Images in vascular medicine. Atypical aortic coarctation.
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Biomedical subjects
Andrzej Szuba
Publications and source records attributed to Andrzej Szuba.
Density of intranodal lymphatics and VEGF-C expression in B-cell lymphoma and reactive lymph nodes.
Lymphatic vasculature in solid tumors may serve as the pathway for metastatic spread of the cancer to the regional lymph nodes and to distant organs. Controversy still exists whether tumors metastasize through existing lymphatics or through newly formed vessels (lymphangiogenesis). The role of lymphangiogenesis in lymphoma spread and proliferation is not clearly established. VEGF-C is the most potent inducer of lymphangiogenesis. LYVE-1 was shown to be a specific marker for lymphatic vessels in normal and tumor tissue. The aim of the present study was the evaluation of lymph node LYVE-1-positive lymphatic sinus density (LSD) and VEGF-C expression in patients with non-Hodgkin's lymphoma (nHL) and in reactive lymph nodes. Sixty paraffin-embedded lymph nodes from newly diagnosed patients with B-cell nHL were evaluated. Twelve lymph node biopsy specimens from adult patients with reactive lymphonodulitis were used as controls. Sections of lymph nodes were stained immunohistochemically for LYVE-1 and VEGF-C. VEGF-C expression in lymph nodes of nHL patients was low and not significantly different from that in the control (p = 0.6). Moreover, VEGF-C expression did not differ significantly between aggressive and indolent lymphomas (p = 0.53). Similarly we did not find differences in LSD in aggressive nHL and in indolent nHL (p=0.49). The mean LSD in reactive lymph nodes was higher than in nHL (p = 0.03). Only in 2 out of 12 reactive lymph nodes LYVE-1-positive vessels were absent. In all groups we demonstrated a strong positive correlation between VEGF-C and LYVE-1-expression (p = 0.0001). Higher LSD in reactive lymph nodes as compared to those of nHL patients suggests that lymphoma proliferation leads to the destruction of the existing lymphatics rather than to lymphangiogenesis within lymph nodes. NHL are not associated with increased expression of VEGF-C nor increased LYVE-1-positive lymphatic sinuses density within lymph nodes.
Adult↗
Abnormal cardiovascular response to exercise in patients with peripheral arterial disease: Implications for management.
Exercise is beneficial in improving claudication and functional capacity in patients with peripheral arterial disease (PAD). However, the physiologic response during and after exercise testing in this patient population has not been fully described. This study examined the cardiovascular response to exercise and explored the potential contribution of vascular noncompliance to exercise-induced hypertension in 124 patients with PAD and claudication and 31 comparison (C) patients with PAD with no walking limitations. Maximal walking distance was determined by an exercise treadmill test. Heart rate and blood pressure were monitored before, during, and immediately after an exercise test. Vascular compliance of the small and large vessels was measured using pulse waveform analysis. Individuals with low supine resting heart rate had longer pain-free walking distance (r = -0.195, P = .019) and maximal walking versus the C group (62 beats/min, standard deviation [SD] = 10, P = .02). Systolic blood pressure during supine rest was significantly lower for the PAD group (mean = 141 mm Hg, +/- SD = 22) versus the C group (mean = 153 mm Hg, +/- SD = 20, P = .003). Vascular compliance of large vessels was higher in the C group (mean = 4.13 +/- 4.13 mL/mm Hg x 100) compared with the PAD group (mean = 2.95 +/- 1.6 mL/mm Hg x 100). This study describes the exaggerated exercise cardiovascular response and impaired vascular compliance in patients with PAD. These results provide further evidence supporting the importance of a monitored treadmill exercise test before initiation of an exercise program to ensure safe and accurate exercise recommendations, and to identify individuals that require more intensive pharmacotherapy to prevent exercise-induced hypertension and tachycardia.
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Literature watch. The addition of manual lymph drainage to compression therapy for breast cancer related lymphedema: a randomized controlled trial.
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Bandages↗
Suboptimal intensity of risk factor modification in PAD.
This study extends earlier trials indicating that atherosclerosis risk factors are underdetected and undertreated in peripheral arterial disease (PAD) patients. Recognition and treatment of hyperlipidemia and hypertension in PAD patients is suboptimal. Diabetes appears to be detected more frequently although glycemic control is still suboptimal. The use of antiplatelet therapy is particularly underutilized. Additionally, despite the demonstrated efficacy of regular exercise in PAD patients, almost half of the study sample was sedentary. Approximately one third of the current study sample was overweight and nearly one third was obese by ATP-III guidelines. Only 31% of subjects were taking dietary measures to improve their cardiovascular health, and even fewer were physically active. To rectify suboptimal management of risk factors, there is a need for increased public awareness of PAD, reimbursement and implementation of screening programs and more aggressive treatment. Future studies are needed to examine innovative interventions for identification and management of cardiovascular risk factors in patients with PAD.
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A pilot study of L-arginine supplementation on functional capacity in peripheral arterial disease.
Peripheral arterial disease (PAD) impairs walking capacity and is often associated with a profound endothelial vasodilator dysfunction, characterized by reduced bioactivity and/or synthesis of endothelium-derived nitric oxide (NO). Previous studies have suggested that dietary supplementation of L-arginine, the precursor of NO, improves endothelium-dependent vasodilation, limb blood flow and walking distance. However, these studies have been small, and have used large intravenous doses of L-arginine. The optimal dose of L-arginine has not been determined. Accordingly, this pilot study was conducted to establish the lowest effective oral dose of L-arginine to improve walking distance in preparation for the definitive study. Patients with PAD and intermittent claudication (n = 80) participated in this study. Eligibility criteria included: (1) ankle-brachial index (ABI) at rest < or = 0.90; (2) post-exercise reduction in ABI > or = 25%; and (3) difference in absolute claudication distance of < or = 25% between two consecutive treadmill tests. Treadmill testing was performed using the Skinner-Gardner protocol and community-based walking was assessed using the walking impairment questionnaire. Patients were randomly assigned to oral doses of 0, 3, 6 or 9 g of L-arginine daily in three divided doses for 12 weeks. Treadmill testing was performed prior to administration of the study drug and again after 12 weeks of treatment. The study drug was well tolerated, with no significant adverse effects of L-arginine therapy. The safety laboratory studies were unremarkable, except for a statistically significant reduction in hematocrit in the L-arginine-treated groups. There was no significant difference observed in absolute claudication distance between the groups. However, a trend was observed for a greater increase in walking distance in the group treated with 3 g L-arginine daily, and there was a trend for an improvement in walking speed in patients treated with L-arginine. This pilot study provided data for safety, for power calculation and for dosing for the larger definitive trial that is now underway.
Administration, Oral↗
[Effect of metals, benzene, pesticides and ethylene oxide on the haematopoietic system].
The hematopoietic system, due to intensive cells proliferation, is very sensitive to toxic substances. Many chemicals, including benzene, pesticides (dithiocarbamines), ethylene oxide and metals (mercury, cadmium, chrome, cobalt, lead, aluminum) exert their toxic effect on the hematopoietic system. Exposure to each of these substances may occur in the work place due to environmental pollution and in municipal or residential areas. Exposure to lead, aluminum, cadmium, and benzene results in the incidence of anemia. In addition, exposure to benzene and its metabolites leads to myelodysplastic syndromes, leukemia, lymphomas and bone marrow aplasia. Ethylene oxide induces neoplasm of the hematopoietic system and lymphomas, especially non-Hodgkin lymphoma. Arsenic compounds act like immunosuppressants. Mercury and chrome affect the immune system by immunosuppression and by evoking autoimmune reactions. Dithiocarbamates are suspected to induce leukemia. An analysis of the pathophysiology of individual substances reveal universal toxic mechanisms. In this paper, the authors discuss the pathomechanism of toxic effects of the aforesaid chemicals on the haematopoietic system and peripheral blood cells from the viewpoint of mutagenesis, apoptosis, myelotoxicity, anemia, immunomodulation, and individual sensitivity.
Benzene↗
Exercise patterns and cardiovascular fitness of patients with peripheral arterial disease.
Peripheral arterial disease (PAD) is characterized by walking impairment as the result of claudication, which is improved by exercise. Few studies have examined the impact of existing exercise patterns in community-dwelling patients with PAD on cardiovascular fitness and absolute claudication distance (ACD). This descriptive study examines exercise patterns, walking distance, and cardiovascular fitness in a sample of community-dwelling older adults with PAD. Approximately 50% of subjects reported walking 4 (+/-2) days per week for 38 +/- 24 minutes. ACD (exercisers = 459.9 +/- 272; non-exercisers = 351.2 +/- 266.3, P = .06) and initial claudication distance (exercisers = 198.5 +/- 139.7; non-exercisers = 138.7 +/- 95.8 P = .02) were similar between groups. The workload accomplished was approximately 4.1-4.7 metabolic equivalents. Resting heart rate (HR) was associated with initial claudication distance ( r = -.37, P = .001) and ACD ( r = -.46, P < .01) and was lower in the group of exercisers versus the non-exercisers ( P = .05). Mean resting SBP was elevated and continued to increase at peak exercise with no difference between groups ( P = .75). Quality of life was poor for both groups. Simultaneous multiple regression analysis was performed to determine predictors of peak exercise HR. The model included gender, age, current exercise, ankle-brachial index, coronary artery disease, beta blockers, ACD, and atrial fibrillation (R = 44%, P = .01). Higher peak exercise HR was associated with older age, female gender, no beta blockers, and greater ACD ( P < .01). The findings from this descriptive study demonstrate the need for larger long-term studies to address issues of exercise adherence and the psychologic and functional benefits of exercise.
Activities of Daily Living↗
Oral administration of L-arginine decreases necrosis of the epigastric skin flap in the rat.
BACKGROUND: We investigated the effect of prolonged oral arginine administration on tissue necrosis and perfusion in the rat skin flap. METHODS: Twenty-five Sprague-Dawley rats had an 8 x 8 - cm epigastric skin flap elevated and were divided in 2 groups, l-Arginine and Control, which respectively received oral 6% l-arginine solution or water for 8 days postoperatively. On postoperative day 8, area of flap necrosis was measured, and the animals were perfused systemically with 15-microm colored fluorescent microspheres before (blue) and after (yellow-green) ligation of the flap pedicle. RESULTS: l-Arginine reduced total flap necrosis (6.53 +/- 3.76 cm versus 11.91 +/- 4.12 cm; P < 0.01). After pedicle ligation, total flap perfusion remained unchanged in Control but diminished in the l-Arginine group (Control: 0.47 +/- 0.23 and 0.42 +/- 0.06; P = nonsignificant versus l-Arginine: 0.58 +/- 0.29 and 0.27 +/- 0.19; P < 0.01). Serum levels of l-arginine were higher in the l-arginine-treated animals (504 +/- 154 versus 152 +/- 34 micromol/l; P < 0.0001). CONCLUSIONS: Postoperative oral administration of l-arginine decreased flap necrosis in the rat epigastric skin flap. Flap perfusion following oral l-arginine was more dependent on the main vascular pedicle.
Administration, Oral↗
Predictors of physical function in patients with peripherial arterial disease and claudication.
Limitation of walking due to claudication is the hallmark of peripheral arterial disease. The purpose of this secondary analysis was to identify biobehavioral predictors of physical function in peripheral arterial disease patients that included walking ability, gender, age, disease severity, environmental factors (social support), and medical comorbidity (arthritis). All subjects performed an exercise treadmill test to determine initial and absolute claudication distance. The sample consisted of 97 peripheral arterial disease patients, 71 (73%) men and 26 (27%) women, with a mean age of 73+/-8 years (range 52-90 years). Initial claudication distance occurred at 171.88+/-136.35 m. Absolute claudication distance was 421.03+/-286.37 m. A simultaneous multiple regression analysis was performed to determine predictors of physical function. The model accounted for 35% of the variance (p<0.001) and included personal characteristics (age, gender, years of education), severity of disease by ankle-brachial index, environmental factors of social support (marital status), absolute claudication distance, and arthritis. Education (p=0.011), absolute claudication distance (p=0.014), social support (p=0.026), arthritis (p=0.028), and age (p=0.033) were the strongest predictors of physical function. This study identifies biobehavioral factors that place peripheral arterial disease patients at greater risk for reduced physical function and provides a rationale for interventions that improve walking ability.
Activities of Daily Living↗
Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine.
BACKGROUND: Endothelial function is impaired by hyperhomocyst(e)inemia. We have previously shown that homocyst(e)ine (Hcy) inhibits NO production by cultured endothelial cells by causing the accumulation of asymmetric dimethylarginine (ADMA). The present study was designed to determine if the same mechanism is operative in humans. METHODS AND RESULTS: We studied 9 patients with documented peripheral arterial disease (6 men; 3 women; age, 64+/-3 years), 9 age-matched individuals at risk for atherosclerosis (older adults; 9 men; age, 65+/-1 years), and 5 young control subjects (younger adults; 5 men; age, 31+/-1 years) without evidence of or risk factors for atherosclerosis. Endothelial function was measured by flow-mediated vasodilatation of the brachial artery before and 4 hours after a methionine-loading test (100 mg/kg body weight, administered orally). In addition, blood was drawn at both time points for measurements of Hcy and ADMA concentrations. Plasma Hcy increased after the methionine-loading test in each group (all, P<0.001). Plasma ADMA levels rose in all subjects, from 0.9+/-0.2 to 1.6+/-0.2 micromol/L in younger adults, from 1.5+/-0.2 to 3.0+/-0.4 micromol/L in older adults, and from 1.8+/-0.1 to 3.9+/-0.3 micromol/L in peripheral arterial disease patients (all, P<0.001). Flow-mediated vasodilatation was reduced from 13+/-2% to 10+/-1% in younger adults, from 6+/-1% to 5+/-1% in older adults, and from 7+/-1% to 3+/-1% in peripheral arterial disease patients (all, P<0.001). Furthermore, we found positive correlations between plasma Hcy and ADMA concentrations (P=0.03, r=0.450), as well as ADMA and flow-mediated vasodilatation (P=0.002, r=0.623). CONCLUSIONS: Our results suggest that experimental hyperhomocyst(e)inemia leads to accumulation of the endogenous NO synthase inhibitor ADMA, accompanied by varying degrees of endothelial dysfunction according to the preexisting state of cardiovascular health.
Adult↗
Animal models for the study of lymphatic insufficiency.
Lymphedema is the term commonly employed to describe the spectrum of pathological states that arise as a consequence of functional lymphatic insufficiency. These human disease entities currently lack an effective cure. Satisfactory therapeutic strategies for both primary and secondary lymphedema will require additional insight into the complex cellular mechanisms and responses that comprise both normal lymphatic function and its regional derangement in states of pathologic dysfunction. Such insights must, initially, be derived from suitable animal models of the chronic human disease process. Historically, efforts to replicate the untreated disease of human lymphedema in animals, through surgery, irradiation, and toxicology, have been fraught with difficulty. The major impediments to the creation of satisfactory animal models have included an inability to reproduce the chronic disease in a stable, reproducible format. Recently, with the promise of potentially successful growth factor-mediated therapeutic lymphangiogenesis, and with the enhanced availability of investigative tools to assess therapeutic responses to molecular therapies, there has been a resurgence of interest in the development of viable animal models of lymphatic insufficiency. Current research has led to the development of genetic and postsurgical models of lymphedema that closely simulate the human conditions of primary and secondary lymphatic insufficiency, respectively. Such models will help to refine the assessment of various therapeutic approaches and their potential applicability to human disease interventions.
Animals↗
Gender differences in perception of PAD: a pilot study.
Patients with peripheral arterial disease (PAD) report profound limitations in all domains of quality of life that are worse than those for patients with chronic pulmonary disease and moderate to severe heart failure. While claudication has detrimental effects on quality of life, little is understood about the factors that influence quality of life and whether these determinants are similar for men and women with PAD and claudication. The purpose of the present investigation was to evaluate the effect of claudication on quality of life in 71 men and 26 women (mean age 72 and 73 years respectively) with PAD. Disease severity as assessed by ankle brachial index (ABI) and community-based walking was similar for men and women, although men reported greater comorbid conditions than women. Despite the similarity in disease severity, women reported decreased physical functioning (p = 0.01), more bodily pain (p = 0.04) and greater mood disturbance (p = 0.012) than men. Claudication and PAD had a greater impact on women than on men and may result from the higher prevalence of mood disturbance and bodily pain reported by women.
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The third circulation: radionuclide lymphoscintigraphy in the evaluation of lymphedema.
Lymphedema-edema that results from chronic lymphatic insufficiency-is a chronic debilitating disease that is frequently misdiagnosed, treated too late, or not treated at all. There are, however, effective therapies for lymphedema that can be implemented, particularly after the disorder is properly diagnosed and characterized with lymphoscintigraphy. On the basis of the lymphoscintigraphic image pattern, it is often possible to determine whether the limb swelling is due to lymphedema and, if so, whether compression garments, massage, or surgery is indicated. Effective use of lymphoscintigraphy to plan therapy requires an understanding of the pathophysiology of lymphedema and the influence of technical factors such as selection of the radiopharmaceutical, imaging times after injection, and patient activity after injection on the images. In addition to reviewing the anatomy and physiology of the lymphatic system, we review physiologic principles of lymphatic imaging with lymphoscintigraphy, discuss different qualitative and quantitative lymphoscintigraphic techniques and their clinical applications, and present clinical cases depicting typical lymphoscintigraphic findings.
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Decongestive lymphatic therapy for patients with breast carcinoma-associated lymphedema. A randomized, prospective study of a role for adjunctive intermittent pneumatic compression.
BACKGROUND: Disruption of the lymphatic circulation through breast carcinoma-associated axillary lymph node dissection, with or without radiation therapy, reportedly is the most common cause of lymphedema in developed countries. There is no cure for breast carcinoma-associated lymphedema. Although intermittent pneumatic compression (IPC) has been acknowledged as a potential component of the multidisciplinary therapeutic strategy in the treatment of patients with breast carcinoma-associated lymphedema, prospective study of its adjunctive safety and efficacy is required. METHODS: IPC was assessed as a component of the initial therapeutic regimen for newly treated patients with breast carcinoma-associated lymphedema. Twenty-three patients who had not previously been treated for lymphedema were randomized to receive either decongestive lymphatic therapy (DLT) alone or DLT with daily adjunctive IPC. Patients with stable, treated, breast carcinoma-associated lymphedema also were assessed in the maintenance phase of therapy. Twenty-seven patients were randomized either to DLT alone or to DLT coupled with daily IPC. In both studies, objective assessment included serial measurement of volume by water displacement, tissue tonometry to assess elasticity of the skin, and goniometry to measure joint mobility. RESULTS: During initial treatment, the addition of IPC to standard DLT yielded an additional mean volume reduction (45.3% vs. 26%; P < 0.05). During maintenance DLT alone, there was a mean increase in volume (32.7 +/- 115.2 mL); with DLT and IPC, there was a mean volume reduction (89.5 +/- 195.5 mL; P < 0.05). In both studies, IPC was tolerated well without detectable adverse effects on skin elasticity or joint range of motion. CONCLUSIONS: When IPC is used adjunctively with other, established elements of DLT, it provides an enhancement of the therapeutic response. IPC is well tolerated and remarkably free of complications.
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Therapeutic lymphangiogenesis with human recombinant VEGF-C.
Chronic regional impairments of the lymphatic circulation often lead to striking architectural abnormalities in the lymphedematous tissues. Lymphedema is a common, disabling disease that currently lacks a cure. Vascular endothelial growth factors C and D mediate lymphangiogenesis through the VEGFR-3 receptor on lymphatic endothelia. The purpose of this study was to investigate the therapeutic potential for lymphangiogenesis with VEGF-C. We developed a rabbit ear model to simulate human chronic postsurgical lymphatic insufficiency. Successful, sustained surgical ablation of the ear lymphatics was confirmed by water displacement volumetry. After complete healing, the experimental animals (n=8) received a single, s.c. 100 microg dose of VEGF-C in the operated ear; controls (n=8) received normal saline. Radionuclide lymphoscintigraphy was performed to quantitate lymphatic function. Immunohistochemistry (IHC) was performed 7-8 days following treatment. After VEGF-C, there was a quantifiable amelioration of lymphatic function. IHC confirmed a significant increase in lymphatic vascularity, along with reversal of the intense tissue hypercellularity of untreated lymphedema. This study confirms the capacity of a single dose of VEGF-C to induce therapeutic lymphangiogenesis in acquired lymphedema. In addition to improving lymphatic function and vascularity, VEGF-C can apparently reverse the abnormalities in tissue architecture that accompany chronic lymphatic insufficiency.
Animals↗
The role of chemokines in human cardiovascular pathology: enhanced biological insights.
A growing body of experimental evidence supports the pivotal role of chemokines in the pathogenesis of vascular disease. The endothelial expression of monocyte chemoattractant protein-1 (MCP-1) is apparently essential for the earliest cellular responses of atherogenesis. Many atherogenic and anti-atherogenic stimuli can be construed to exert their effects predominantly upon MCP-1 expression within the vascular wall. The atherogenic effects of interleukin-8 (IL-8) seem to be mediated through the down-regulation of the tissue inhibitor of metalloproteinase-1 (TIMP-1). Biological expression of these two important vascular chemokines is further modulated by NF-kappaB. The delineation of these molecular forces that drive atherogenesis increasingly underscores the pivotal role of various chemokines. It is anticipated that more precise delineation of these patterns of gene expression will help to identify molecular targets for the prevention and treatment of atherosclerosis.
Animals↗
Diagnosis and treatment of concomitant venous obstruction in patients with secondary lymphedema.
PURPOSE: It has been proposed that concomitant iatrogenic venous obstruction substantially contributes to the appearance and severity of the secondary lymphedema that follows cancer surgery, radiation, and other traumas. The purpose of this study was to investigate the frequency of venous obstruction in the clinical presentation of patients with secondary lymphedema and to analyze the efficacy of interventional therapy in this patient population. MATERIALS AND METHODS: The experience of the university center for lymphatic and venous disorders with combined lymphaticovenous edema was retrospectively examined. The records and clinical course were reviewed for all patients referred to a university lymphedema center for evaluation between January 1996 and March 1999. During this interval, in 365 patients with lymphedema, 35 radiocontrast venograms were obtained to evaluate the suspected presence of mixed lymphaticovenous edema. Venographic evidence of venous stenosis (>50%) or occlusion was analyzed, as were the technical success of the intervention, determined by ability to cross the affected segment of the vein and perform venoplasty and place the stent, and the clinical success of the intervention assessed by relief of clinical symptoms (edema, pain) within 24 hours. RESULTS: The diagnosis of venous obstruction was confirmed in 17 patients (4.6% of all patients with lymphedema; 49% of patients studied with venography). Venography disclosed clinically relevant venous stenosis in five of seven patients with edema of the upper extremity and in six of 10 patients with leg lymphedema. Venous occlusion was found in two of seven patients with upper extremity edema and in four of 10 patients with leg lymphedema. Percutaneous endovascular venoplasty was attempted in all 17 patients and was successful in 16. Subsequent venous stent placement was performed in three patients with upper extremity edema and in all patients with lower extremity lymphedema. Clinical amelioration of edema was observed in 15 of these 17 patients. Amelioration was assessed by relief of symptoms, improvement in function, and reduction in limb girth. CONCLUSIONS: This study supports the clinical importance of concomitant venous obstruction in some patients with chronic secondary lymphedema. Edema can often be ameliorated through percutaneous catheter-based interventions.
Adult↗