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High-Fat, High-Sugar Diet-Induced Subendothelial Matrix Stiffening is Mitigated by Exercise.
Kohn JC, Azar J, Seta F, Reinhart-King CA
(2018) Cardiovasc Eng Technol 9: 84-93
MeSH Terms: Animals, Aorta, Abdominal, Arterial Pressure, Diet, High-Fat, Dietary Sugars, Disease Models, Animal, Elastic Modulus, Exercise Therapy, Extracellular Matrix, Healthy Diet, Male, Mice, Inbred C57BL, Microscopy, Atomic Force, Peripheral Arterial Disease, Pulse Wave Analysis, Risk Reduction Behavior, Time Factors, Vascular Stiffness
Show Abstract · Added December 7, 2017
Consumption of a high-fat, high-sugar diet and sedentary lifestyle are correlated with bulk arterial stiffening. While measurements of bulk arterial stiffening are used to assess cardiovascular health clinically, they cannot account for changes to the tissue occurring on the cellular scale. The compliance of the subendothelial matrix in the intima mediates vascular permeability, an initiating step in atherosclerosis. High-fat, high-sugar diet consumption and a sedentary lifestyle both cause micro-scale subendothelial matrix stiffening, but the impact of these factors in concert remains unknown. In this study, mice on a high-fat, high-sugar diet were treated with aerobic exercise or returned to a normal diet. We measured bulk arterial stiffness through pulse wave velocity and subendothelial matrix stiffness ex vivo through atomic force microscopy. Our data indicate that while diet reversal mitigates high-fat, high-sugar diet-induced macro- and micro-scale stiffening, exercise only significantly decreases micro-scale stiffness and not macro-scale stiffness, during the time-scale studied. These data underscore the need for both healthy diet and exercise to maintain vascular health. These data also indicate that exercise may serve as a key lifestyle modification to partially reverse the deleterious impacts of high-fat, high-sugar diet consumption, even while macro-scale stiffness indicators do not change.
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18 MeSH Terms
Predictors of major amputation despite patent bypass grafts.
Smith AD, Hawkins AT, Schaumeier MJ, de Vos MS, Conte MS, Nguyen LL
(2016) J Vasc Surg 63: 1279-88
MeSH Terms: Aged, Aged, 80 and over, Amputation, Chi-Square Distribution, Comorbidity, Critical Illness, Disease Progression, Double-Blind Method, Female, Humans, Ischemia, Limb Salvage, Lower Extremity, Male, Middle Aged, Multivariate Analysis, Nutritional Status, Peripheral Arterial Disease, Proportional Hazards Models, Prospective Studies, Quality of Life, Reoperation, Risk Assessment, Risk Factors, Time Factors, Treatment Outcome, Vascular Grafting, Vascular Patency, Veins
Show Abstract · Added September 27, 2016
OBJECTIVE - Despite patent vein bypass grafts, some patients with critical limb ischemia (CLI) receive major amputations. We analyzed the predictive factors leading to major amputation in the presence of patent lower extremity bypass (LEB) grafts.
METHODS - Data from the Project of Ex-Vivo vein graft Engineering via Transfection III (PREVENT III), a large prospective randomized trial of 1404 patients who underwent LEB with vein graft for CLI, were queried for outcomes. The primary outcome was major amputation with patent (PMA) LEB compared with patients with patent LEB who achieved limb salvage (PLS). The population excluded those who received amputation for occluded grafts. A Cox proportional hazard model identified independent predictors.
RESULTS - Of 1404 LEB patients, 162 (11.5%) had major amputation: 89 (6.3%) with patent and 73 (5.2%) with occluded LEB. For PMA, 21 of 89 (23.6%) developed critical stenosis and 11 of 21 (52.4%) were revised. For PLS, 460 of 1242 (37.0%) developed critical stenosis and 351 of 460 (76.3%) were revised. Predictive patient factors included having preoperative gangrene (vs rest pain; hazard ratio [HR], 3.504; 95% confidence interval [CI], 1.533-8.007; P = .0029), diabetes (HR, 1.800; 95% CI, 1.006-3.219; P = .0477), black (vs white) race (HR, 1.779; 95% CI, 1.051-3.011; P = .0321), baseline creatinine clearance <25 mL/min (vs >65 mL/min; HR, 1.759; 95% CI, 1.016-3.048; P = .0439), prior history of coronary artery bypass grafting (HR, 1.702; 95% CI, 1.080-2.683; P = .0221), and lower baseline activity quality of life score (HR, 1.401; 95% CI, 1.105-1.778; P = .0054). Postoperative wound factors included gangrenous changes (HR, 5.830; 95% CI, 1.647-20.635; P = .0063), surgical wound necrosis (HR, 5.319; 95% CI, 1.478-19.146; P = .0105), deep (vs superficial) wound infection (HR, 3.815; 95% CI, 1.220-11.927; P = .0213), and wound healing abnormally (HR, 3.754; 95% CI, 1.061-13.278; P = .0402). Associated postoperative consequences leading to PMA included having recurrent CLI symptoms (HR, 2.915; 95% CI, 1.816-4.681; P < .0001), a severe (vs mild) adverse event (HR, 2.751; 95% CI, 1.391-5.443; P = .0036), fewer percutaneous revisions (HR, 2.425; 95% CI, 1.573-3.740; P < .0001), discharge on low-molecular-weight heparin (HR, 2.087; 95% CI, 1.309-3.326; P = .0020), and decreasing days to critical stenosis/occlusion/revision/amputation (HR, 1.010; 95% CI, 1.007-1.012; P < .0001).
CONCLUSIONS - Whereas a patent vein graft is important to all vascular surgeons, additional factors should be considered in trying to attain limb salvage for patients with CLI. These factors include intervening surgically before CLI has progressed to a state of gangrene or limited activity and optimizing nutrition, diabetes control, cardiac conditions, and activity level. Revision offers hope for clinical improvement but may be delayed when there is no graft lesion identified. The absence of a graft lesion to revise may also portend amputation despite a patent graft because of nongraft-related factors such as infection. Finally, the experience of a severe (vs mild) adverse event may also result in limb loss despite a patent graft. Systematic efforts to reduce severe adverse events among patients may also lead to increased limb salvage.
Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
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29 MeSH Terms
Impact of Expanded Insurance Coverage on Racial Disparities in Vascular Disease: Insights From Massachusetts.
Loehrer AP, Hawkins AT, Auchincloss HG, Song Z, Hutter MM, Patel VI
(2016) Ann Surg 263: 705-11
MeSH Terms: Adolescent, Adult, Aged, Databases, Factual, Health Care Reform, Health Services Accessibility, Health Status Disparities, Healthcare Disparities, Humans, Insurance Coverage, Insurance, Health, Linear Models, Massachusetts, Middle Aged, Multivariate Analysis, Patient Protection and Affordable Care Act, Peripheral Arterial Disease, Retrospective Studies, Risk Adjustment, Severity of Illness Index, Young Adult
Show Abstract · Added September 27, 2016
OBJECTIVE - To evaluate the impact of health insurance expansion on racial disparities in severity of peripheral arterial disease.
BACKGROUND - Lack of insurance and non-white race are associated with increased severity, increased amputation rates, and decreased revascularization rates in patients with peripheral artery disease (PAD). Little is known about how expanded insurance coverage affects disparities in presentation with and management of PAD. The 2006 Massachusetts health reform expanded coverage to 98% of residents and provided the framework for the Affordable Care Act.
METHODS - We conducted a retrospective cohort study of nonelderly, white and non-white patients admitted with PAD in Massachusetts (MA) and 4 control states. Risk-adjusted difference-in-differences models were used to evaluate changes in probability of presenting with severe disease. Multivariable linear regression models were used to evaluate disparities in disease severity before and after the 2006 health insurance expansion.
RESULTS - Before the 2006 MA insurance expansion, non-white patients in both MA and control states had a 12 to 13 percentage-point higher probability of presenting with severe disease (P < 0.001) than white patients. After the expansion, measured disparities in disease severity by patient race were no longer statistically significant in Massachusetts (+3.0 percentage-point difference, P = 0.385) whereas disparities persisted in control states (+10.0 percentage-point difference, P < 0.001). Overall, non-white patients in MA had an 11.2 percentage-point decreased probability of severe PAD (P = 0.042) relative to concurrent trends in control states.
CONCLUSIONS - The 2006 Massachusetts insurance expansion was associated with a decreased probability of patients presenting with severe PAD and resolution of measured racial disparities in severe PAD in MA.
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21 MeSH Terms
The Exercise Ankle-Brachial Index: A Leap Forward in Noninvasive Diagnosis and Prognosis.
Drachman DE, Beckman JA
(2015) JACC Cardiovasc Interv 8: 1245-1247
MeSH Terms: Ankle Brachial Index, Endovascular Procedures, Exercise Test, Female, Humans, Lower Extremity, Male, Peripheral Arterial Disease, Vascular Surgical Procedures
Added January 15, 2016
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9 MeSH Terms
Critical limb ischemia and intermediate-term survival.
Beckman JA, Creager MA
(2014) JACC Cardiovasc Interv 7: 1450-2
MeSH Terms: Decision Support Techniques, Female, Humans, Ischemia, Life Expectancy, Lower Extremity, Male, Peripheral Arterial Disease
Added January 15, 2016
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8 MeSH Terms
ROS-responsive microspheres for on demand antioxidant therapy in a model of diabetic peripheral arterial disease.
Poole KM, Nelson CE, Joshi RV, Martin JR, Gupta MK, Haws SC, Kavanaugh TE, Skala MC, Duvall CL
(2015) Biomaterials 41: 166-75
MeSH Terms: Animals, Antioxidants, Cell Survival, Chemokine CCL2, Curcumin, Diabetes Mellitus, Experimental, Endocytosis, Female, Hindlimb, Hydrogen Peroxide, Interferon-gamma, Intracellular Space, Ischemia, Kinetics, Lipopolysaccharides, Macrophage Activation, Mice, Microspheres, Muscles, NIH 3T3 Cells, Oxygen, Particle Size, Perfusion, Peripheral Arterial Disease, Polymers, Reactive Oxygen Species, Sulfides
Show Abstract · Added January 20, 2015
A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for "on demand" antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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27 MeSH Terms
Uncoupling angiogenesis and inflammation in peripheral artery disease with therapeutic peptide-loaded microgels.
Zachman AL, Wang X, Tucker-Schwartz JM, Fitzpatrick ST, Lee SH, Guelcher SA, Skala MC, Sung HJ
(2014) Biomaterials 35: 9635-48
MeSH Terms: Angiogenesis Inducing Agents, Animals, Anti-Inflammatory Agents, Cell Line, Drug Carriers, Human Umbilical Vein Endothelial Cells, Inflammation, Injections, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Neovascularization, Physiologic, Oligopeptides, Peripheral Arterial Disease, Polyesters, Tumor Necrosis Factor-alpha
Show Abstract · Added October 30, 2014
Peripheral artery disease (PAD) is characterized by vessel occlusion and ischemia in the limbs. Treatment for PAD with surgical interventions has been showing limited success. Moreover, recent clinical trials with treatment of angiogenic growth factors proved ineffective as increased angiogenesis triggered severe inflammation in a proportionally coupled fashion. Hence, the overarching goal of this research was to address this issue by developing a biomaterial system that enables controlled, dual delivery of pro-angiogenic C16 and anti-inflammatory Ac-SDKP peptides in a minimally-invasive way. To achieve the goal, a peptide-loaded injectable microgel system was developed and tested in a mouse model of PAD. When delivered through multiple, low volume injections, the combination of C16 and Ac-SDKP peptides promoted angiogenesis, muscle regeneration, and perfusion recovery, while minimizing detrimental inflammation. Additionally, this peptide combination regulated inflammatory TNF-α pathways independently of MMP-9 mediated pathways of angiogenesis in vitro, suggesting a potential mechanism by which angiogenic and inflammatory responses can be uncoupled in the context of PAD. This study demonstrates a translatable potential of the dual peptide-loaded injectable microgel system for PAD treatment.
Copyright © 2014 Elsevier Ltd. All rights reserved.
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16 MeSH Terms
A systematic review of functional and quality of life assessment after major lower extremity amputation.
Hawkins AT, Henry AJ, Crandell DM, Nguyen LL
(2014) Ann Vasc Surg 28: 763-80
MeSH Terms: Activities of Daily Living, Amputation, Amputees, Disability Evaluation, Exercise Test, Humans, Lower Extremity, Peripheral Arterial Disease, Predictive Value of Tests, Quality of Life, Recovery of Function, Surveys and Questionnaires, Treatment Outcome
Show Abstract · Added September 27, 2016
BACKGROUND - When judging the success or failure of major lower extremity (MLE) amputation, the assessment of appropriate functional and quality of life (QOL) outcomes is paramount. The heterogeneity of the scales and tests in the current literature is confusing and makes it difficult to compare results. We provide a primer for outcome assessment after amputation and assess the need for the additional development of novel instruments.
METHODS - MEDLINE, EMBASE, and Google Scholar were searched for all studies using functional and QOL instruments after MLE amputation. Assessment instruments were divided into functional and QOL categories. Within each category, they were subdivided into global and amputation-specific instruments. An overall assessment of instrument quality was obtained.
RESULTS - The initial search revealed 746 potential studies. After a review of abstracts, 102 were selected for full review, and 40 studies were then included in this review. From the studies, 21 different assessment instruments were used 63 times. There were 14 (67%) functional measures and 7 (33%) QOL measures identified. Five (36%) of the functional instruments and 3 (43%) of the QOL measures were specific for MLE amputees. Sixteen instruments were used >1 time, but only 5 instruments were used >3 times. An additional 5 instruments were included that were deemed important by expert opinion. The 26 assessment instruments were rated. Fourteen of the best-rated instruments were then described.
CONCLUSIONS - The heterogeneity of instruments used to measure both functional and QOL outcomes make it difficult to compare MLE amputation outcome studies. Future researchers should seek to use high-quality instruments. Clinical and research societies should endorse the best validated instruments for future use in order to strengthen overall research in the field.
Copyright © 2014 Elsevier Inc. All rights reserved.
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13 MeSH Terms
National variation in the utilization of alternative imaging in peripheral arterial disease.
de Vos MS, Hawkins AT, Hevelone ND, Hamming JF, Nguyen LL
(2014) J Vasc Surg 59: 1315-22.e1
MeSH Terms: Aged, Chi-Square Distribution, Comorbidity, Critical Illness, Diagnostic Imaging, Female, Health Care Surveys, Hospital Bed Capacity, Hospitals, Teaching, Humans, Intermittent Claudication, Ischemia, Logistic Models, Magnetic Resonance Angiography, Male, Multivariate Analysis, Odds Ratio, Peripheral Arterial Disease, Practice Patterns, Physicians', Predictive Value of Tests, Time Factors, Tomography, X-Ray Computed, Ultrasonography, Doppler, Duplex, United States
Show Abstract · Added September 27, 2016
OBJECTIVE - The value and cost-effectiveness of less invasive alternative imaging (AI) modalities (duplex ultrasound scanning, computed tomography angiography, and magnetic resonance angiography) in the care of peripheral arterial disease (PAD) has been reported; however, there is no consensus on their role. We hypothesized that AI utilization is low compared with angiography in the United States and that patient and hospital characteristics are both associated with AI utilization.
METHODS - The Nationwide Inpatient Sample (2007-2010) was used to identify patients with an International Classification of Diseases-Ninth Edition diagnosis of claudication or critical limb ischemia (CLI) as well as PAD treatment (surgical, endovascular, or amputation). Patients with AI and those with angiography or expected angiography (endovascular procedures without imaging codes) were selected and compared. Multivariable logistic regression was performed for receiving AI stratified by claudication and CLI and adjusting for patient and hospital factors.
RESULTS - We identified 290,184 PAD patients, of whom 5702 (2.0%) received AI. Patients with AI were more likely to have diagnosis of CLI (78.8% vs 48.6%; P < .0001) and receive open revascularizations (30.4% vs 18.8%; P < .0001). Van Walraven comorbidity scores (mean [standard error] 5.85 ± 0.22 vs 4.10 ± 0.05; P < .0001) reflected a higher comorbidity burden in AI patients. In multivariable analysis for claudicant patients, AI was associated with large bed size (odds ratio [OR], 3.26, 95% confidence interval [CI], 1.16-9.18; P = .025), teaching hospitals (OR, 1.97; 95% CI, 1.10-3.52; P = .023), and renal failure (OR, 1.52; 95% CI, 1.13-2.05; P = .006). For CLI patients, AI was associated with black race (OR, 1.53; 95% CI, 1.13-2.08; P = .006) and chronic heart failure (OR, 1.29; 95% CI, 1.04-1.60; P = .021) and was negatively associated with renal failure (OR, 0.80; 95% CI, 0.67-0.95; P = .012). The Northeast and West regions were associated with higher odds of AI in claudicant patients (OR, 2.41; 95% CI, 1.23-4.75; P = .011; and OR, 2.59; 95% CI, 1.34-5.02; P = .005, respectively) and CLI patients (OR, 4.31; 95% CI, 2.20-8.36; P < .0001; and OR, 2.18; 95% CI, 1.12-4.22; P = .021, respectively). Rates of AI utilization across states were not evenly distributed but showed great variability, with ranges from 0.31% to 9.81%.
CONCLUSIONS - National utilization of AI for PAD is low and shows great variation among institutions in the United States. Patient and hospital factors are both associated with receiving AI in PAD care, and AI utilization is subject to significant regional variation. These findings suggest differences in systems of care or practice patterns and call for a clearer understanding and a more unified approach to imaging strategies in PAD care.
Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
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24 MeSH Terms
Quantitative optical imaging of vascular response in vivo in a model of peripheral arterial disease.
Poole KM, Tucker-Schwartz JM, Sit WW, Walsh AJ, Duvall CL, Skala MC
(2013) Am J Physiol Heart Circ Physiol 305: H1168-80
MeSH Terms: Animals, Arteries, Collateral Circulation, Disease Models, Animal, Femoral Artery, Hindlimb, Ligation, Male, Mice, Muscle, Skeletal, Optical Imaging, Oxygen, Perfusion Imaging, Peripheral Arterial Disease, Regional Blood Flow, Tomography, Optical Coherence
Show Abstract · Added March 7, 2014
The mouse hind limb ischemia (HLI) model is well established for studying collateral vessel formation and testing therapies for peripheral arterial disease, but there is a lack of quantitative techniques for intravitally analyzing blood vessel structure and function. To address this need, non-invasive, quantitative optical imaging techniques were developed to assess the time-course of recovery in the mouse HLI model. Hyperspectral imaging and optical coherence tomography (OCT) were used to non-invasively image hemoglobin oxygen saturation and microvessel morphology plus blood flow, respectively, in the anesthetized mouse after induction of HLI. Hyperspectral imaging detected significant increases in hemoglobin saturation in the ischemic paw as early as 3 days after femoral artery ligation (P < 0.01), and significant increases in distal blood flow were first detected with OCT 14 days postsurgery (P < 0.01). Intravital OCT images of the adductor muscle vasculature revealed corkscrew collateral vessels characteristic of the arteriogenic response to HLI. The hyperspectral imaging and OCT data significantly correlated with each other and with laser Doppler perfusion imaging (LDPI) and tissue oxygenation sensor data (P < 0.01). However, OCT measurements acquired depth-resolved information and revealed more sustained flow deficits following surgery that may be masked by more superficial measurements (LDPI, hyperspectral imaging). Therefore, intravital OCT may provide a robust biomarker for the late stages of ischemic limb recovery. This work validates non-invasive acquisition of both functional and morphological data with hyperspectral imaging and OCT. Together, these techniques provide cardiovascular researchers an unprecedented and comprehensive view of the temporal dynamics of HLI recovery in living mice.
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16 MeSH Terms