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1.  Risk index for predicting perioperative stroke, myocardial infarction, or death risk in asymptomatic patients undergoing carotid endarterectomy 
Journal of vascular surgery  2012;57(2):318-326.
The latest guidelines recommend performance of carotid endarterectomy (CEA) on asymptomatic patients with high-grade carotid stenosis, only if the combined perioperative stroke, myocardial infarction (MI), or death risk is ≤3%. Our objective was to develop and validate a risk index to estimate the combined risk of perioperative stroke, MI, or death in asymptomatic patients undergoing elective CEA.
Asymptomatic patients who underwent an elective CEA (n = 17,692) were identified from the 2005-2010 National Surgical Quality Improvement Program, a multicenter, prospective database. Multivariable logistic regression analysis was performed with primary outcome of interest being the composite of any stroke, MI, or death during the 30-day periprocedural period. Bootstrapping was used for internal validation. A risk index was created by assigning weighted points to each predictor using the β-coefficients from the regression analysis.
Fifty-eight percent of the patients were men with a median age of 72 years. Thirty-day incidences of stroke, MI, and death were 0.9% (n = 167), 0.6% (n = 108), and 0.4% (n = 72), respectively. The combined 30-day stroke, MI, or death incidence was 1.8% (n = 324). On multivariable analysis, six independent predictors were identified and a risk index created by assigning weighted points to each predictor using the β-coefficients from the regression analysis. The predictors included age in years (<60: 0 point; 60-69: −1 point; 70-79: −1 point; ≥80: 2 points), dyspnea (2 points), chronic obstructive pulmonary disease (3 points), previous peripheral revascularization or amputation (3 points), recent angina within 1 month (4 points), and dependent functional status (5 points). Patients were classified as low (<3%), intermediate (3%-6%), or high (>6%) risk for combined 30-day stroke, MI, or death, based on a total point score of <4, 4-7, and >7, respectively. There were 15,249 patients (86.2%) in the low-risk category, 2233 (12.6%) in the intermediate-risk category, and 210 (1.2%) in the high-risk category.
The validated risk index can help identify asymptomatic patients who are at greatest risk for 30-day stroke, MI, and death after CEA, thereby aiding patient selection.
PMCID: PMC3650300  PMID: 23159474
2.  Development and validation of a risk calculator for prediction of mortality after infrainguinal bypass surgery 
Journal of vascular surgery  2012;56(2):372-379.
For peripheral arterial disease, infrainguinal bypass grafting (BPG) carries a higher perioperative risk compared with peripheral endovascular procedures. The choice between the open and endovascular therapies is to an extent dependent on the expected periprocedural risk associated with each. Tools for estimating the periprocedural risk in patients undergoing BPG have not been reported in the literature. The objective of this study was to develop and validate a calculator to estimate the risk of perioperative mortality ≤30 days of elective BPG.
We identified 9556 patients (63.9% men) who underwent elective BPG from the 2007 to 2009 National Surgical Quality Improvement Program data sets. Multivariable logistic regression analysis was performed to identify risk factors associated with 30-day perioperative mortality. Bootstrapping was used for internal validation. The risk factors were subsequently used to develop a risk calculator.
Patients had a median age of 68 years. The 30-day mortality rate was 1.8% (n = 170). Multivariable logistic regression analysis identified seven preoperative predictors of 30-day mortality: increasing age, systemic inflammatory response syndrome, chronic corticosteroid use, chronic obstructive pulmonary disease, dependent functional status, dialysis dependence, and lower extremity rest pain. Bootstrapping was used for internal validation. The model demonstrated excellent discrimination (C statistic, 0.81; bias-corrected C statistic, 0.81) and calibration. The validated risk model was used to develop an interactive risk calculator using the logistic regression equation.
The validated risk calculator has excellent predictive ability for 30-day mortality in a patient after an elective BPG. It is anticipated to aid in surgical decision making, informed patient consent, preoperative optimization, and consequently, risk reduction.
PMCID: PMC3613335  PMID: 22632800
3.  Human Enterovirus in the Gastrocnemius of Patients With Peripheral Arterial Disease 
Peripheral arterial disease (PAD) is characterized by myofiber degeneration and loss of function in muscles of the lower limbs. Human enterovirus (HEV) infection has been implicated in the pathogenesis of a number of muscle diseases. However, its association with PAD has not been studied. In this study, we tested the hypothesis that infectious HEV is present in skeletal muscle of patients with PAD and is associated with severity of disease.
Methods and Results
Gastrocnemius biopsies from 37 patients with PAD and 14 controls were examined for the presence of HEV RNA, viral capsid protein, viral RNA copy number, and viral infectivity. HEV RNA was detected in 54% of the biopsies from patients with PAD but was not detected in muscle biopsies from control patients. This difference in prevalence among PAD and control patients was significant at P<0.001. Viral RNA copy numbers were increased significantly at the later stages of disease; Fontaine Stage IV (105.50 copies/mg muscle wet weight, at P<0.005) and Stage III (104.87 copies/mg, at P<0.010) compared to Stage II (102.50 copies/mg). Viral replication was confirmed by the presence of the negative‐strand of viral RNA in all specimens positive for HEV RNA. Cultures of HeLa and human skeletal muscle cells treated with muscle homogenates showed HEV replication and the presence of HEV capsid protein.
Our data identified infectious HEV in the gastrocnemius of PAD patients but not in controls. Viral copy number and prevalence of infection were higher in the later stages of disease. Our data point to the need for further studies to determine the contribution of HEV infection to the pathophysiology of PAD.
PMCID: PMC3828788  PMID: 23920231
coxsackievirus; human enterovirus; peripheral arterial disease; skeletal muscle degeneration
The Journal of surgical research  2011;176(1):329-336.
The mechanical environment and properties of the carotid artery play an important role in the formation and progression of atherosclerosis in the carotid bifurcation. The purpose of this work was to measure and compare the range and variation of circumferential stress and tangent elastic moduli in the human common (CCA), external (ECA) and internal (ICA) carotid arteries over the cardiac cycle in vivo.
Measurements were performed in the surgically exposed proximal cervical CCA, distal ECA and distal ICA of normotensive patients (n = 16) undergoing carotid endarterectomy. All measurements were completed in vivo over the cardiac cycle in the repaired carotid bifurcation after the atherosclerotic plaque was successfully removed. B-mode Duplex ultrasonography was used for measurement of arterial diameter and wall thickness, and an angiocatheter placed in the CCA was used for concurrent measurement of blood pressure. A semi-automatic segmentation algorithm was used to track changes in arterial diameter and wall thickness in response to blood pressure. These measurements were then used to calculate the variation of circumferential (hoop) stresses, tangent elastic moduli (the slope of the stress-strain curve at specified stresses), and stress-induced stiffness of the arterial wall (stiffening in response to intraluminal blood pressure fluctuation) for each patient.
The diameter and wall thickness of the segments (CCA, ECA and ICA) of the carotid bifurcation were found to decrease and stress-induced stiffness to increase from proximal CCA to distal ECA and ICA. The circumferential stress from end-diastole (minimum pressure) to peak-systole (maximum pressure) varied nonlinearly from 25±7 to 63±23 kPa (CCA), from 22±7 to 57±19 kPa (ECA) and from 28±8 to 67±23 kPa (ICA). Tangent elastic moduli also varied nonlinearly from end-diastole to peak-systole as follows: from 0.40±0.25 to 1.50±2.05 MPa (CCA), from 0.49±0.34 to 1.14±0.52 MPa (ECA) and from 0.68±0.31 to 1.51±0.69 MPa (ICA). The stress-induced stiffness of CCA and ECA increased more than 3-fold and the stiffness of ICA increased more than 2.5-fold at peak-systole compared to end-diastole.
The in vivo mechanical behavior of the three segments of the carotid bifurcation was qualitatively similar, but quantitatively different. All three arteries – CCA, ECA and ICA – exhibited nonlinear variations of circumferential stress and tangent elastic moduli within the normal pressure range. The variability in the properties of the three segments of the carotid bifurcation indicates a need for development of carotid models that match the in vivo properties of the carotid segments. Finally, the observed nonlinear behavior of the artery points to the need for future vascular mechanical studies to evaluate the mechanical factors of the arterial wall over the entire cardiac cycle.
PMCID: PMC3470810  PMID: 22099586
common carotid artery; external carotid artery; internal carotid artery; in vivo mechanical properties; circumferential stress; stiffening
5.  Predictive Factors for Mortality following Open Repair of Paravisceral Abdominal Aortic Aneurysm 
Journal of vascular surgery  2011;55(3):666-673.
The use of fenestrated and branched stent graft technology for paravisceral abdominal aortic aneurysms (PAAA) is on the rise; however, its application is limited in the United States to only a few selected centers. The majority of the PAAAs are currently repaired using an open approach. The objective of this study was to determine which patients are at highest risk with open PAAA repair and might benefit most from endovascular repair using fenestrated or branched stent grafts.
Design of the study
Retrospective cohort study.
American College of Surgeons National Surgical Quality Improvement Program (NSQIP) hospitals.
Patients who underwent elective open PAAA repair (n=598) were identified from the 2007–09 NSQIP - a prospective database maintained at multiple centers (>250).
Main outcome measure
Thirty-day postoperative mortality.
The median age was 73 years and 27.6% were females. Thirty-day major morbidity and mortality rates were 30.1% and 4.5%, respectively. Major complications included reintubation (10.0%), sepsis (10.7%), return to operating room (9.2%), new dialysis requirement (5.9%), cardiac arrest/myocardial infarction (4.5%), and stroke (1.2%). On multivariate analyses, 4 predictors of postoperative mortality after open PAAA repair were identified: peripheral arterial disease requiring revascularization or amputation (PAD), chronic obstructive pulmonary disease (COPD), anesthesia time, and female gender. PAD and COPD were present in only 5.2% and 20.4% patients, but were associated with 16.1% and 9.0% mortality rate, respectively. Mortality rate in females was 7.3% in contrast to 3.5% for males (P= .045).
PAD, COPD, and female gender are major risk factors for postoperative mortality following open PAAA repair. Fenestrated or branched stent graft repair may be a more valuable alternative to open repair for patients with one or more of these characteristics who have suitable access vessels.
PMCID: PMC3470812  PMID: 22209613
Paravisceral; Abdominal Aortic Aneurysm; Open; Fenestrated; Branched
6.  Abnormal Joint Powers Before And After The Onset Of Claudication Symptoms 
Claudication is the most common manifestation of peripheral arterial disease, producing significant ambulatory compromise. The purpose of our study was to evaluate patients with bilateral lower limb claudication and characterize their gait abnormality based on advanced biomechanical analysis using joint torques and powers.
Twenty patients with bilateral claudication (ten with isolated aortoiliac disease and ten with combined aortoiliac and femoropopliteal disease) and sixteen matched controls ambulated on a walkway while three dimensional biomechanical data were collected. Patients walked before and after onset of claudication pain. Joint torques and powers at early-, mid-, and late-stance for the hip, knee and ankle joints were calculated for claudicating patients before and after the onset of claudication pain, and were compared to control subjects.
Claudicating patients exhibited significantly reduced hip and knee power at early-stance (weight acceptance phase) due to decreased torques produced by the hip and knee extensors. In mid-stance (single limb support phase), patients had significantly reduced knee and hip power due to the decreased torques produced by the knee extensors and the hip flexors. In late-stance (propulsion phase), reduced propulsion was noted with significant reduction in ankle plantar flexor torques and power. These differences were present before and after the onset of pain with certain parameters worsening in association with pain.
The gait of claudication is characterized by failure of specific and identifiable muscle groups needed to perform normal walking (weight acceptance, single limb support and propulsion). Parameters of gait are abnormal with the first steps taken, in the absence of pain, and certain of these parameters worsen after the onset of claudication pain.
PMCID: PMC2921796  PMID: 20670775
7.  Endothelial FoxO1 is an intrinsic regulator of thrombospondin 1 expression that restrains angiogenesis in ischemic muscle 
Angiogenesis  2013;16(4):10.1007/s10456-013-9353-x.
Peripheral artery disease (PAD) is characterized by chronic muscle ischemia. Compensatory angiogenesis is minimal within ischemic muscle despite an increase in angiogenic factors. This may occur due to the prevalence of angiostatic factors. Regulatory mechanisms that could evoke an angiostatic environment during ischemia are largely unknown. Forkhead box O (FoxO) transcription factors, known to repress endothelial cell proliferation in vitro, are potential candidates. Our goal was to determine whether FoxO proteins promote an angiostatic phenotype within ischemic muscle. FoxO1 and the angiostatic matrix protein thrombospondin 1 (THBS1) were elevated in ischemic muscle from PAD patients, or from mice post-femoral artery ligation. Mice with conditional endothelial cell-directed deletion of FoxO proteins (Mx1Cre+, FoxO1,3,4L/L, referred to as FoxOΔ) were used to assess the role of endothelial FoxO proteins within ischemic tissue. FoxO deletion abrogated the elevation of FoxO1 and THBS1 proteins, enhanced hindlimb blood flow recovery and improved neovascularization in murine ischemic muscle. Endothelial cell outgrowth from 3D explant cultures was more robust in muscles derived from FoxOΔ mice. FoxO1 overexpression induced THBS1 production, and a direct interaction of endogenous FoxO1 with the THBS1 promoter was detectable in primary endothelial cells. We provide evidence that FoxO1 directly regulates THBS1 within ischemic muscle. Altogether, these findings bring novel insight into the regulatory mechanisms underlying the repression of angiogenesis within peripheral ischemic tissues.
PMCID: PMC3822003  PMID: 23677673
Endothelium; Ischemia; Angiogenesis; Peripheral artery disease; Skeletal muscle; Capillary
9.  Development of a Fatal Noncompressible Truncal Hemorrhage Model with Combined Hepatic and Portal Venous Injury in Normothermic Normovolemic Swine 
PLoS ONE  2014;9(9):e108293.
Noncompressible truncal hemorrhage and brain injury currently account for most early mortality of warfighters on the battlefield. There is no effective treatment for noncompressible truncal hemorrhage, other than rapid evacuation to a surgical facility. The availability of an effective field treatment for noncompressible truncal hemorrhage could increase the number of warfighters salvaged from this frequently-lethal scenario. Our intent was to develop a porcine model of noncompressible truncal hemorrhage with a ∼50% one-hour mortality so that we could develop new treatments for this difficult problem. Normovolemic normothermic domestic swine (barrows, 3 months old, 34–36 kg) underwent one of three injury types through a midline incision: 1) central stellate injury (N = 6); 2) excision of a portal vein branch distal to the main PV trunk (N = 6); or 3) hemi-transection of the left lateral lobe of the liver at its base (N = 10). The one-hour mortality of these injuries was 0, 82, and 40%, respectively; the final mean arterial pressure was 65, 24, and 30 mm Hg, respectively; and the final hemoglobin was 8.3, 2.3, and 3.6 g/dL, respectively. Hemi-transection of the left lateral lobe of the liver appeared to target our desired mortality rate better than the other injury mechanisms.
PMCID: PMC4176969  PMID: 25251401
10.  Surface‐enhanced Raman spectral biomarkers correlate with Ankle Brachial Index and characterize leg muscle biochemical composition of patients with peripheral arterial disease 
Physiological Reports  2014;2(9):e12148.
Peripheral arterial disease (PAD) is characterized by atherosclerotic blockages of the arteries supplying the lower extremities, which cause a progressive accumulation of ischemic injury to the skeletal muscles of the lower limbs. This injury includes altered metabolic processes, damaged organelles, and compromised bioenergetics in the affected muscles. The objective of this study was to explore the association of Raman spectral signatures of muscle biochemistry with the severity of atherosclerosis in the legs as determined by the Ankle Brachial Index (ABI) and clinical presentation. We collected muscle biopsies from the gastrocnemius (calf muscle) of five patients with clinically diagnosed claudication, five patients with clinically diagnosed critical limb ischemia (CLI), and five control patients who did not have PAD. A partial least squares regression (PLSR) model was able to predict patient ABI with a correlation coefficient of 0.99 during training and a correlation coefficient of 0.85 using a full cross‐validation. When using the first three PLS factor scores in combination with linear discriminant analysis, the discriminant model was able to correctly classify the control, claudicating, and CLI patients with 100% accuracy, using a full cross‐validation procedure. Raman spectroscopy is capable of detecting and measuring unique biochemical signatures of skeletal muscle. These signatures can discriminate control muscles from PAD muscles and correlate with the ABI and clinical presentation of the PAD patient. Raman spectroscopy provides novel spectral biomarkers that may complement existing methods for diagnosis and monitoring treatment of PAD patients.
Raman spectroscopy is capable of detecting and measuring unique biochemical signatures of skeletal muscle. These signatures can discriminate control muscles from peripheral arterial disease (PAD) muscles and correlate with the ABI and clinical presentation of the PAD patient. Raman spectroscopy provides novel spectral biomarkers that may complement existing methods for diagnosis and monitoring treatment of PAD patients.
PMCID: PMC4270241  PMID: 25247767
Linear discriminant analysis; muscle biochemistry; partial least squares regression; peripheral arterial disease; Raman spectroscopy
11.  Metabolic reprogramming induced by ketone bodies diminishes pancreatic cancer cachexia 
Cancer & Metabolism  2014;2:18.
Aberrant energy metabolism is a hallmark of cancer. To fulfill the increased energy requirements, tumor cells secrete cytokines/factors inducing muscle and fat degradation in cancer patients, a condition known as cancer cachexia. It accounts for nearly 20% of all cancer-related deaths. However, the mechanistic basis of cancer cachexia and therapies targeting cancer cachexia thus far remain elusive. A ketogenic diet, a high-fat and low-carbohydrate diet that elevates circulating levels of ketone bodies (i.e., acetoacetate, β-hydroxybutyrate, and acetone), serves as an alternative energy source. It has also been proposed that a ketogenic diet leads to systemic metabolic changes. Keeping in view the significant role of metabolic alterations in cancer, we hypothesized that a ketogenic diet may diminish glycolytic flux in tumor cells to alleviate cachexia syndrome and, hence, may provide an efficient therapeutic strategy.
We observed reduced glycolytic flux in tumor cells upon treatment with ketone bodies. Ketone bodies also diminished glutamine uptake, overall ATP content, and survival in multiple pancreatic cancer cell lines, while inducing apoptosis. A decrease in levels of c-Myc, a metabolic master regulator, and its recruitment on glycolytic gene promoters, was in part responsible for the metabolic phenotype in tumor cells. Ketone body-induced intracellular metabolomic reprogramming in pancreatic cancer cells also leads to a significantly diminished cachexia in cell line models. Our mouse orthotopic xenograft models further confirmed the effect of a ketogenic diet in diminishing tumor growth and cachexia.
Thus, our studies demonstrate that the cachectic phenotype is in part due to metabolic alterations in tumor cells, which can be reverted by a ketogenic diet, causing reduced tumor growth and inhibition of muscle and body weight loss.
PMCID: PMC4165433  PMID: 25228990
Pancreatic cancer; Cancer cachexia; Cancer metabolism; Ketone bodies
Annals of biomedical engineering  2012;41(8):1692-1702.
Insufficient blood flow is one possible mechanism contributing to altered gait patterns in lower extremity peripheral arterial disease (PAD). Previously, our laboratory found that induced occlusion alters gait variability patterns in healthy young individuals. However the effect of age was not explored. The purpose of this study was to account for age by investigating gait variability following induced vascular occlusion in healthy older individuals and to identify amount of change from baseline to post vascular occlusion between younger and older individuals. Thirty healthy younger individuals and 30 healthy older individuals walked on a treadmill during baseline and post vascular occlusion conditions while lower extremity joint kinematics were captured. Vascular occlusion was induced by thigh cuffs inflated bilaterally on the upper thighs. Amount and temporal structure of gait variability was assessed. Older individuals exhibited significantly increased values of temporal structure of variability post vascular occlusion. Post vascular occlusion values were similar between younger and older individuals after adjusting for baseline measurements. Results show blood flow contributes to altered gait variability. However alterations were less severe than previously documented in symptomatic PAD patients, suggesting that neuromuscular problems in the lower extremities of PAD patients also contribute to gait alterations in these patients.
PMCID: PMC3568451  PMID: 23053301
Gait patterns; nonlinear analysis; nonlinear dynamics; vascular disease; atherosclerosis
13.  Oxidative damage in the gastrocnemius of patients with peripheral artery disease is myofiber type selective 
Redox Biology  2014;2:921-928.
Peripheral artery disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in the arteries supplying the legs, affects approximately 5% of Americans. We have previously, demonstrated that a myopathy characterized by myofiber oxidative damage and degeneration is central to PAD pathophysiology.
In this study, we hypothesized that increased oxidative damage in the myofibers of the gastrocnemius of PAD patients is myofiber-type selective and correlates with reduced myofiber size.
Needle biopsies were taken from the gastrocnemius of 53 PAD patients (28 with early PAD and 25 with advanced PAD) and 25 controls. Carbonyl groups (marker of oxidative damage), were quantified in myofibers of slide-mounted tissue, by quantitative fluorescence microscopy. Myofiber cross-sectional area was determined from sarcolemma labeled with wheat germ agglutinin. The tissues were also labeled for myosin I and II, permitting quantification of oxidative damage to and relative frequency of the different myofiber Types (Type I, Type II and mixed Type I/II myofibers). We compared PAD patients in early (N=28) vs. advanced (N=25) disease stage for selective, myofiber oxidative damage and altered morphometrics.
The carbonyl content of gastrocnemius myofibers was higher in PAD patients compared to control subjects, for all three myofiber types (p<0.05). In PAD patients carbonyl content was higher (p<0.05) in Type II and I/II fibers compared to Type I fibers. Furthermore, the relative frequency and cross-sectional area of Type II fibers were lower, while the relative frequencies and cross-sectional area of Type I and Type I/II fibers were higher, in PAD compared to control gastrocnemius (p<0.05). Lastly, the type II-selective oxidative damage increased and myofiber size decreased as the disease progressed from the early to advanced stage.
Our data confirm increased myofiber oxidative damage and reduced myofiber size in PAD gastrocnemius and demonstrate that the damage is selective for type II myofibers and is worse in the most advanced stage of PAD.
Graphical abstract
•Peripheral artery disease, is characterized by the formation of atherosclerotic plaques that limit blood flow to the legs.•There was increased myofiber oxidative damage and degeneration in the gastrocnemius of PAD patients compared to controls.•Myofiber oxidative damage and morphology were worse for Type II myofibers.•Type II-selective oxidative damage and abnormal morphology worsened as the PAD progressed from the early to advanced stage.•Myofiber oxidative damage and degeneration is a significant contributors to the pathophysiology of PAD.
PMCID: PMC4143812  PMID: 25180168
carbonyl groups; oxidative damage; Fontaine Stage
14.  Peripheral Arterial Disease Affects the Frequency Response of Ground Reaction Forces During Walking 
Clinical biomechanics (Bristol, Avon)  2012;27(10):1058-1063.
Walking is problematic for patients with Peripheral Arterial Disease. The purpose of this study was to investigate the frequency domain of the ground reaction forces during walking to further elucidate the ambulatory impairment of these patients.
Nineteen bilateral peripheral arterial disease patients and nineteen controls were included in this study. Subjects were matched for age and gait speed. Participants walked over a force plate sampling at 600Hz. PAD patients were tested before (pain-free condition) after the onset of claudication symptoms (pain). We calculated median frequency, frequency bandwidth, and frequency containing 99.5% of the signal for the vertical and anterior-posterior ground reaction forces.
Our results showed reduced median frequency in the vertical and anterior-posterior components of the ground reaction forces between the control group and both peripheral arterial disease conditions. We found reduced frequency bandwidth in the anterior-posterior direction between controls and the peripheral arterial disease pain-free condition. There were no differences in median frequency or bandwidth between peripheral arterial disease pain-free and pain conditions, but an increase in the frequency content for 99.5% of the signal was observed in the pain condition.
Reduced frequency phenomena during gait in peripheral arterial disease patients compared to velocity-matched controls suggests more sluggish activity within the neuromotor system. Increased frequency phenomena due to pain in these patients suggests a more erratic application of propulsive forces when walking. Frequency domain analysis thus offers new insights into the gait impairments associated with this patient population.
PMCID: PMC3501537  PMID: 22967739
Gait; intermittent claudication; occlusion; power spectrum
15.  External work is deficient in both limbs of patients with unilateral PAD 
Medical engineering & physics  2012;34(10):1421-1426.
External work was utilized to measure differences between the unaffected and the affected limb in patients with unilateral peripheral arterial disease compared to healthy controls. Patients with unilateral peripheral arterial disease have shown deficits in peak joint powers during walking in the unaffected and affected legs. However, no research has detailed the amount of work that is being performed by each leg compared to healthy controls even though such an analysis would provide valuable information on the energy output from the affected and the unaffected legs. Two hypotheses were tested: a) the unaffected and affected leg would perform less work than healthy controls in a pain-free state, and b) the onset of symptomatic claudication pain would result in further changes in the external work. Results showed that during a pain-free state, both the unaffected and affected legs perform less work than the healthy controls. After onset of claudication pain, the work output by the affected limb becomes further decreased while the unaffected limb experiences changes in negative external work. These findings combined with recent evidence of decreased peak powers in both legs in unilateral peripheral arterial disease patients reflects altered pathomechanics in both limbs compared to healthy controls.
PMCID: PMC3360992  PMID: 22321812
gait; locomotion; arterial disease; atherosclerosis; biomechanics
16.  Oxidative damage and myofiber degeneration in the gastrocnemius of patients with peripheral arterial disease 
Peripheral arterial disease (PAD), a manifestation of systemic atherosclerosis that produces blockages in arteries supplying the legs, affects an estimated 27 million people in Europe and North America. Increased production of reactive oxygen species by dysfunctional mitochondria in leg muscles of PAD patients is viewed as a key mechanism of initiation and progression of the disease. Previous studies demonstrated increased oxidative damage in homogenates of biopsy specimens from PAD gastrocnemius compared to controls, but did not address myofiber-specific damage. In this study, we investigated oxidative damage to myofibers as a possible cause of the myopathy of PAD. To achieve this, we developed and validated fluorescence microscopy procedures for quantitative analysis of carbonyl groups and 4-hydroxy-2-nonenal (HNE) adducts in myofibers of biopsy specimens from human gastrocnemius. PAD and control specimens were evaluated for differences in 1) myofiber content of these two forms of oxidative damage and 2) myofiber cross-sectional area. Furthermore, oxidative damage to PAD myofibers was tested for associations with clinical stage of disease, degree of ischemia in the affected leg, and myofiber cross-sectional area. Carbonyl groups and HNE adducts were increased 30% (p < 0.0001) and 40% (p < 0.0001), respectively, in the myofibers of PAD (N = 34) compared to control (N = 21) patients. Mean cross-sectional area of PAD myofibers was reduced 29.3% compared to controls (p < 0.0003). Both forms of oxidative damage increased with clinical stage of disease, blood flow limitation in the ischemic leg, and reduced myofiber cross-sectional area. The data establish oxidative damage to myofibers as a possible cause of PAD myopathy.
PMCID: PMC3849592  PMID: 24067235
17.  Parallel Changes in Neuronal AT1R and GRK5 Expression Following Exercise Training in Heart Failure 
Hypertension  2012;60(2):354-361.
Although exercise training (ExT) is an important therapeutic strategy for improving quality of life in patients with chronic heart failure (CHF), the central mechanisms by which ExT is beneficial are not well understood. The angiotensin II type 1 receptor (AT1R) plays a pivotal role in the development of CHF, and is upregulated in a number of tissues due in part to transcription factor nuclear factor kappa B (NF-κB). In addition, AT1R is marked for internalization and recycling via G protein coupled receptor kinase (GRK) phosphorylation. Because previous studies have shown that the beneficial effects of ExT in CHF rely on a reduction in Ang II, we hypothesized ExT would decrease AT1R, GRK5 and NF-κB protein expression in the paraventricular nucleus (PVN) and rostral ventrolateral medulla (RVLM) of CHF rats. Following infarction by coronary artery ligation, animals were exercised four weeks post-surgery on a treadmill at a final speed of 25 m/min for 60 minutes, 5 days/week for 6 weeks. Western blot analysis of PVN and RVLM micropunches revealed an upregulation of AT1R, GRK5 and NF-κB in the infarcted group that was reversed by ExT. Furthermore, the relative expression of phosphorylated AT1R and AT1R/GRK5 physical association was increased in the CHF sedentary group, and reversed by ExT. Overexpression of GRK5 in cultured CATH.a neurons blunted angiotensin II-mediated upregulation of AT1R and NF-κB; conversely, silencing of GRK5 exacerbated angiotensin II-mediated AT1R and NF-κB upregulation. Taken together, increased GRK5 may regulate AT1R expression in CHF, and ExT mitigates AT1R and its pathway components.
PMCID: PMC3409876  PMID: 22753221
angiotensin II; GRK5; NF-κB; receptor turnover
18.  Patients with peripheral arterial disease exhibit reduced joint powers compared to velocity-matched controls 
Gait & posture  2012;36(3):506-509.
Previous studies have shown major deficits in gait for individuals with peripheral arterial disease before and after the onset of pain. However, these studies did not have subjects ambulate at similar velocities and potential exists that the differences in joint powers may have been due to differences in walking velocity. The purpose of this study was to examine the joint moments and powers of peripheral arterial disease limbs for subjects walking at similar self-selected walking velocities as healthy controls prior to onset of any symptoms. Results revealed peripheral arterial disease patients have reduced peak hip power absorption in midstance (p=0.017), reduced peak knee power absorption in early and late stance (p=0.037 and p=0.020 respectively), and reduced peak ankle power generation in late stance (p=0.021). This study reveals that the gait of patients with peripheral arterial disease walking prior to the onset of any leg symptoms is characterized by failure of specific and identifiable muscle groups needed to perform normal walking and that these gait deficits are independent of reduced gait velocity.
PMCID: PMC3407282  PMID: 22677467
gait; joint moments; locomotion; biomechanics; vascular diseases
Recent research demonstrated that intermittent claudication patients have increased gait variability prior to the onset of claudication. However, it is unknown if these patients experience additional gait adaptations after the onset of claudication. Thus, we sought to determine how gait variability is affected by claudication in an effort to contribute to improved clinical management.
Twenty-six intermittent claudication patients and 20 controls walked on a treadmill at self-selected speed; intermittent claudication patients were tested before (pain free) and after (pain) the onset of claudication. Variability of the ankle, knee, and hip joint angles was assessed using the largest Lyapunov exponent, standard deviation and coefficient of variation. Dependent t-tests were used to compare the pain free and pain conditions. Independent t-tests were used to compare intermittent claudication patients and controls.
Pain free and pain conditions were not significantly different for any of the parameters evaluated except the ankle. Compared to controls, patients had significantly greater values for the largest Lyapunov exponent in both conditions for all joints.
Gait variability was essentially the same before and after the onset of claudication at the knee and the hip, and was increased in both conditions compared to controls. This indicates altered cooperation between components of the locomotor system of intermittent claudication patients, likely due to the associated myopathy since differences were present even before the onset of claudication. This research helps provide essential biomechanical knowledge of intermittent claudication that contributes to improved clinical management.
PMCID: PMC3134603  PMID: 21450380
Joint kinematics; peripheral arterial disease; Lyapunov exponent; locomotion; walking
20.  Tourniquet-induced acute ischemia-reperfusion injury in mouse skeletal muscles: involvement of superoxide 
European journal of pharmacology  2010;650(1):328-334.
Although arterial limb tourniquet is one of the first-line treatments to prevent exsanguinating hemorrhage in both civilian pre-hospital and battlefield casualty care, prolonged application of a limb tourniquet can lead to serious ischemia-reperfusion injury. However, the underlying pathomechanisms of tourniquet-induced ischemia-reperfusion injury are still poorly understood. Using a murine model of acute limb ischemia-reperfusion, we investigated if acute limb ischemia-reperfusion injury is mediated by superoxide overproduction and mitochondrial dysfunction. Hind limbs of C57/BL6 mice were subjected to 3 h ischemia and 4 h reperfusion via placement and release of a rubber tourniquet at the greater trochanter. Approximately 40% gastrocnemius muscle suffered infarction in this model. Activities of mitochondrial electron transport chain complexes including complex I, II, III, and IV in gastrocnemius muscle were decreased in the ischemia-reperfusion group compared to sham. Superoxide production was increased while activity of manganese superoxide dismutase (MnSOD, the mitochondria-targeted SOD isoform) was decreased in the ischemia-reperfusion group compared to sham group. Pretreatment with tempol (a SOD mimetic, 50 mg/kg) or co-enzyme Q10 (50 mg/kg) not only decreased the superoxide production, but also reduced the infarct size and normalized mitochondrial dysfunction in the gastrocnemius muscle. Our results suggest that tourniquet-induced skeletal muscle ischemia-reperfusion injuries including infarct size and mitochondrial dysfunction may be mediated via the superoxide over-production and reduced antioxidant activity. In the future, this murine ischemia-reperfusion model can be adapted to mechanistically evaluate anti-ischemic molecules in tourniquet-induced skeletal muscle injury.
PMCID: PMC3008320  PMID: 21036124
Infarct size; Ischemia-reperfusion injury; Mitochondria; Superoxide; Tourniquet
21.  The effect of pharmacological treatment on gait biomechanics in peripheral arterial disease patients 
Pharmacological treatment has been advocated as a first line therapy for Peripheral Arterial Disease (PAD) patients suffering from intermittent claudication. Previous studies document the ability of pharmacological treatment to increase walking distances. However, the effect of pharmacological treatment on gait biomechanics in PAD patients has not been objectively evaluated as is common with other gait abnormalities.
Sixteen patients were prescribed an FDA approved drug (Pentoxifylline or Cilostazol) for the treatment of symptomatic PAD. Patients underwent baseline gait testing prior to medication use which consisted of acquisition of ground reaction forces and kinematics while walking in a pain free state. After three months of treatment, patients underwent repeat gait testing.
Patients with symptomatic PAD had significant gait abnormalities at baseline during pain free walking as compared to healthy controls. However, pharmacological treatment did not produce any identifiable alterations on the biomechanics of gait of the PAD patients as revealed by the statistical comparisons performed between pre and post-treatment and between post-treatment and the healthy controls.
Pharmacological treatment did not result in statistically significant improvements in the gait biomechanics of patients with symptomatic PAD. Future studies will need to further explore different cohorts of patients that have shown to improve significantly their claudication distances and/or their muscle fiber morphology with the use of pharmacological treatment and determine if this is associated with an improvement in gait biomechanics. Using these methods we may distinguish the patients who benefit from pharmacotherapy and those who do not.
PMCID: PMC2892501  PMID: 20529284

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