations in arterial compliance and the immune response.
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http://dx.doi.org/10.1038/s41598-018-30752-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6104051PMC
August 2018

Reversible secretome and signaling defects in diabetic mesenchymal stem cells from peripheral arterial disease patients.

J Vasc Surg 2018 12 10;68(6S):137S-151S.e2. Epub 2018 Aug 10.

Department of Surgery, Emory University School of Medicine, Atlanta, Ga; Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta, Ga; Surgery and Research Services, Atlanta VA Medical Center, Atlanta, Ga. Electronic address:

Objective: Regenerative medicine seeks to stall or to reverse the pathologic consequences of chronic diseases. Many people with diabetes have peripheral arterial disease (PAD), which increases their already high risk of major amputation. Cellular therapies are a promising regenerative medicine approach to PAD that can be used to focally inject regenerative cells to endangered tissue beds. Mesenchymal stem cells (MSCs) are known to promote tissue regeneration through stromal support and paracrine stimulation of new blood vessels (angiogenesis). Whereas little is known about human diabetic MSCs (dMSCs), particularly those from patients with PAD, dMSCs have a limited expansion capacity but can be improved with human platelet lysate (PL) supplementation. PL is rich in many growth factors, including epidermal growth factor (EGF), which is known to be important to cell proliferation and survival signaling pathways. We hypothesize that dMSCs have a reversible defect in EGF receptor pathways. The objective of this work was to test this hypothesis using dMSCs from PAD patients.

Methods: The secretome expression of EGF and prominent angiogens was characterized from bone marrow (BM)-derived and adipose tissue-derived (ATD) dMSCs from five patients (six limbs) undergoing major amputation. Western blot was used to characterize the AKT and extracellular signal-regulated protein kinases 1 and 2 expression in dMSCs under standard culture (5% fetal bovine serum plus fibroblast growth factor 2 [FGF2]), 5% human PL, or 5% fetal bovine serum plus EGF. Healthy donor MSCs were control cells. The angiogenic activity of BM- and ATD-dMSCs was tested on human umbilical vein endothelial cells (ECs). Paired t-test, analysis of variance, and Kruskal-Wallis tests were used as appropriate.

Results: Both BM- and ATD-dMSCs had typical MSC surface marker expression and similar expansion profiles, and they did not express EGF in their secretome. PL supplementation of dMSCs improved AKT signaling, but they were resistant to FGF2 activation of extracellular signal-regulated protein kinases 1 and 2. EGF supplementation led to similar AKT expression as with PL, but PL had greater phosphorylation of AKT at 30 and 60 minutes. The conditioned media from both BM- and ATD-dMSCs had robust levels of prominent angiogens (vascular endothelial growth factor, monocyte chemoattractant protein 1, hepatocyte growth factor), which stimulated EC proliferation and migration, and the co-culture of dMSCs with ECs led to significantly longer EC sprouts in three-dimensional gel than EC-alone pellets.

Conclusions: PL and EGF supplementation improves AKT expression in dMSCs over that of FGF2, but PL improved pAKT over that of EGF. Thus, PL supplementation strategies may improve AKT signaling, which could be important to MSC survival in cellular therapies. Furthermore, BM- and ATD-dMSCs have similar secretomes and robust in vitro angiogenic activity, which supports pursuing dMSCs from both reservoirs in regenerative medicine strategies.
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http://dx.doi.org/10.1016/j.jvs.2018.05.223DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252140PMC
December 2018

Invited commentary.

Authors:
Luke P Brewster

J Vasc Surg 2018 08;68(2):586-587

Atlanta, Ga.

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http://dx.doi.org/10.1016/j.jvs.2017.08.026DOI Listing
August 2018

Human diabetic mesenchymal stem cells from peripheral arterial disease patients promote angiogenesis through unique secretome signatures.

Surgery 2018 04 1;163(4):870-876. Epub 2018 Feb 1.

Department of Surgery, Division of Vascular Surgery, Emory University Hospital, Atlanta, GA; Surgical and Research Services, Atlanta VAMC, Decatur, GA. Electronic address:

Background: Diabetic patients are at increased risk of complications from severe peripheral arterial disease. Mesenchymal stem cells (MSC) may be useful in limiting these complications. Our objective is to test the angiogenic potential of diabetic versus healthy MSCs.

Methods: MSCs' angiogenic potential was tested by endothelial cell (EC) proliferation, migration, and 3-dimensional sprouting. Diabetic conditions were simulated with 5.5, 20, or 40 mM glucose. MSC secretome was quantified by enzyme-linked immunosorbent assay.

Results: Human aortic ECs were most sensitive to glucose conditions and were used for all MSC experiments. Diabetic MSCs had greater 3-dimensional invasion than healthy MSCs (P<.05), but EC sprouting was decreased in high glucose conditions in both diabetic and healthy MSCs. Secretome analysis demonstrated that 20mM glucose stimulated epidermal growth factor (EGF) expression in diabetic and healthy MSCs, but that diabetic MSCs had a unique secretome with increased levels of chemokine (C-X-C motif) ligand 1 (CXCL-1), interleukin six (IL-6), and monocyte chemoattractant protein 1 (MCP-1) (P<.05).

Conclusion: Despite having similar in vitro angiogenic activity, diabetic MSCs secrete a unique and inflammatory angiogenic signature that may influence MSC survival and function after transplantation in cell therapy applications. Strategies that normalize secretome in diabetic patients may improve the utility of autologous MSCs in this population of patients.
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http://dx.doi.org/10.1016/j.surg.2017.11.018DOI Listing
April 2018

Race and Socioeconomic Status Independently Affect Risk of Major Amputation in Peripheral Artery Disease.

J Am Heart Assoc 2018 01 12;7(2). Epub 2018 Jan 12.

Division of Cardiology, Emory University School of Medicine, Atlanta, GA.

Background: Black race has been shown to be a risk factor for amputation in peripheral artery disease (PAD); however, race has been argued to be a marker for socioeconomic status (SES) rather than true disparity. The aim of this study is to study the impact of race and SES on amputation risk in PAD patients.

Methods And Results: Patients with incident PAD in the national Veterans Affairs Corporate Data Warehouse were identified from 2003 to 2014 (N=155 647). The exposures were race and SES (measured by median income in residential ZIP codes). The outcome was incident major amputation. Black veterans were significantly more likely to live in low-SES neighborhoods and to present with advanced PAD. Black patients had a higher amputation risk in each SES stratum compared with white patients. In Cox models (adjusting for covariates), black race was associated with a 37% higher amputation risk compared with white race (hazard ratio: 1.37; 95% confidence interval, 1.30-1.45), whereas low SES was independently predictive of increased risk of amputation (hazard ratio: 1.12; 95% confidence interval, 1.06-1.17) and showed no evidence of interaction with race. In predicted amputation risk analysis, black race and low SES continued to be significant risk factors for amputation regardless of PAD presentation.

Conclusions: Black race significantly increases the risk of amputation within the same SES stratum compared with white race and has an independent effect on limb loss after controlling for comorbidities, severity of PAD at presentation, and use of medications.
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http://dx.doi.org/10.1161/JAHA.117.007425DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850162PMC
January 2018

Association of Statin Dose With Amputation and Survival in Patients With Peripheral Artery Disease.

Circulation 2018 04 12;137(14):1435-1446. Epub 2018 Jan 12.

Division of Cardiology (P.W.F.W.).

Background: Statin dose guidelines for patients with peripheral artery disease (PAD) are largely based on coronary artery disease and stroke data. The aim of this study is to determine the effect of statin intensity on PAD outcomes of amputation and mortality.

Methods: Using an observational cohort study design and a validated algorithm, we identified patients with incident PAD (2003-2014) in the national Veterans Affairs data. Highest statin intensity exposure (high-intensity versus low-to-moderate-intensity versus antiplatelet therapy but no statin use) was determined within 1 year of diagnosis of PAD. Outcomes of interest were lower extremity amputations and death. The association of statin intensity with incident amputation and mortality was assessed with Kaplan-Meier plots, Cox proportional hazards modeling, propensity score-matched analysis, and sensitivity and subgroup analyses, as well, to reduce confounding.

Results: In 155 647 patients with incident PAD, more than a quarter (28%) were not on statins. Use of high-intensity statins was lowest in patients with PAD only (6.4%) in comparison with comorbid coronary/carotid disease (18.4%). Incident amputation and mortality risk declined significantly with any statin use in comparison with the antiplatelet therapy-only group. In adjusted Cox models, the high-intensity statin users were associated with lower amputation risk and mortality in comparison with antiplatelet therapy-only users (hazard ratio, 0.67; 95% confidence interval, 0.61-0.74 and hazard ratio, 0.74; 95% confidence interval, 0.70-0.77, respectively). Low-to-moderate-intensity statins also had significant reductions in the risk of amputation and mortality (hazard ratio amputation, 0.81; 95% confidence interval, 0.75- 0.86; hazard ratio death, 0.83; 95% confidence interval, 0.81-0.86) in comparison with no statins (antiplatelet therapy only), but effect size was significantly weaker than the high-intensity statins (<0.001). The association of high-intensity statins with lower amputation and death risk remained significant and robust in propensity score-matched, sensitivity, and subgroup analyses.

Conclusions: Statins, especially high-intensity formulations, are underused in patients with PAD. This is the first population-based study to show that high-intensity statin use at the time of PAD diagnosis is associated with a significant reduction in limb loss and mortality in comparison with low-to-moderate-intensity statin users, and patients treated only with antiplatelet medications but not with statins, as well.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.117.032361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5882502PMC
April 2018

High hemoglobin A associated with increased adverse limb events in peripheral arterial disease patients undergoing revascularization.

J Vasc Surg 2018 01 31;67(1):217-228.e1. Epub 2017 Aug 31.

Division of Vascular Surgery and Endovascular Therapy, Department of Surgery, Emory University School of Medicine, Atlanta, Ga.

Objective: Diabetes and peripheral arterial disease (PAD) are independently associated with increased risk of amputation. However, the effect of poor glycemic control on adverse limb events has not been studied. We examined the effects of poor glycemic control (high hemoglobin A level) on the risk of amputation and modified major adverse limb events (mMALEs) after lower extremity revascularization.

Methods: Patients undergoing PAD revascularization who had hemoglobin A (HbA) levels available within 6 months were identified in the Veterans Affairs database of 2003 to 2014 (N = 26,799). The diagnosis of preoperative diabetes mellitus (PreopDM) was defined using diabetes diagnosis codes and evidence of treatment. Amputation and mMALE risk was compared for HbA levels using Kaplan-Meier analysis. Cox proportional hazards models were created to assess the effect of high HbA levels on amputation and mMALE (adjusted for age, gender, race, socioeconomic status, comorbidities, cholesterol levels, creatinine concentration, suprainguinal or infrainguinal procedure, open or endovascular procedure, severity of PAD, year of cohort entry, and medications) for all patients and stratified by PreopDM.

Results: High HbA levels were present in 33.2% of the cohort, whereas 59.9% had PreopDM. Amputations occurred in 4359 (16.3%) patients, and 10,580 (39.5%) had mMALE. Kaplan-Meier curves showed the worst outcomes in patient with PreopDM and high HbA levels. In the Cox model, incremental HbA levels of 6.1% to 7.0%, 7.1% to 8.0%, and >8% were associated with 26% (hazard ratio [HR], 1.26; 95% confidence interval [CI], 1.15-1.39), 53% (HR, 1.53; 95% CI, 1.37-1.7), and 105% (HR, 2.05; 95% CI, 1.87-2.26) higher risk of amputation, respectively. Similarly, the risk of mMALE also increased by 5% (HR, 1.05; 95% CI, 0.99-1.11), 21% (HR, 1.21; 95% CI, 1.13-1.29), and 33% (HR, 1.33, 95% CI, 1.25-1.42) with worsening HbA levels of 6.1% to 7.0%, 7.1% to 8.0%, and >8%, respectively (vs HbA ≤6.0%). In stratified analysis by established PreopDM, the relative risk of amputation or mMALE was much higher with poor glycemic control (HbA >7.0%) in patients without PreopDM.

Conclusions: PAD patients with worse perioperative glycemic control have a significantly higher risk of amputation and mMALE. Incremental increases in HbA levels are associated with higher hazards of adverse limb outcomes independent of PreopDM status. Poor glycemic control (HbA >7.0%) in patients without a PreopDM diagnosis carries twice the relative risk of amputation and mMALE than in those with good glycemic control. These results suggest that screening of diabetic status and better management of glycemic control could be a target for improvement of perioperative and long-term outcomes in PAD patients.
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http://dx.doi.org/10.1016/j.jvs.2017.06.101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741490PMC
January 2018

Disturbed Flow Promotes Arterial Stiffening Through Thrombospondin-1.

Circulation 2017 Sep 4;136(13):1217-1232. Epub 2017 Aug 4.

From Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta (C.W.K., A.P.-P., S.K., D.-W.K., J.R., R.L.G., H.J., L.P.B.); Department of Microbiology, College of Medicine, Inha University, Incheon, Republic of Korea (C.W.K.); Department of Surgery, Emory University, Atlanta, GA (A.P.-P., A.D.M., T.C., K.M.K., H.L., L.P.B.); Department of Radiology and Imaging Sciences, Emory University, Atlanta, GA (L.H.T.); Department of Bioengineering, University of Utah, Salt Lake City (L.H.T.); Mercer University School of Medicine, Macon, GA (S.D.); Life Science Center, Tsukuba Advanced Research Alliance, University of Tsukuba, Ibaraki, Japan (H.Y.); George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta (R.L.G.); Surgical and Research Services, Atlanta VA Medical Center, Decatur, GA (L.P.B.); and Parker H. Petit Institute for Bioengineering and Biosciences, Georgia Institute of Technology, Atlanta (L.P.B.).

Background: Arterial stiffness and wall shear stress are powerful determinants of cardiovascular health, and arterial stiffness is associated with increased cardiovascular mortality. Low and oscillatory wall shear stress, termed disturbed flow (d-flow), promotes atherosclerotic arterial remodeling, but the relationship between d-flow and arterial stiffness is not well understood. The objective of this study was to define the role of d-flow on arterial stiffening and discover the relevant signaling pathways by which d-flow stiffens arteries.

Methods: D-flow was induced in the carotid arteries of young and old mice of both sexes. Arterial stiffness was quantified ex vivo with cylindrical biaxial mechanical testing and in vivo from duplex ultrasound and compared with unmanipulated carotid arteries from 80-week-old mice. Gene expression and pathway analysis was performed on endothelial cell-enriched RNA and validated by immunohistochemistry. In vitro testing of signaling pathways was performed under oscillatory and laminar wall shear stress conditions. Human arteries from regions of d-flow and stable flow were tested ex vivo to validate critical results from the animal model.

Results: D-flow induced arterial stiffening through collagen deposition after partial carotid ligation, and the degree of stiffening was similar to that of unmanipulated carotid arteries from 80-week-old mice. Intimal gene pathway analyses identified transforming growth factor-β pathways as having a prominent role in this stiffened arterial response, but this was attributable to thrombospondin-1 (TSP-1) stimulation of profibrotic genes and not changes to transforming growth factor-β. In vitro and in vivo testing under d-flow conditions identified a possible role for TSP-1 activation of transforming growth factor-β in the upregulation of these genes. TSP-1 knockout animals had significantly less arterial stiffening in response to d-flow than wild-type carotid arteries. Human arteries exposed to d-flow had similar increases TSP-1 and collagen gene expression as seen in our model.

Conclusions: TSP-1 has a critical role in shear-mediated arterial stiffening that is mediated in part through TSP-1's activation of the profibrotic signaling pathways of transforming growth factor-β. Molecular targets in this pathway may lead to novel therapies to limit arterial stiffening and the progression of disease in arteries exposed to d-flow.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.116.026361DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614852PMC
September 2017

Promoting Limb Salvage through Multi-Disciplinary Care of the Diabetic Patient.

Curr Treat Options Cardiovasc Med 2017 Jul;19(7):55

Division of Vascular Surgery, Atlanta VA Medical Center, Surgery and Research Services, Emory University, 101 Woodruff Circle Suite 5105, Atlanta, GA, 30322, USA.

Opinion Statement: Despite an explosion in the number of options available for helping diabetic patients heal wounds, major amputation remains a critical issue for these persons. Since diabetes prematurely ages tissues and no organ system is immune to its presence, it makes inherent sense that multi-disciplinary team approaches to these patients is necessary to make significant strides forward. Here, we present literature from the fields of podiatric surgery/medicine, vascular and plastic surgery and introduce the successes that a multi-disciplinary limb salvage center can have on the lives and limbs of patients with diabetes.
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http://dx.doi.org/10.1007/s11936-017-0547-1DOI Listing
July 2017

A Novel Approach to Assess the In Situ Versus Ex Vivo Mechanical Behaviors of the Coronary Artery.

J Biomech Eng 2017 01;139(1)

George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, GA 30332;Parker H. Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, 315 Ferst Drive, IBB 2305, Atlanta, GA 30332 e-mail:

Ex vivo mechanical testing has provided tremendous insight toward prediction of the in vivo mechanical behavior and local mechanical environment of the arterial wall; however, the role of perivascular support on the local mechanical behavior of arteries is not well understood. Here, we present a novel approach for quantifying the impact of the perivascular support on arterial mechanics using intravascular ultrasound (IVUS) on cadaveric porcine hearts. We performed pressure-diameter tests (n = 5) on the left anterior descending coronary arteries (LADCAs) in situ while embedded in their native perivascular environment using IVUS imaging and after removal of the perivascular support of the artery. We then performed standard cylindrical biaxial testing on these vessels ex vivo and compared the results. Removal of the perivascular support resulted in an upward shift of the pressure-diameter curve. Ex vivo testing, however, showed significantly lower circumferential compliance compared to the in situ configuration. On a second set of arteries, local axial stretch ratios were quantified (n = 5) along the length of the arteries. The average in situ axial stretch ratio was 1.28 ± 0.16; however, local axial stretch ratios showed significant variability, ranging from 1.01 to 1.70. Taken together, the data suggest that both the perivascular loading and the axial tethering have an important role in arterial mechanics. Combining nondestructive testing using IVUS with traditional ex vivo cylindrical biaxial testing yields a more comprehensive assessment of the mechanical behavior of arteries.
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http://dx.doi.org/10.1115/1.4035262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5188853PMC
January 2017

An endovascular model of ischemic myopathy from peripheral arterial disease.

J Vasc Surg 2017 09 29;66(3):891-901. Epub 2016 Sep 29.

Department of Surgery, Emory University School of Medicine, Atlanta, Ga; Surgical and Research Services, Atlanta VA Medical Center, Atlanta, Ga. Electronic address:

Objective: Peripheral arterial disease (PAD) is a significant age-related medical condition with limited pharmacologic options. Severe PAD, termed critical limb ischemia, can lead to amputation. Skeletal muscle is the end organ most affected by PAD, leading to ischemic myopathy and debility of the patient. Currently, there are not any therapeutics to treat ischemic myopathy, and proposed biologic agents have not been optimized owing to a lack of preclinical models of PAD. Because a large animal model of ischemic myopathy may be useful in defining the optimal dosing and delivery regimens, the objective was to create and to characterize a swine model of ischemic myopathy that mimics patients with severe PAD.

Methods: Yorkshire swine (N = 8) underwent acute right hindlimb ischemia by endovascular occlusion of the external iliac artery. The effect of ischemia on limb function, perfusion, and degree of ischemic myopathy was quantified by weekly gait analysis, arteriography, hindlimb blood pressures, femoral artery duplex ultrasound scans, and histologic examination. Animals were terminated at 5 (n = 5) and 6 (n = 3) weeks postoperatively. Ossabaw swine (N = 8) fed a high-fat diet were used as a model of metabolic syndrome for comparison of arteriogenic recovery and validation of ischemic myopathy.

Results: There was persistent ischemia in the right hindlimb, and occlusion pressures were significantly depressed compared with the untreated left hindlimb out to 6 weeks (systolic blood pressure, 31 ± 21 vs 83 ± 15 mm Hg, respectively; P = .0007). The blood pressure reduction resulted in a significant increase of ischemic myopathy in the gastrocnemius muscle in the treated limb. Gait analysis revealed a functional deficit of the right hindlimb immediately after occlusion that improved rapidly during the first 2 weeks. Peak systolic velocity values in the right common femoral artery were severely diminished throughout the entire study (P < .001), and the hemodynamic environment after occlusion was characterized by low and oscillatory wall shear stress. Finally, the internal iliac artery on the side of the ischemic limb underwent significant arteriogenic remodeling (1.8× baseline) in the Yorkshire but not in the Ossabaw swine model.

Conclusions: This model uses endovascular technology to produce the first durable large animal model of ischemic myopathy. Acutely (first 2 weeks), this model is associated with impaired gait but no tissue loss. Chronically (2-6 weeks), this model delivers persistent ischemia, resulting in ischemic myopathy similar to that seen in PAD patients. This model may be of use for testing novel therapeutics including biologic therapies for promoting neovascularization and arteriogenesis.
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http://dx.doi.org/10.1016/j.jvs.2016.07.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5374046PMC
September 2017

Advances, Pauses, and Future Opportunity for the Prevention of Venous Thromboembolism in the Trauma Population.

JAMA Surg 2017 01;152(1):41

Division of Vascular Surgery, Vascular Surgery Laboratory, Atlanta, Georgia3Surgical and Research Services, Atlanta Veterans Affairs Medical Center, Decatur, Georgia.

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http://dx.doi.org/10.1001/jamasurg.2016.3124DOI Listing
January 2017

The Readmission Event after Vascular Surgery: Causes and Costs.

Ann Vasc Surg 2016 Oct 16;36:7-12. Epub 2016 Jun 16.

Department of Surgery, Emory University School of Medicine, Atlanta, GA.

Background: The study evaluates the readmission diagnoses after vascular surgical interventions and the associated hospital costs.

Methods: Patients readmitted after undergoing carotid artery stenting (CAS), carotid endarterectomy (CEA), infrarenal endovascular abdominal aortic aneurysm repair (EVAR), open abdominal aortic aneurysm repair (OAAA), suprainguinal revascularization (SUPRA), or infrainguinal revascularization (INFRA) between January 1, 2008 and October 20, 2013 at a single academic institution were retrospectively identified. Demographic, preoperative, and postoperative event variables were obtained by chart review. The diagnoses and the costs of the readmission event were obtained by chart review and from hospital financial data. Readmission indications were grouped as unrelated or planned readmissions, procedure-specific complications, wound complications, cardiac causes, and other. Univariate analyses of categorical variables were performed with χ or Fisher exact test where appropriate. Continuous variables were analyzed using the Wilcoxon rank-sum test.

Results: A total of 1,170 patient records were identified. Thirty-day readmission occurred in 112 patients (9.6%). The readmission rate was significantly different between groups: 4.5% in CAS (n = 8/177), 8.5% in CEA (21/246), 5.8% in EVAR (18/312), 11.4% in OAAA (4/35), 15.6% in INFRA (33/212), 13.5% in SUPRA (24/178), and 40% in combined SUPRA and INFRA (4/10) (P < 0.0001). Readmissions were unrelated or planned in 19.6% of patients. Wound complications were the most common readmission diagnoses (36.6%, 41/112).There was a difference in the distribution of readmission indications among procedure groups, with wound complications being predominant in INFRA and SUPRA groups (60.6% and 58.3%, respectively), and cardiac events predominantly in EVAR patients (42%) (P < 0.001). In univariable analysis of predictors of readmission, significant preoperative factors were chronic obstructive pulmonary disease, renal insufficiency, and lower hematocrit. Significant postoperative predictors included any postoperative complication, number of complications, increased length of stay, wound complications, postoperative infections, blood transfusion, and reoperation. The median hospital cost for readmission for wound complications was 29,723 USD (interquartile range 23,841-36,878), and for cardiac complications was 39,784 USD (26,305-46,918). The median cost of readmission for bypass graft occlusion was 33,366 USD (20,530-43,170). The median length of stay also differed depending on the readmission diagnosis and was highest for bypass graft occlusion (8.5 days).

Conclusions: Readmissions after vascular procedures are associated with high cost and hospital bed utilization. Wound complications continue to be the dominant readmission etiology. The characterization of these costs and risk factors in this study can allow for resource allocation to minimize preventable related readmissions. A significant proportion of readmissions after vascular interventions are planned or unrelated, which should be taken into consideration in metric benchmarking and performance comparisons.
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http://dx.doi.org/10.1016/j.avsg.2016.02.024DOI Listing
October 2016

Preoperative Frailty Increases Risk of Nonhome Discharge after Elective Vascular Surgery in Home-Dwelling Patients.

Ann Vasc Surg 2016 Aug 2;35:19-29. Epub 2016 Jun 2.

Division of Vascular Surgery, Department of Surgery, University of Nebraska Medical Center, Omaha, NE.

Background: Patient-centered quality outcomes such as disposition after surgery are increasingly being scrutinized. Preoperative factors predictive of nonhome discharge (DC) may identify at-risk patients for targeted interventions. This study examines the association among preoperative risk factors, frailty, and nonhome DC after elective vascular surgery procedures in patients living at home.

Methods: The 2011-2012 National Surgical Quality Improvement Project database was queried to identify all home-dwelling patients who underwent elective vascular procedures (endovascular and open aortic aneurysm repair, suprainguinal and infrainguinal bypasses, peripheral endovascular interventions, carotid endarterectomy, and stent). Preoperative frailty was measured using the modified frailty index (mFI; derived from Canadian Study of Health and Aging). Univariate and multivariate logistic regression analysis was performed to examine the association of frailty and nonhome DC.

Results: Of 15,843 home-dwelling patients, 1,177 patients (7.4%) did not return home postoperatively. Frailty (mFI > 0.25) conferred a significantly increased 2-fold risk of nonhome DC disposition for each procedure type. Frailty, female gender, open procedures, increasing age, end-stage renal disease, and occurrence of any postoperative complication were associated with increased risk of nonhome DC. On multivariate logistic regression analysis, frailty increased the odds of nonhome DC by 60% (odds ratio 1.6, 95% confidence interval 1.4-1.8) after adjusting for other covariates. In the presence of complications, the risk of nonhome DC was 27.5% in frail versus 16.5% in nonfrail patients (P < 0.001). In the absence of complications, although absolute risk was lower, frail patients were nearly twice as likely to not return home (frail 5.5% vs. nonfrail 2.75%, P < 0.001).

Conclusions: Frail home-dwelling patients undergoing elective vascular procedures are at high risk of not returning home after surgery. Preoperative frailty assessment appears to hold potential for counseling regarding postsurgery disposition and DC planning.
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http://dx.doi.org/10.1016/j.avsg.2016.01.052DOI Listing
August 2016

Women undergoing aortic surgery are at higher risk for unplanned readmissions compared with men especially when discharged home.

J Vasc Surg 2016 Jun 19;63(6):1496-1504.e1. Epub 2016 Apr 19.

Division of Vascular Surgery, Department of Surgery, Emory University, Atlanta, Ga; Surgery Service Line, Atlanta VA Medical Center, Decatur, Ga. Electronic address:

Objective: Women undergoing vascular surgery have higher morbidity and mortality. Our study explores gender-based differences in patient-centered outcomes such as readmission, length of stay (LOS), and discharge destination (home vs nonhome facility) in aortic aneurysm surgery.

Methods: Patients were identified from the American College of Surgeons National Surgical Quality Improvement Project database (2011-2013) undergoing abdominal, thoracic, and thoracoabdominal aortic aneurysms (N = 17,763), who were discharged and survived their index hospitalization. The primary outcome was unplanned readmission, and secondary outcomes were discharge to a nonhome facility, LOS, and reasons for unplanned readmission. Univariate, multivariate, and stratified analyses based on gender and discharge destination were used.

Results: Overall, 1541 patients (8.7%) experienced an unplanned readmission, with a significantly higher risk in women vs men (10.8% vs 8%; P < .001) overall (Procedure subtypes: abdominal aortic aneurysm [10.1% vs 7.7%; P < .001], thoracic aortic aneurysm [14.1% vs 13.5%; P = .8], and thoracoabdominal aortic aneurysm [14.8% vs 10%; P = .051]). The higher odds of readmission in women compared with men persisted in multivariate analysis after controlling for covariates (odds ratio [OR], 1.21; 95% confidence interval [CI], 1.05-1.4). Similarly, the rate of discharge to a nonhome facility was nearly double in women compared with men (20.6% vs 10.7%; P < .001), but discharge to a nonhome facility was not a significant predictor of unplanned readmission. Upon stratification by discharge destination, the higher odds of readmissions in women compared with men occurred in patients who were discharged home (OR, 1.2; 95% CI, 1.02-1.4) but not in those who were discharged to a nonhome facility (OR, 1.06; 95% CI, 0.8-1.4). Significant differences in LOS were seen in patients who were discharged home. No gender differences were found in reasons for readmission with the three most common reasons being thromboembolic events, wound infections, and pneumonia.

Conclusions: Gender disparity exists in the risk of unplanned readmission among aortic aneurysm surgery patients. Women who were discharged home have a higher likelihood of unplanned readmission despite longer LOS than men. These data suggest that further study into the discharge planning processes, social factors, and use of rehabilitation services is needed for women undergoing aortic procedures to decrease readmissions.
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http://dx.doi.org/10.1016/j.jvs.2015.12.054DOI Listing
June 2016

A novel platelet lysate hydrogel for endothelial cell and mesenchymal stem cell-directed neovascularization.

Acta Biomater 2016 05 4;36:86-98. Epub 2016 Mar 4.

Emory University, Department of Surgery, Atlanta, GA 30322, USA; Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA 30322, USA; Atlanta Veterans Affairs Medical Center, Surgical and Research Services, Decatur, GA 30030, USA. Electronic address:

Unlabelled: Mesenchymal stem cells (MSC) hold promise in promoting vascular regeneration of ischemic tissue in conditions like critical limb ischemia of the leg. However, this approach has been limited in part by poor cell retention and survival after delivery. New biomaterials offer an opportunity to localize cells to the desired tissue after delivery, but also to improve cell survival after delivery. Here we characterize the mechanical and microstructural properties of a novel hydrogel composed of pooled human platelet lysate (PL) and test its ability to promote MSC angiogenic activity using clinically relevant in vitro and in vivo models. This PL hydrogel had comparable storage and loss modulus and behaved as a viscoelastic solid similar to fibrin hydrogels despite having 1/4-1/10th the fibrin content of standard fibrin gels. Additionally, PL hydrogels enabled sustained release of endogenous PDGF-BB for up to 20days and were resistant to protease degradation. PL hydrogel stimulated pro-angiogenic activity by promoting human MSC growth and invasion in a 3D environment, and enhancing endothelial cell sprouting alone and in co-culture with MSCs. When delivered in vivo, the combination of PL and human MSCs improved local tissue perfusion after 8days compared to controls when assessed with laser Doppler perfusion imaging in a murine model of hind limb ischemia. These results support the use of a PL hydrogel as a scaffold for MSC delivery to promote vascular regeneration.

Statement Of Significance: Innovative strategies for improved retention and viability of mesenchymal stem cells (MSCs) are needed for cellular therapies. Human platelet lysate is a potent serum supplement that improves the expansion of MSCs. Here we characterize our novel PL hydrogel's desirable structural and biologic properties for human MSCs and endothelial cells. PL hydrogel can localize cells for retention in the desired tissue, improves cell viability, and augments MSCs' angiogenic activity. As a result of these unique traits, PL hydrogel is ideally suited to serve as a cell delivery vehicle for MSCs injected into ischemic tissues to promote vascular regeneration, as demonstrated here in a murine model of hindlimb ischemia.
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http://dx.doi.org/10.1016/j.actbio.2016.03.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4846562PMC
May 2016

Gender and frailty predict poor outcomes in infrainguinal vascular surgery.

J Surg Res 2016 Mar 23;201(1):156-65. Epub 2015 Oct 23.

Division of Vascular Surgery and Endovascular Therapy, Emory University School of Medicine, Atlanta, Georgia; Surgical Service Line, Atlanta VA Medical Center, Decatur, Georgia. Electronic address:

Background: Women have poorer outcomes after vascular surgery as compared to men as shown by studies recently. Frailty is also an independent risk factor for postoperative morbidity and mortality. This study examines the interplay of gender and frailty on outcomes after infrainguinal vascular procedures.

Materials And Methods: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all patients who underwent infrainguinal vascular procedures from 2005-2012. Frailty was measured using a modified frailty index (mFI; derived from the Canadian Study of Health and Aging). Univariate and multivariate analysis were performed to investigate the association of preoperative frailty and gender, on postoperative outcomes.

Results: Of 24,645 patients (92% open, 8% endovascular), there were 533 deaths (2.2%) and 6198 (25.1%) major complications within 30 d postoperatively. Women were more frail (mean mFI = 0.269) than men (mean mFI = 0.259; P < 0.001). Women and frail patients (mFI>0.25) were more likely to have a major morbidity (P < 0.001) or mortality (P < 0.001) with the highest risk in frail women. On multivariate logistic regression analysis, female gender and increasing mFI were independently significantly associated with mortality (P < 0.05) as well as major complications. The interaction of gender and frailty in multivariate analysis showed the highest adjusted 30-d mortality and morbidity in frail females at 2.8% and 30.1%, respectively and that was significantly higher (P < 0.001) than nonfrail males, nonfrail females and frail males.

Conclusions: Female gender and frailty are both associated with increased risk of complications and death following infrainguinal vascular procedures with the highest risk in frail females. Further studies are needed to explore the mechanisms of interaction of gender and frailty and its effect on long-term outcomes for peripheral vascular disease.
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http://dx.doi.org/10.1016/j.jss.2015.10.026DOI Listing
March 2016

Posttraumatic Resuscitation Affects Stent Graft Sizing in Patients with Blunt Thoracic Aortic Injury.

Am Surg 2016 Jan;82(1):75-8

Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.

Patients with blunt aortic injury often present to the emergency department in a relatively hypovolemic state. These patients undergo extensive inhospital resuscitation. The effect of posttraumatic resuscitation on aortic diameter has implications for stent graft sizing. The potential utility of repeat aortic imaging after resuscitation remains unclear. A retrospective chart review of all adult patients presenting to a Level I trauma center between the years 2007 and 2013 was performed. Fifty-three patients were identified with a diagnosis of traumatic aortic injury. Of those, 10 had 2 CT scans before aortic repair and were selected as the study population for analysis. After resuscitation, there was a significant increase in aortic diameter both proximal and distal to the aortic injury: proximal aortic diameter increase of 1.97 mm and distal aortic diameter increase of 1.48 mm. This retrospective study shows that after resuscitation, there is a significant increase in proximal and distal aortic diameter. Interval reimaging of the thoracic aorta may be beneficial after adequate stabilization of the patient's other injuries. In certain cases, more appropriate sizing may prevent a device-related complication.
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January 2016

Hydrogen Sulfide Levels and Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Activity Are Attenuated in the Setting of Critical Limb Ischemia (CLI).

J Am Heart Assoc 2015 May 14;4(5). Epub 2015 May 14.

Cardiovascular Center of Excellence, Louisiana State University Health Sciences Center, New Orleans, LA (K.N.I., D.J.P., E.D., D.J.L.).

Background: Cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase are endogenous enzymatic sources of hydrogen sulfide (H2S). Functions of H2S are mediated by several targets including ion channels and signaling proteins. Nuclear factor-erythroid 2-related factor 2 is responsible for the expression of antioxidant response element-regulated genes and is known to be upregulated by H2S. We examined the levels of H2S, H2S-producing enzymes, and nuclear factor-erythroid 2-related factor 2 activation status in skeletal muscle obtained from critical limb ischemia (CLI) patients.

Methods And Results: Gastrocnemius tissues were attained postamputation from human CLI and healthy control patients. We found mRNA and protein levels of cystathionine γ-lyase, cystathionine β-synthase, and 3-mercaptopyruvate sulfurtransferase were significantly decreased in skeletal muscle of CLI patients as compared to control. H2S and sulfane sulfur levels were significantly decreased in skeletal muscle of CLI patients. We also observed significant reductions in nuclear factor-erythroid 2-related factor 2 activation as well as antioxidant proteins, such as Cu, Zn-superoxide dismutase, catalase, and glutathione peroxidase in skeletal muscle of CLI patients. Biomarkers of oxidative stress, such as malondialdehyde and protein carbonyl formation, were significantly increased in skeletal muscle of CLI patients as compared to healthy controls.

Conclusions: The data demonstrate that H2S bioavailability and nuclear factor-erythroid 2-related factor 2 activation are both attenuated in CLI tissues concomitant with significantly increased oxidative stress. Reductions in the activity of H2S-producing enzymes may contribute to the pathogenesis of CLI.
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http://dx.doi.org/10.1161/JAHA.115.001986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599428PMC
May 2015

Late mortality in females after endovascular aneurysm repair.

J Surg Res 2015 Oct 4;198(2):508-14. Epub 2015 Apr 4.

Department of Surgery, Emory University, Atlanta, GA; Surgical and Research Services, Atlanta VA Medical Center, Atlanta, GA.

Background: Abdominal aortic aneurysm (AAA) rupture is an adverse arterial remodeling event with high mortality risk. Because females have increased rupture risk with smaller AAAs (<5.5 cm), many recommend elective repair before the AAA reaches 5.5 cm. Elective repair improves survival for large AAAs, but long-term benefits of endovascular aneurysm repair (EVAR) for small AAAs in females remain less understood. The objective of this study was to identify if differences in late mortality exist between females undergoing elective EVAR at our institution for small and/or slow-growing AAAs compared with those who meet standard criteria.

Methods: We retrospectively analyzed all patients that underwent EVAR for infrarenal AAA from June, 2009-June, 2013. We excluded patients that were male, treated emergently or for iliac artery aneurysm, and that received renal and/or mesenteric artery stenting. Patients did not meet anatomic criteria if preoperative AAA diameter was <5.5 cm or enlarged <0.5 cm over 6 mo. Late mortality was assessed from the social security death index.

Results: Thirty-six of 162 elective EVAR patients (22.2%) were female (mean follow-up, 37.2 mo). Twenty patients (55.6%) met AAA size and/or growth criteria, whereas 16 (44.4%) did not meet criteria. Despite comparable demographics, comorbidities, and complications, patients that did not meet criteria had higher late mortality (37.5% versus 5%; P = 0.03) with a trend toward increased reoperation rate (25% versus. 5%; P = 0.48). Meeting size and/or growth criteria decreased odds of late death (odds ratio, 0.09; 95% confidence intervals, 0.01-0.83).

Conclusions: There is increased late mortality in females receiving elective EVAR at our institution for small and/or slow-growing AAAs. This late mortality may limit the benefits of EVAR for this population.
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http://dx.doi.org/10.1016/j.jss.2015.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561000PMC
October 2015

Sustained release nitrite therapy results in myocardial protection in a porcine model of metabolic syndrome with peripheral vascular disease.

Am J Physiol Heart Circ Physiol 2015 Jul 8;309(2):H305-17. Epub 2015 May 8.

Cardiovascular Center of Excellence and Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, Louisiana;

Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg · kg(-1) · day(-1) bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.
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http://dx.doi.org/10.1152/ajpheart.00163.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4504965PMC
July 2015

Therapeutic potential of sustained-release sodium nitrite for critical limb ischemia in the setting of metabolic syndrome.

Am J Physiol Heart Circ Physiol 2015 Jul 24;309(1):H82-92. Epub 2015 Apr 24.

Cardiovascular Center of Excellence and Department of Pharmacology, LSU Health Sciences Center, New Orleans, Louisiana;

Nitrite is a storage reservoir of nitric oxide that is readily reduced to nitric oxide under pathological conditions. Previous studies have demonstrated that nitrite levels are significantly reduced in cardiovascular disease states, including peripheral vascular disease. We investigated the cytoprotective and proangiogenic actions of a novel, sustained-release formulation of nitrite (SR-nitrite) in a clinically relevant in vivo swine model of critical limb ischemia (CLI) involving central obesity and metabolic syndrome. CLI was induced in obese Ossabaw swine (n = 18) by unilateral external iliac artery deployment of a full cross-sectional vessel occlusion device positioned within an endovascular expanded polytetrafluoroethylene-lined nitinol stent-graft. At post-CLI day 14, pigs were randomized to placebo (n = 9) or SR-nitrite (80 mg, n = 9) twice daily by mouth for 21 days. SR-nitrite therapy increased nitrite, nitrate, and S-nitrosothiol in plasma and ischemic skeletal muscle. Oxidative stress was reduced in ischemic limb tissue of SR-nitrite- compared with placebo-treated pigs. Ischemic limb tissue levels of proangiogenic growth factors were increased following SR-nitrite therapy compared with placebo. Despite the increases in cytoprotective and angiogenic signals with SR-nitrite therapy, new arterial vessel formation and enhancement of blood flow to the ischemic limb were not different from placebo. Our data clearly demonstrate cytoprotective and proangiogenic signaling in ischemic tissues following SR-nitrite therapy in a very severe model of CLI. Further studies evaluating longer-duration nitrite therapy and/or additional nitrite dosing strategies are warranted to more fully evaluate the therapeutic potential of nitrite therapy in peripheral vascular disease.
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http://dx.doi.org/10.1152/ajpheart.00115.2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491519PMC
July 2015

Frailty increases the risk of 30-day mortality, morbidity, and failure to rescue after elective abdominal aortic aneurysm repair independent of age and comorbidities.

J Vasc Surg 2015 Feb 12;61(2):324-31. Epub 2014 Oct 12.

Division of Vascular Surgery, Emory University School of Medicine, Atlanta, Ga.

Background: Frailty, defined as a biologic syndrome of decreased reserve and resistance to stressors, has been linked to adverse outcomes after surgery. We evaluated the effect of frailty on 30-day mortality, morbidity, and failure to rescue (FTR) in patients undergoing elective abdominal aortic aneurysm (AAA) repair.

Methods: Patients undergoing elective endovascular AAA repair (EVAR) or open AAA repair (OAR) were identified in the National Surgical Quality Improvement Program database for the years 2005 to 2012. Frailty was assessed using the modified frailty index (mFI) derived from the Canadian Study of Health and Aging (CSHA). The primary outcome was 30-day mortality, and secondary outcomes included 30-day morbidity and FTR. The effect of frailty on outcomes was assessed by multivariate regression analysis, adjusted for age, American Society of Anesthesiology (ASA) class, and significant comorbidities.

Results: Of 23,207 patients, 339 (1.5% overall; 1.0% EVAR and 3.0% OAR) died ≤30 days of repair. One or more complications occurred in 2567 patients (11.2% overall; 7.8% EVAR and 22.1% OAR). Odds ratios (ORs) for mortality adjusted for age, ASA class, and other comorbidities in the group with the highest frailty score were 1.9 (95% confidence interval [CI], 1.2-3.0) after EVAR and 2.3 (95% CI, 1.4-3.7) after OAR. Similarly, compared with the least frail, the most frail patients were significantly more likely to experience severe (Clavien-Dindo class IV) complications after EVAR (OR, 1.7; 95% CI, 1.3-2.1) and OAR (OR, 1.8; 95%, CI, 1.5-2.1). There was also a higher FTR rate among frail patients, with 1.7-fold higher risk odds of mortality (95% CI, 1.2-2.5) in the highest tertile of frailty compared with the lowest when postoperative complications occurred.

Conclusions: Higher mFI, independent of other risk factors, is associated with higher mortality and morbidity in patients undergoing elective EVAR and OAR. The mortality in frail patients is further driven by FTR from postoperative complications. Preoperative recognition of frailty may serve as a useful adjunct for risk assessment.
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http://dx.doi.org/10.1016/j.jvs.2014.08.115DOI Listing
February 2015
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