Brian S Knipp

University of Michigan, Ann Arbor, MI, United States

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Publications (25)44.82 Total impact

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    ABSTRACT: No prior studies, to our knowledge, have examined the performance of the Acute Physiology and Chronic Health Evaluation (APACHE) III score in predicting mortality of patients undergoing open thoracoabdominal aortic aneurysm (TAAA) or open abdominal aortic aneurysm (AAA) repair. We sought to evaluate APACHE III scores in the prediction of postoperative mortality in elective TAAA and AAA repairs. Over a 9-year period (July 1998 through June 2007), prospective data (demographics, admitting diagnosis, APACHE III score, intensive care unit [ICU] and hospital length of stay, ICU and hospital mortality) were collected by a dedicated APACHE III coordinator for all patients admitted to a tertiary academic surgical ICU (20 beds). Observational and comparative analyses were performed. Emergent repairs for ruptured aneurysms were excluded from the study. Forty-one patients underwent open elective repair of TAAA and 404 underwent open elective repair of AAA. Mean age of the TAAA group was 63.4 ± 9.8 years and the AAA group was 70.3 ± 8.3 years. Mean APACHE III score was 54 (range: 10-103) for the TAAA group and 45 (range: 11-103) for the AAA group. The in-hospital mortality rate for TAAA patients was 4.9% (n = 2) and for AAA patients was 2.0% (n = 8). Mean APACHE III scores on ICU admission were significantly greater in nonsurvivors versus survivors (79 vs. 45, p < 0.0001). For the entire patient cohort, the APACHE III score on ICU admission was an excellent discriminator of hospital mortality (receiver operating characteristic and area under the curve 0.92 [standard error of 0.05, 95% CI: 0.83-1.0]). APACHE III is an accurate predictor of survival to hospital discharge in both open elective TAAA and AAA repairs.
    Annals of Vascular Surgery 11/2010; 24(8):1060-7. · 0.99 Impact Factor
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    ABSTRACT: Introduction Le traitement endovasculaire des anévrysmes (EVAR) est de plus en plus utilisé au cours de la prise en charge des anévrysmes rompus de l’aorte abdominale (rAAA). L’utilisation de produit de contraste iodé lors d’EVAR pour rAAA présente plusieurs inconvénients, dont la néphropathie au produit de contraste, le risque allergique, et la nécessité d’une injection à haute pression. Nous évaluons l’utilisation du dioxyde de carbone (CO2) comme produit de contraste de première intention au cours du traitement endovasculaire des anévrysmes aortiques rompus. Méthodes De Décembre 2007 à Juillet 2009, nous avons revu rétrospectivement notre expérience concernant les patients ayant eu un traitement endovasculaire pour rAAA, utilisant le CO2 comme produit de contraste principal, et les comparions aux patients ayant eu EVAR avec un produit de contraste iodé. Résultats Quatre patients avaient le traitement endovasculaire d’un rAAA avec une artériographie au CO2 (groupe 1) et sept avec du produit de contraste iodé (groupe 2). L’âge moyen des patients n’était pas différent entre les deux groupes (p = 0,353). Les patients du groupe 1 recevaient 443 ± 99 mL de CO2 en moyenne et 4,3 ± 8,5 mL de produit de contraste iodé. Les patients du groupe 2 recevaient 110,2 ± 37,6 mL de produit de contraste iodé (p < 0,001). La mortalité globale n’était pas différente entre le groupe 1 (0,0%) et le groupe 2 (28,6%, p = 0,491). Chez les patients survivants à la sortie, les variations de créatininémie entre l’admission et la sortie étaient plus importantes dans le groupe 2, sans toutefois atteindre la significativité statistique (0,25 ± 0,19 mg/dL pour le groupe 1 vs. 0,58 ± 0,25 mg/dL pour le groupe 2, p = 0,066). Il n’y avait pas de différence concernant la durée de séjour entre le groupe 1 (soins intensifs, 1,00 ± 0,82 jours ; hôpital, 4,25 ± 0,96 jours) et le groupe 2 (soins intensifs, 3,60 ± 3,44 jours ; hôpital, 9,00 ± 6,60 jours). Conclusion Le traitement endovasculaire des rAAA utilisant le CO2 comme produit de contraste est techniquement faisable et sûre. Les bénéfices potentiels de l’artériographie au CO2 soutiennent la poursuite de son utilisation en cas d’anévrysme rompu. De nouvelles études sont nécessaires pour déterminer si l’utilisation de CO2 améliore la survie et limite la progression de la dysfonction rénale après traitement endovasculaire pour rAAA.
    Annales de Chirurgie Vasculaire. 10/2010; 24(7):919–925.
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    ABSTRACT: Endovascular aneurysm repair (EVAR) has become a common approach to the management of ruptured abdominal aortic aneurysms (rAAA). The use of iodinated contrast during EVAR for rAAA has several disadvantages, including contrast nephropathy, potential allergic response, and the need for high-pressure injection. We evaluated the use of carbon dioxide (CO(2)) as the primary contrast agent for endovascular repair of ruptured aortic aneurysms. Between December 2007 and July 2009, we retrospectively reviewed our experience with patients undergoing endovascular repair of rAAA, with CO(2)as the principal contrast agent, and compared them with patients who underwent EVAR using iodinated contrast. Four patients underwent endovascular repair of rAAA with CO(2) angiography (group 1) and seven with iodinated contrast (group 2). The mean age of the patients was not different between groups (p = 0.353). Patients in group 1 received a mean of 443 ± 99 mL of CO(2) and 4.3 ± 8.5 mL of iodinated contrast. Patients in group 2 received 110.2 ± 37.6 mL of iodinated contrast (p < 0.001). Overall mortality was not different between group 1 (0.0%) and group 2 (28.6%, p = 0.491). In patients who survived to discharge, the change in creatinine between admission and discharge was greater in group 2 although not statistically significant (0.25 ± 0.19 mg/dL for group 1 vs. 0.58 ± 0.25 mg/dL for group 2, p = 0.066). There was no significant difference in length of stay between group 1 (intensive care unit, 1.00 ± 0.82 days; hospital, 4.25 ± 0.96 days) and group 2 (intensive care unit, 3.60 ± 3.44 days; hospital, 9.00 ± 6.60 days). Endovascular repair of rAAA using CO(2) as a contrast agent is technically feasible and safe. The potential benefits of CO(2) angiography support the continued use of CO(2) in cases of ruptured aneurysms. Further studies are necessary to determine whether CO(2) improves survival and limits the progression of renal dysfunction after endovascular repair of rAAA.
    Annals of Vascular Surgery 10/2010; 24(7):845-50. · 0.99 Impact Factor
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    ABSTRACT: Paraneoplastic pemphigus is a rare cause of acute diffuse blistering in the adult patient. It commonly presents with subepidermal blistering, epidermal necrosis, and symptoms of mucosal irritation, such as conjunctivitis and vaginal ulceration. Because of its rarity, it is frequently misdiagnosed as Stevens-Johnson syndrome or toxic epidermal necrolysis. In this study, the authors will describe clinical and histologic manifestations of paraneoplastic pemphigus. This case report describes a 45-year-old woman with paraneoplastic pemphigus who was admitted and treated in a burn intensive care unit. Although initially diagnosed with Stevens-Johnson syndrome, the patient had progression of desquamation when potentially offending medications were discontinued. Diffuse adenopathy was noted on examination, and biopsy confirmed a low-grade lymphoma. Paraneoplastic pemphigus is a rare but important cause of acute diffuse blistering in adults. This disorder should be considered in the differential diagnosis of patients with diffuse blistering.
    Journal of burn care & research: official publication of the American Burn Association 08/2010; 31(5):826-9. · 1.54 Impact Factor
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    ABSTRACT: Objectif Aucune étude à notre connaissance n’a étudié la pertinence du score Acute Physiology and Chronic Health Evaluation (APACHE III) afin de prédire la mortalité des patients opérés d’une chirurgie ouverte d’un anévrysme de l’aorte thoraco-abdominale (ATA) ou abdominale (AAA). Les auteurs ont recherché à évaluer les scores APACHE III dans la prédiction de la mortalité post-opératoire dans le traitement électif des ATA et des AAA. Méthodes Sur une période de 9 ans (de juillet 1998 à juin 2007), les données prospectives (démographiques, diagnostic à l‘admission, score APACHE III, durée d’hospitalisation ou de séjour en unité de soins intensifs, mortalité hospitalière et en unité de soins intensifs) ont été collectées par un coordinateur désigné pour APACHE III pour tous les patients admis dans une unité de soins intensifs chirurgicale (20 lits). Des analyses comparatives et d’observation ont été effectuées. Les chirurgies en urgence pour rupture d’anévrysme ont été exclues de l’étude. Résultats 41 patients ont été opérés d’une chirurgie ouverte pour ATA et 404 pour AAA. L’âge moyen du groupe ATA était de 63,4 ans, ± 9,8 ans et de 70,3 ans pour le groupe AAA ± 8,3 ans. Le score APACHE III moyen était de 54 (10-103) pour le groupe ATA et de 45 (11-103) pour le groupe AAA. Le taux de mortalité hospitalière était de 4,9% pour le groupe ATA (n = 2) et de 2% pour le groupe AAA (n = 8). Le score APACHE III moyen était à l’admission en unité de soins intensifs bien plus important chez les survivants que chez les non-survivants (79 contre 45, p < 0,0001). Pour toute la cohorte des patients, le score APACHE III à l’admission en soins intensifs était un excellent facteur discriminatif de la mortalité hospitalière (courbe ROC et aire sous la courbe à 0,92 [erreur standard de 0,05, 95% IC : 0,83-1,0]). Conclusions le score APACHE III est un indicateur fiable de survie hospitalière dans la chirurgie des ATA et des AAA.
    Annales De Chirurgie Vasculaire. 01/2010; 24(8):1148-1155.
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    ABSTRACT: We hypothesize that endovenous laser ablation (EVA) therapy is equally successful in improving venous insufficiency symptoms in patients with or without deep venous insufficiency (DVI). From January 2005 through August 2007, EVA of the great saphenous vein (GSV) was attempted in 364 patients (460 limbs) with symptomatic GSV reflux. The GSV was successfully cannulated and obliterated in all but 17 limbs. EVA was performed alone in 308 limbs (69.5%) and with phlebectomy or perforator ligation (EVAP) in 135 limbs (30.5%). Venous clinical severity scores (VCSS) were recorded preoperatively and at 30, 90, 180, and 360 days postoperatively. Patients were classified as those with or without DVI based on duplex imaging valve closure times at the common femoral vein (CFV) and popliteal vein (PV). In a subset of 181 patients undergoing EVA therapy in the operating room, perioperative thrombosis prophylaxis was administered based on a risk-stratification protocol. Patients were assessed with direct end points (VCSS) and indirect end points (vein occlusion rates). Successful performance of EVA led to complete saphenous vein ablation in 99.8% at 1 month and 95.9% at 1 year. Median VCSS preoperatively was 6 (interquartile range, 5-8), generally decreasing over all time points to 4 (interquartile range, 2-5) beyond 360 days (P < .001). Male gender was independently associated with greater improvement in scores with time (P = .019). Changes in VCSS and duration of vessel occlusion were equivalent regardless of DVI for both isolated EVA and EVAP. For EVAP, the true deep venous thrombosis (DVT) rate was 2.2%, whereas for isolated EVA, the rate was 0% (P = .028); the rate of saphenofemoral thrombus extension was 5.9% for EVAP vs 7.8% for isolated EVA (P = .554). The use of risk-adjusted heparin prophylaxis in patients undergoing EVAP did not have a significant effect on thrombotic complications. There were no differences in true DVT, thrombus extension, or superficial thrombophlebitis between patients with or without DVI. Performance of concomitant phlebectomy, DVI, gender, and age had no effect on the duration of vessel occlusion. EVA produces successful ablation and is associated with sustained improvement in VCSS. These outcomes are independent of the presence of DVI. Finally, the use of a risk-adjusted thrombosis prevention protocol had no effect on the rate of superficial thrombus extension from EVA or EVAP in patients undergoing general anesthesia.
    Journal of vascular surgery: official publication, the Society for Vascular Surgery [and] International Society for Cardiovascular Surgery, North American Chapter 10/2008; 48(6):1538-45. · 3.52 Impact Factor
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    ABSTRACT: Iliac vein compression syndrome (IVCS) results from compression of the left iliac vein by the overlying right iliac artery against the pelvic brim. In many cases, patients are symptomatic. In symptomatic cases, management consists of angioplasty and stenting. Although therapy is often initially successful, factors associated with long-term outcome have been poorly defined. The purpose of this study was to identify factors associated with stent patency. The medical records of all patients who underwent iliac vein percutaneous transluminal angioplasty and stenting from January 1996 to December 2006 for symptomatic IVCS were reviewed retrospectively. There were 50 women and 8 men, with a mean age of 42 years (median, 39 years; range, 17-71 years). Primary, assisted primary, and secondary patency rates were determined. Patient characteristics and clinical variables were evaluated by univariate and multivariate analysis to determine association with vein patency. Symptoms consisted of lower extremity swelling (81%) and lower extremity pain (67%). Iliac vein obstruction was treated with pharmacologic thrombolysis (31% of patients) and mechanical thrombus fragmentation (17% of patients). The primary, assisted primary, and secondary patency rates of angioplasty/stenting were 74.1%, 79.7%, and 85.8% at 1 year and 38.1%, 62.8%, and 73.8% at 5 years, respectively. Using a Cox proportional risk model, male sex (hazard ratio, 6.5; P = .001), recent trauma (hazard ratio, 5.3; P = .001), and age younger than 40 years (hazard ratio, 3.8; P = .015) were associated with decreased primary patency. In the absence of any risk factors, primary patency was 94.4% at 1 year and 63.0% at 5 years, decreasing to 28.6% and 0% for two or more risk factors. Patency rates for iliac vein percutaneous transluminal angioplasty and stenting in patients with IVCS can potentially be predicted on the basis of a multivariate model. Assessing risk factors allows for patient stratification and appropriate clinical decision making. Prospective validation of these variables is necessary.
    Journal of Vascular Surgery 11/2007; 46(4):743-749. · 2.88 Impact Factor
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    ABSTRACT: Despite recent advances, reported mortality rates after repair for acute type A aortic dissection vary from 5% to 30%. This study was conducted to assess cross-sectional mortality after operative repair of type A dissection in the United States, and to determine whether a volume-outcome relationship exists for this operative procedure. Data were obtained from the Nationwide Inpatient Sample, which is a cross-sectional administrative database incorporating 20% of all annual US hospital discharges. From 1995 to 2003, a cohort of 3013 patients with thoracic or thoracoabdominal dissection who underwent aortic resection was identified. Patient demographics, hospital volumes, and teaching status were included as independent variables. The mean age was 62 +/- 14 years (65% male). In-hospital mortality for the study period was 26%, but it decreased from 27% in 1995 to 23% in 2003 (P = .03). A significant correlation was found between procedural volume and mortality (P < .001). By multivariate analysis, independent predictors of mortality included increasing age (P < .0001) and operation at a non-teaching hospital (P = .002). Operative mortality for repair of ascending aortic dissection in the United States has shown modest temporal improvements. More importantly, operative mortality seems to be dependent on the arena of care.
    Surgery 10/2007; 142(4):524-8; discussion 528.e1. · 3.37 Impact Factor
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    ABSTRACT: Trends in the management of renovascular hypertension were evaluated by using a representative national database to determine whether a shift in treatment technology and outcomes has occurred. Clinical information regarding the treatment of renovascular hypertension in 5433 patients from 1988 to 2001 was derived from the Nationwide Inpatient Sample (NIS) database. Patients were classified into 3 groups: combined aortic and renal revascularization, isolated renal revascularization, and catheter-based procedures (angioplasty with or without stenting). Population-based trends were determined by using sampling weights for each year to estimate the total number of each intervention in the United States. Outcomes were compared using multivariate logistic regression analysis for risk-adjustment. A 73% decrease in combined aortic and renal revascularizations ( P = .033) and a 56% decrease in isolated renal revascularizations ( P < .001) occurred during the study period. Catheter-based procedures have increased 173% from 0.4 to 1.1 procedures per 100,000 adults during this same time period ( P < .001). Predictors favoring catheter-based treatment were admission acuity, increasing age, nonwhite race, and high socioeconomic status. Predictors of mortality for all 3 treatment groups included increasing age, emergent admission, and nonwhite race. A significant change in the management of patients with renovascular hypertension has occurred, with a shift towards less invasive catheter-based interventions. A better understanding of the diffusion of this technology in the treatment of individuals with renovascular hypertension will influence the training and distribution of future vascular specialists responsible for these patients.
    Journal of Vascular Surgery 10/2004; 40(4):717-23. · 2.88 Impact Factor
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    ABSTRACT: To determine the mechanism underlying increased expression and activity of matrix metalloproteinase 9 (MMP-9) by rat aortic smooth muscle cells (RA-SMC) after inhibition of inducible nitric oxide synthase (iNOS). Treatment of interleukin-1beta-stimulated RA-SMC with aminoguanidine led to an increase of 96% in MMP-9 activity (P = 0.003) by gelatin zymography, a 40% increase in pro-MMP-9 protein (P = 0.018) by Western blot, and a 155% increase in MMP-9 mRNA (P = 0.06) by reverse transcription polymerase chain reaction. Aminoguanidine also caused a 26% decrease in cytosolic IkappaB levels (P = 0.014) by Western blot, as well as a 97% increase in nuclear factor-kappaB binding and a 216% increase in activator protein-1 binding as measured by electrophoretic mobility shift assay. No significant changes were noted in MMP-2 or TIMP-1 expression, protein levels, or activity after aminoguanidine administration. MMP-9 expression and activity is increased in cytokine stimulated RA-SMCs after iNOS inhibition, coincident with activation of the nuclear factor-kappaB and activator protein-1 pathways. We speculate that local derangements in iNOS may favor MMP-9-dependent vessel wall damage in vivo via an inflammatory cascade mechanism.
    Journal of Surgical Research 02/2004; 116(1):70-80. · 2.02 Impact Factor
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    ABSTRACT: Objective To determine the mechanism underlying increased expression and activity of matrix metalloproteinase 9 (MMP-9) by rat aortic smooth muscle cells (RA-SMC) after inhibition of inducible nitric oxide synthase (iNOS).
    Journal of Surgical Research - J SURG RES. 01/2004; 116(1):70-80.
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    ABSTRACT: Neutrophil influx is one of the first events in a formed deep venous thrombosis (DVT), but whether these cells are active participants in the resolution process is not clear. This study tests the hypothesis that neutrophils (PMN) are active participants in DVT resolution. Thrombosis was induced by inferior vena caval (IVC) ligation in male Sprague-Dawley rats, and rats were sacrificed at 2, 4, or 7 days for evaluation of the thrombus. Neutropenia was induced by rabbit anti-rat PMN serum, and controls received rabbit serum. Venography was performed at the 7-day time point. Immunohistochemical staining was performed to quantify intrathrombus PMNs and monocytes, and the myeloperoxidase (MPO) assay was performed to assess intrathrombus neutrophil activity. Intrathrombus concentrations of kerotinocyte cytokine (KC), macrophage inflammatory protein-2 (MIP-2), gamma interferon inducible protein-10 (IP-10), macrophage inflammatory protein-1 alpha (MIP-1 alpha), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor (TNF)-alpha were quantified by enzyme immunoassay at each time point and normalized to total protein. Total collagen was determined at day 7. Peripheral blood smears showed a 94% PMN reduction at 2 days (P <.05), recovering to 44% of control at 7 days. Intrathrombus PMNs were significantly lower in neutropenic rats at 2 and 4 days, but there were no differences in intrathrombus monocytes. The MPO assay confirmed reduced neutrophil activity at 4 days. Thrombi from neutropenic rats were larger at 2 and 7 days compared with controls. In vivo thrombus area at 7 days as assessed by venography was also greater in neutropenic rats as compared with controls. The intrathrombus KC concentration was increased more than 20-fold in the neutropenic rats at 2 days, but there were no significant differences in other intrathrombus chemokines. Finally, intrathrombus collagen was increased over threefold in neutropenic rats as compared with controls. Neutropenia impairs DVT resolution by several measures, most likely by altering normal fibrinolytic activity and thrombus collagen turnover.
    Journal of Vascular Surgery 11/2003; 38(5):1090-8. · 2.88 Impact Factor
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    ABSTRACT: This investigation was undertaken to evaluate transabdominal ultrasound (US) measurements of aortic diameters in rats and mice as a complementary method to video microscopy (VM), the current standard for assessing the diameter of rodent aortas. Aortic diameters were measured in 64 rats (n = 132 sets) and 12 mice (n = 36 sets) following experimental induction of aortic aneurysms. Diameters were measured at the renal vein, midinfrarenal aorta, and aortic bifurcation. In the rat, anteroposterior (AP) US measurements were closely correlated with transverse VM measurements, with correlation coefficients ranging from 0.66 to 0.77 (P < 0.0001) for axial US images and 0.58 to 0.63 (P < 0.0001) for sagittal US images. In the mouse, significant correlation coefficients were 0.57 (P < 0.001) near the renal vein and 0.44 (P = 0.007) at the midinfrarenal aorta. Aortic diameters increased significantly with increasing animal age and weight (R = 0.40, P = 0.003 at the renal vein, R = 0.29, P = 0.04 in the midinfrarenal aorta, and R = 0.39, P = 0.004 at the aortic bifurcation), suggesting that weight matched rodents must be used to define aortic dimensions in treatment groups as opposed to repeated comparisons with baseline measurements in a growing rat. Noninvasive aortic US measurements throughout the course of a rodent study of aneurysmal disease provide a practical alternative to VM for the repeated determinations of aortic diameters.
    Journal of Surgical Research 06/2003; 112(1):97-101. · 2.02 Impact Factor
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    ABSTRACT: This investigation was undertaken to determine whether intrinsic or regional factors at different anatomic sites of the aorta affect expression and activity of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Aortas from Sprague-Dawley rats (n = 22) were divided into arch, descending thoracic, and infrarenal abdominal segments. Specimens were stimulated with interleukin-1beta (IL-1beta) (2 ng/mL) for 72 hours. In separate experiments, syngeneic aortic segments were transplanted from the thoracic or abdominal aortas of donor rats into the infrarenal aortic position of recipient rats (n = 12 each). At 4 weeks, aortas from rats who had received transplants were harvested, sectioned into arch, thoracic, and transplanted thoracic or transplanted abdominal segments, and stimulated with IL-1beta. Reverse transcriptase polymerase chain reaction, zymography, and reverse zymography were performed to assess MMP-9, MMP-2, and TIMP-1 in all aortic segments. Differences were assessed with analysis of variance (ANOVA) and post-hoc Tukey test. In control rats, abdominal segments had significantly higher MMP-9 expression compared with arch and thoracic segments (P <.002). Total MMP-9 activity was also higher in abdominal segments (P <.02). In rats who received transplants, transplanted thoracic (P <.004) and transplanted abdominal (P <.05) segments demonstrated upregulation of MMP-9 expression, compared with control arch and thoracic segments. Zymography documented increased total MMP-9 activity in transplanted thoracic (P <.03) and transplanted abdominal (P <.04) segments versus arch and thoracic segments. No significant difference in MMP-9 expression was found between control abdominal, transplanted thoracic, or transplanted abdominal segments. No significant differences in MMP-2 or TIMP-1 expression or activity were demonstrated in either control or transplanted segments. These data demonstrate that variations in aortic MMP-9 expression and activity result from regional factors affecting the aorta rather than intrinsic aortic wall differences. Increases in abdominal aortic MMP-9 may contribute to the predilection for aneurysm to develop in the infrarenal aorta.
    Journal of Vascular Surgery 06/2003; 37(5):1059-66. · 2.88 Impact Factor
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    ABSTRACT: The purpose of this study was to quantify the fibrin content of thrombi produced in a mouse model of venous thrombosis and correlate this to thrombus mass. The role of P-selectin, E-selectin, and IL-10 on thrombus fibrin content was analyzed using knockout (KO) mice. Five groups of mice were evaluated: control (N = 10), P-selectin KO (N = 7), E-selectin KO (N = 5), combined E-/P-selectin KO (N = 12), and IL-10 KO (N = 10). Venous thrombosis was induced by ligation of the infrarenal IVC. Mice were sacrificed on postoperative days (POD) 2 and 6. Thrombus mass was calculated. Sections of IVC were stained with an antibody that cross reacts with mouse fibrin. The distribution of RGB color pixels was generated from digitized micrographs of the thrombus of each animal. The mean pixel value for each group was compiled and analyzed using 2-way ANOVA. Mean pixel value per group was correlated with the mean thrombus mass per group. Color analysis demonstrated significant decreases in the analyzed fibrin content on POD-2 between the control vs E-/P-selectin KO (P < 0.05) and control vs IL-10 KO (P < 0.05) groups. In addition, significantly less fibrin staining was noted on POD-6 between the control vs E-selectin KO (P = 0.03), control vs P-selectin KO (P = 0.01), and control vs E-/P-selectin KO (P < 0.01). There was a strong overall correlation between the mean pixel value for each group and the thrombus mass (R = 0.964; P < 0.01). This study demonstrates a difference in fibrin content of thrombi produced in animals deficient in E-selectin, P-selectin, and IL-10, supporting their importance in thrombus amplification, fibrin formation, and the mass of thrombus formed.
    Journal of Surgical Research 02/2003; 109(1):1-7. · 2.02 Impact Factor
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    ABSTRACT: The purpose of this study was to compare the efficacy of P-selectin inhibition with standard anticoagulant and thrombolytic therapy in a rodent model of established deep vein thrombosis (DVT). Rats underwent temporary inferior vena cava (IVC) ligation for 2 days to create a stasis-induced thrombosis. On day 2, the animals had the IVC ligature removed and received either recombinant P-selectin glycoprotein ligand-Ig (rPSGL-Ig; 4 mg/kg) intravenously, low-molecular weight heparin (LMWH; 450 IU/kg) subcutaneously, tissue plasminogen activator (tPA; 0.5 mg/kg) intravenously, combination rPSGL-Ig plus tPA, or saline vehicle. IVC segments were harvested from rats at 4 (n = 8) and 7 (n = 3) days after treatment. All treatments were given as a single dose except for daily LMWH. Evaluation included contrast venography with computer image analysis, thrombus weight/length (mass), vein wall leukocyte counts, cytokine and tissue factor analysis with enzyme-linked immunosorbent assay, and (ED1) monocyte immunohistochemical staining. Collagen was estimated with a quantitative assay. Contrast venography revealed that rats with both rPSGL-Ig and tPA treatment had significantly smaller thrombi as compared with controls at day 7 (0.34 +/- 0.07 cm(2) and 0.34 +/- 0.05 cm(2) versus 0.68 +/- 0.13 cm(2); P <.05). LMWH and tPA groups had significantly decreased thrombus mass at harvest compared with controls on day 4 (0.06 +/- 0.009 g/cm and 0.08 +/- 0.01 g/cm versus 0.1 +/- 0.005 g/cm; P <.05), and rPSGL-Ig showed a similar trend (P =.072). Vein wall, but not thrombus, monocytes were more numerous in those rats receiving rPSGL-Ig versus controls at day 4 (30 +/- 4 cells/5 high power fields [HPFs] versus 19 +/- 2 cells/5 HPFs; P <.05) and at day 7 (32 +/- 2 cells/5 HPFs versus 20 +/- 3 cells/5 HPFs; P <.05). rPSGL-Ig treatment was associated with significantly reduced vein wall collagen at day 7 versus controls (1.3 +/- 0.6 pg/mg versus 3.7 +/- 0.5 pg/mg; P <.05) and a trend toward lower tissue factor levels. rPSGL-Ig, LMWH, and tPA showed equal DVT resolution efficacy over 7 days. However, only rPSGL-Ig was associated with a decrease in vein wall fibrosis, suggesting that purely accelerating DVT resolution may not decrease long-term vein scarring.
    Journal of Vascular Surgery 12/2002; 36(5):928-38. · 2.88 Impact Factor
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    ABSTRACT: We tested the hypothesis that a venous thromboembolism to the pulmonary arterial system (pulmonary embolism [PE]) would cause an inflammatory response within the pulmonary arterial (PA) wall marked by elevated cytokines and chemokines and an influx of inflammatory cells. Experimental PE was induced in 70 rats and confirmed with angiography and O(2) saturation depression, and an additional 70 rats underwent sham operations. PA and lung tissue were removed at 3 hours and at 1, 2, 4, 6, 8, and 14 days (n = 10 per time point), were analyzed for proinflammatory cytokines and chemokines, and underwent histologic analysis. Data were analyzed with analysis of variance and the unpaired Student t test. Average gross PE resolution was 40% at 2 days, 90% at 4 days, and 100% at 6 days. Only monocyte chemoattractant protein-1 levels were greater in affected PAs compared with sham PAs at 3 hours, 1 day, and 2 days (137 +/- 13 pg/mg protein, 285 +/- 40 pg/mg protein, and 249 +/- 36 pg/mg protein versus 101 +/- 6 pg/mg protein, 150 +/- 36 pg/mg protein, and 92 +/- 3 pg/mg protein; P <.01 for all). Keratinocyte-derived chemokine, tissue necrosis factor, interleukin-10, nitric oxide, P-selectin, and E-selectin levels were not elevated. Neutrophils infiltrated the PA wall beginning at 3 hours, peaked at 2 days (69.4 +/- 21.7 per five high-power fields; P <.01), and returned to baseline by 8 days after PE. Macrophages peaked at 1 day after PE (29.3 +/- 6.9; P <.01) and returned to baseline by 4 days after PE. PE also was associated with a significantly increased intima to media ratio (P <.05), apparent at 4 days after PE and persisting through 14 days. PE is associated with an early influx of polymorphonuclears and macrophages and monocyte chemoattractant protein-1 elevation within the PA wall. These are temporally associated with thrombus resolution and intimal hyperplasia. These factors may mediate these two processes after PE. This offers targets for further study with the hopes of minimizing the pathophysiologic response to PE.
    Journal of Vascular Surgery 10/2002; 36(3):581-8. · 2.88 Impact Factor
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    ABSTRACT: Deep venous thrombosis (DVT), and its sequela, pulmonary embolism (PE), is the leading cause of preventable in-hospital mortality in the USA and other developed countries. After it is detected, acute clots must be differentiated from chronic DVT for appropriate treatment. However, there are no reliable thrombus staging methods presently available in clinical practice. In this study, we tested the hypothesis that blood clots can be detected and staged using a triplex ultrasound (US) test. Triplex US is based on a "gold standard" duplex US technique augmented by US-based reconstructive elasticity imaging. Fibrin-composed blood clots harden with development and organization. By imaging clot elasticity, it may be possible to both detect and differentiate clots and, therefore, provide an urgently needed noninvasive means of DVT staging.
    Ultrasound in Medicine & Biology 07/2002; 28(6):757-67. · 2.46 Impact Factor
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    ABSTRACT: This investigation was designed to determine whether differences in vasoreactivity occur in patients with abdominal aortic aneurysms (AAAs) as compared with patients with peripheral arterial occlusive disease (PAOD) or individuals (controls) without known vascular disease. Brachial artery vasoreactivity was assessed in a blinded fashion, after endothelium-dependent (ED) and endothelium-independent (EI) flow-mediated vasodilation, in age-matched, male patients with AAAs (n = 11) or PAOD (n = 9) or in controls (n = 10). There were no significant differences in prestudy systolic or diastolic blood pressure, body mass index, or antilipidemic medications among the groups studied. Exclusion criteria included diabetes and tobacco use within 3 months. Quantitative ultrasound scan measurements of brachial artery diameters were performed at rest and after either forearm ischemia (ED) or administration of 0.4 mg sublingual nitroglycerin (EI). Plasma nitric oxide (NO(X) = NO(2) + NO(3)) was measured with the Saville assay. Asymmetric dimethylarginine, an endogenous inhibitor of NO(X) synthase, was measured with liquid chromatography. Initial brachial artery diameters were not significantly different among the groups studied (4.85 +/- 0.18 mm for AAA group, 4.82 +/- 0.17 mm for PAOD group, 4.68 +/- 0.20 mm for controls). ED and EI vasodilation was significantly less (P =.02 and.03, respectively) in the AAA group (-1.71 +/- 1.52 and 8.33 +/- 1.13, respectively) when compared with the controls (2.96 +/- 1.04 and 13.88 +/- 2.16, respectively). However, plasma NO(X) was significantly increased (P =.01) in the AAA group (7.86 +/- 0.85 micromol/L) as compared with both controls (5.13 +/- 0.63 micromol/L) and PAOD (4.85 +/- 0.46 micromol/L). Asymmetric dimethylarginine levels were decreased in the AAA group (0.34 +/- 0.05 micromol/L) as compared with the PAOD group (0.46 +/- 0.09 micromol/L). No correlation existed between aneurysm size and ED or EI vasodilation or plasma NO(X). This study is the first to document a divergence between ED and EI vasoreactivity and systemic NO metabolites in patients with AAAs. It is speculated that a dysfunctional vessel wall response, rather than a lack of NO, may be important in the pathogenesis of AAAs.
    Journal of Vascular Surgery 03/2002; 35(2):363-7. · 2.88 Impact Factor
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    ABSTRACT: Objective: We tested the hypothesis that a venous thromboembolism to the pulmonary arterial system (pulmonary embolism [PE]) would cause an inflammatory response within the pulmonary arterial (PA) wall marked by elevated cytokines and chemokines and an influx of inflammatory cells. Methods: Experimental PE was induced in 70 rats and confirmed with angiography and O2 saturation depression, and an additional 70 rats underwent sham operations. PA and lung tissue were removed at 3 hours and at 1, 2, 4, 6, 8, and 14 days (n = 10 per time point), were analyzed for proinflammatory cytokines and chemokines, and underwent histologic analysis. Data were analyzed with analysis of variance and the unpaired Student t test. Results: Average gross PE resolution was 40% at 2 days, 90% at 4 days, and 100% at 6 days. Only monocyte chemoattractant protein-1 levels were greater in affected PAs compared with sham PAs at 3 hours, 1 day, and 2 days (137 ± 13 pg/mg protein, 285 ± 40 pg/mg protein, and 249 ± 36 pg/mg protein versus 101 ± 6 pg/mg protein, 150 ± 36 pg/mg protein, and 92 ± 3 pg/mg protein; P < .01 for all). Keratinocyte-derived chemokine, tissue necrosis factor, interleukin-10, nitric oxide, P-selectin, and E-selectin levels were not elevated. Neutrophils infiltrated the PA wall beginning at 3 hours, peaked at 2 days (69.4 ± 21.7 per five high-power fields; P < .01), and returned to baseline by 8 days after PE. Macrophages peaked at 1 day after PE (29.3 ± 6.9; P < .01) and returned to baseline by 4 days after PE. PE also was associated with a significantly increased intima to media ratio (P < .05), apparent at 4 days after PE and persisting through 14 days. Conclusion: PE is associated with an early influx of polymorphonuclears and macrophages and monocyte chemoattractant protein-1 elevation within the PA wall. These are temporally associated with thrombus resolution and intimal hyperplasia. These factors may mediate these two processes after PE. This offers targets for further study with the hopes of minimizing the pathophysiologic response to PE. (J Vasc Surg 2002;36:581-8.)
    Journal of Vascular Surgery - J VASC SURG. 01/2002; 36(3):581-588.