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1.
J Zhejiang Univ Sci B ; 20(8): 687-692, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31273966

RESUMO

The objective of this study was to assess the angiogenic potential expressed as a quotient of vascular endothelial growth factor A (VEGF-A), as an indicator of proangiogenic activity, and the circulating receptors (soluble VEGF receptor protein R1 (sVEGFR-1) and sVEGFR-2), as indicators of the effect of angiogenic inhibition, depending on the concentrations of matrix metalloproteinase 2 (MMP-2) and MMP-9 and their tissue inhibitor 1 (TIMP-1) and TIMP-2 in the plasma of patients with lower extremity artery disease (LEAD). These blood parameters in patients with intermittent claudication (IC) and critical limb ischemia (CLI) were compared for select clinical and biochemical features. Stimulation of angiogenesis in the plasma of individuals with LEAD was evident as indicated by the significant increase in VEGF-A concentration along with reduced inhibition depending on circulating receptors sVEGFR-1 and sVEGFR-2. Critical ischemia was associated with higher VEGF-A, MMP-9, TIMP-1, and TIMP-2 concentrations than in the case of IC.


Assuntos
Claudicação Intermitente/sangue , Isquemia/sangue , Extremidade Inferior/irrigação sanguínea , Metaloproteinase 9 da Matriz/sangue , Neovascularização Patológica , Inibidor Tecidual de Metaloproteinase-1/sangue , Inibidor Tecidual de Metaloproteinase-2/sangue , Idoso , Inibidores da Angiogênese/farmacologia , Feminino , Regulação da Expressão Gênica , Humanos , Claudicação Intermitente/tratamento farmacológico , Isquemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Fator A de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/sangue
2.
Vasc Med ; 24(5): 414-421, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31277561

RESUMO

Extensive atherosclerotic plaque burden in the lower extremities often leads to symptomatic peripheral artery disease (PAD) including impaired walking performance and claudication. Interleukin-1ß (IL-1ß) may play an important pro-inflammatory role in the pathogenesis of this disease. Interruption of IL-1ß signaling was hypothesized to decrease plaque progression in the leg macrovasculature and improve the mobility of patients with PAD with intermittent claudication. Thirty-eight patients (mean age 65 years; 71% male) with symptomatic PAD (confirmed by ankle-brachial index) were randomized 1:1 to receive canakinumab (150 mg subcutaneously) or placebo monthly for up to 12 months. The mean vessel wall area (by 3.0 T black-blood magnetic resonance imaging (MRI)) of the superficial femoral artery (SFA) was used to measure plaque volume. Mobility was assessed using the 6-minute walk test. Canakinumab was safe and well tolerated. Markers of systemic inflammation (interleukin-6 and high-sensitivity C-reactive protein) fell as early as 1 month after treatment. MRI (32 patients at 3 months; 21 patients at 12 months) showed no evidence of plaque progression in the SFA in either placebo-treated or canakinumab-treated patients. Although an exploratory endpoint, placebo-adjusted maximum and pain-free walking distance (58 m) improved as early as 3 months after treatment with canakinumab when compared with placebo. Although canakinumab did not alter plaque progression in the SFA, there is an early signal that it may improve maximum and pain-free walking distance in patients with symptomatic PAD. Larger studies aimed at this endpoint will be required to definitively demonstrate this. ClinicalTrials.gov Identifier: NCT01731990.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Claudicação Intermitente/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Idoso , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Biomarcadores/sangue , Método Duplo-Cego , Tolerância ao Exercício/efeitos dos fármacos , Feminino , Alemanha , Humanos , Mediadores da Inflamação/sangue , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Jordânia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Estudo de Prova de Conceito , Estudos Prospectivos , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
3.
J Vasc Surg ; 70(1): 148-156, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30922760

RESUMO

OBJECTIVE: Supervised exercise training (walking) is recommended in patients with intermittent claudication, both as a means to improve symptoms (walking distance and quality of life [QoL]) and as a means to improve general cardiovascular health (including vascular function and heart rate variability [HRV]). Our aim was to compare two types of supervised training (moderate-pain and pain-free walking) with comparable intensity based on heart rate, in terms of walking capacity, QoL, vascular function, biomarkers, and HRV in patients with intermittent claudication. METHODS: Thirty-six adults with intermittent claudication were randomized to either moderate-pain or pain-free exercise training (36 sessions, two or three times a week) or usual care (no supervised exercise). Initial walking distance and absolute walking distance using treadmill testing, flow-mediated vasodilation and pulse wave velocity using ultrasound, N-terminal pro-B-type natriuretic peptide and fibrinogen levels, HRV, and QoL (36-Item Short Form Health Survey questionnaire) were determined at baseline and after the intervention period. RESULTS: Twenty-nine patients (mean age, 64 ± 9 years; 72% male) completed the study. Both training programs similarly improved walking capacity. Initial walking distance and absolute walking distance significantly increased with either moderate-pain walking (median, 50 m to 107 m [P = .005] and 85 m to 194 m [P = .005], respectively) or pain-free walking (median, 53 m to 128 m [P = .003] and 92 m to 163 m [P = .003], respectively). QoL also similarly improved with both training modalities, whereas only moderate-pain walking was also associated with a statistically significant improvement in the vascular parameters flow-mediated vasodilation (4.4% to 8.0%; P = .002) and pulse wave velocity (6.6 m/s to 6.1 m/s; P = .013). Neither training program was associated with changes in biomarker levels and HRV. CONCLUSIONS: Both moderate-pain and pain-free training modalities were safe and similarly improved walking capacity and health-related QoL. Conversely, vascular function improvements were associated with only moderate-pain walking.


Assuntos
Terapia por Exercício/métodos , Tolerância ao Exercício , Hemodinâmica , Claudicação Intermitente/terapia , Doença Arterial Periférica/terapia , Caminhada , Idoso , Biomarcadores/sangue , Feminino , Fibrinogênio/metabolismo , Nível de Saúde , Frequência Cardíaca , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Medição da Dor , Fragmentos de Peptídeos/sangue , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Estudos Prospectivos , Qualidade de Vida , Recuperação de Função Fisiológica , Eslovênia , Fatores de Tempo , Resultado do Tratamento , Rigidez Vascular , Vasodilatação , Teste de Caminhada
4.
J Surg Res ; 238: 48-56, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30738358

RESUMO

BACKGROUND: Leptin, adiponectin, and resistin are in a class of hormones called adipokines that are produced by adipocytes and have been implicated in the causal pathway of atherosclerosis. We examined the association between adipokine levels and peripheral artery disease (PAD), hypothesizing that after adjusting for fat mass, leptin and resistin would be higher, whereas adiponectin would be lower, in patients with PAD. METHODS: A cross-sectional sample of 179 predominately male (97%) vascular surgery outpatients was recruited from the San Francisco Veterans Affairs Medical Center (SFVAMC). PAD was defined as either an ankle-brachial index < 0.9 plus symptoms of claudication or prior revascularization for symptomatic PAD (n = 141). Controls had an ankle-brachial index ≥0.9 and no history of atherosclerotic disease (n = 38). Adipokines were assayed using commercially available ELISA kits and values were log-transformed. Fat mass was measured using bioelectrical impedance. RESULTS: In an analysis adjusting for body mass index (BMI) and atherosclerotic risk factors, higher serum leptin was associated with PAD (OR 2.54, 95% CI 1.07-6.01, P = 0.03), whereas high molecular weight adiponectin was inversely associated, though not significantly (OR 0.60, 95% CI 0.33-1.08, P = 0.09). Resistin was not associated with PAD. Sensitivity analyses using fat mass/height2 rather than BMI yielded similar results. CONCLUSIONS: These results indicate that after adjusting for BMI or fat mass, serum leptin levels are positively and independently associated with PAD, whereas high molecular weight adiponectin might be inversely associated. Using a more representative, nonveteran sample, further investigations should focus on the potential role of adipokines in the pathophysiology of PAD as well as determine whether leptin levels have clinical utility in predicting PAD outcomes.


Assuntos
Claudicação Intermitente/diagnóstico , Leptina/sangue , Doença Arterial Periférica/diagnóstico , Adiponectina/sangue , Idoso , Estudos Transversais , Feminino , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/cirurgia , Masculino , Pessoa de Meia-Idade , Ambulatório Hospitalar , Doença Arterial Periférica/sangue , Doença Arterial Periférica/cirurgia , Estados Unidos , United States Department of Veterans Affairs , Veteranos
5.
Ann Vasc Surg ; 58: 134-141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30684623

RESUMO

OBJECTIVES: This is a pilot study, and the objective of the study was to investigate the possible uses of microdialysis in the calf muscle to assess the metabolic response to intermittent claudication (IC) and in addition evaluate the simultaneous systemic inflammatory reaction. METHODS: Dialysate and venous blood sampling was performed before, during and after walking on a treadmill to maximal tolerable claudication (controls 10 min) using 1 microdialysis catheter inserted in the gastrocnemius muscle, 1 subcutaneously in the pectoral region (as a reference), and a peripheral venous catheter. RESULTS: A total of 9 participants were recruited, 6 patients with IC and 3 healthy control subjects. At baseline, patients with IC and control subjects did not differ in metabolic findings (glucose, lactate, pyruvate, and glycerol) in the gastrocnemius muscle. Subcutaneous glucose concentration was higher in control subjects. After physical exertion, gastrocnemius and subcutaneous glycerol, lactate, and pyruvate concentrations increased in patients with IC. Plasma concentrations of tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß), hepatocyte growth factor, and vascular endothelial growth factor were higher in IC subjects at baseline, and TNF-α, IL-6, and IL-18 increased after walking as did IL-6 and IL-1ß in control subjects. The muscle catheters did not show any signs of harm. CONCLUSIONS: Microdialysis can be used to study the ongoing metabolic response during walking and claudication. Our results suggest both an acute local and a systemic inflammatory reaction during development of claudication.


Assuntos
Metabolismo Energético , Mediadores da Inflamação/sangue , Claudicação Intermitente/sangue , Microdiálise/métodos , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Doença Arterial Periférica/sangue , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Casos e Controles , Teste de Esforço , Tolerância ao Exercício , Estudos de Viabilidade , Feminino , Humanos , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Perna (Membro) , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Projetos Piloto , Fluxo Sanguíneo Regional , Fatores de Tempo
6.
Circ Res ; 123(6): 654-659, 2018 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-29976553

RESUMO

RATIONALE: A primary goal of therapy for patients with peripheral artery disease (PAD) and intermittent claudication is increased ambulatory function. Supervised exercise rehabilitation was recently shown to confer superior walking benefits to pharmacological or surgical interventions. Increases in plasma inorganic nitrite, via oral nitrate, have been shown to increase exercise performance in both human and animal models, especially in hypoxic conditions. OBJECTIVE: To determine whether a 36-session exercise rehabilitation program while consuming oral inorganic nitrate (4.2 mmol concentrated beetroot juice) would produce superior benefits over exercise plus placebo in pain-free walking and markers of increased skeletal muscle perfusion in patients with PAD and intermittent claudication. METHODS AND RESULTS: This was a randomized, double-blind, per-protocol study design. After the 12-week protocol, claudication onset time on a maximal treadmill test increased by 59.2±57.3 s for the exercise plus placebo group (n=13) and by 180.3±46.6 s for the exercise plus beetroot juice group (n=11; P≤0.05). This produced a between treatment medium to large standardized effect size (Cohen d) of 0.62 (95% CI, -0.23 to +1.44). The data for 6-minute walk distance showed a similar pattern with increases of 24.6±12.1 and 53.3±19.6 m ( P≤0.05) in the exercise plus placebo and exercise plus beetroot juice groups, respectively. Measures of gastrocnemius perfusion, including ankle-brachial index, peak reactive hyperemic blood flow, and tissue deoxygenation characteristics, during exercise (assessed my near-infrared spectroscopy) all changed significantly for the exercise plus beetroot juice group with moderate-to-large effect sizes over exercise plus placebo changes. CONCLUSIONS: Although it is premature to speculate on overall clinical utility of a nitrate-based therapy for PAD, this early pilot study evidence is encouraging. Specifically, our data suggests that increasing plasma nitrite before exercise may allow PAD subjects to train with less pain, at higher workloads for longer durations at each training session, thereby maximizing the beneficial peripheral vascular and skeletal muscle adaptations. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01684930 and NCT01785524.


Assuntos
Beta vulgaris , Terapia por Exercício/métodos , Tolerância ao Exercício , Sucos de Frutas e Vegetais , Claudicação Intermitente/reabilitação , Extremidade Inferior/irrigação sanguínea , Doença Arterial Periférica/reabilitação , Raízes de Plantas , Idoso , Biomarcadores/sangue , Método Duplo-Cego , Feminino , Hemodinâmica , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Nitritos/sangue , North Carolina , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Projetos Piloto , Recuperação de Função Fisiológica , Fluxo Sanguíneo Regional , Fatores de Tempo , Resultado do Tratamento , Regulação para Cima
7.
Atherosclerosis ; 276: 117-123, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30059842

RESUMO

Exertional lower limb pain is a frequent diagnostic issue in elderly patients. Arterial claudication results from the mismatch between the oxygen requirement of, and oxygen delivery to the exercising muscles. Non-invasive vascular investigations (ultrasound imaging, plethysmography or segmental pressure) are used in routine at rest or following exercise, but none can be used during walking or to directly monitor cutaneous oxygen delivery to the limb. Here, we review the methods, tips and traps of the transcutaneous oxygen pressure measurement technique and potential applications. Transcutaneous oxygen pressure measurement is largely used in vascular medicine for patients with critical limb ischemia. It can also detect regional blood flow impairment at the proximal and distal limb simultaneously and bilaterally during exercise. Exercise-oximetry can also analyze systemic oxygen pressure changes on a reference area on the chest, to screen for occult pulmonary disease. As a surface technique, it does not directly measure muscle oxygen content but provides a reliable estimation of regional blood flow impairment. With the use of a recently reported index that is independent of the unknown transcutaneous gradient for oxygen, exercise-oximetry provides some accurate information compared to classical non-invasive vascular investigations to argue for a vascular or non-vascular origin of exertional lower limb pain during exercise. Although a time consuming technique, it is a simple test and it is progressively spreading among referral vascular centers as a useful non-invasive diagnostic tool for patients suspected of arterial claudication.


Assuntos
Monitorização Transcutânea dos Gases Sanguíneos , Teste de Esforço , Claudicação Intermitente/diagnóstico , Isquemia/diagnóstico , Extremidade Inferior/irrigação sanguínea , Oxigênio/sangue , Doença Arterial Periférica/diagnóstico , Biomarcadores/sangue , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/fisiopatologia , Isquemia/sangue , Isquemia/fisiopatologia , Doença Arterial Periférica/sangue , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Prognóstico , Fluxo Sanguíneo Regional
8.
Heart Vessels ; 33(12): 1453-1462, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29946762

RESUMO

The association among serum homocysteine (HCY), symmetric dimethylarginine (SDMA), and asymmetric dimethylarginine (ADMA) is of interest in endothelial dysfunction, although the underlying pathology is not fully elucidated. We investigated the relationship of HCY with SDMA and ADMA regarding their long-time outcome and the age dependency of HCY, SDMA, and ADMA values in claudicant patients with lower extremity arterial disease. 120 patients were included in a prospective observational study (observation time 7.96 ± 1.3 years) with cardiovascular mortality as the main outcome parameter. Patients with intermittent claudication prior to their first endovascular procedure were included. HCY, SDMA, and ADMA were measured by high-performance liquid chromatography. Cutoff values for HCY (≤/>15 µmol/l), SDMA (≤/>0.75 µmol/l), and ADMA (≤/>0.8 µmol/l) differed significantly regarding cardiovascular mortality (p < 0.001, p < 0.001, p = 0.017, respectively). Age correlated significantly with HCY (r = 0.393; p < 0.001), SDMA (r = 0.363; p < 0.001), and ADMA (r = 0.210; p = 0.021). HCY and SDMA (r = 0.295; p = 0.001) as well as SDMA and ADMA (r = 0.380; p < 0.001) correlated with each other, while HCY and ADMA did not correlate (r = 0.139; p = 0.130). Patients older than 65 years had higher values of HCY (p < 0.001) and SDMA (p = 0.01), but not of ADMA (p = 0.133). In multivariable linear regression, age was the only significant independent risk factor for cardiovascular death (beta coefficient 0.413; 95% CI 0.007-0.028; p = 0.001). Age correlated significantly with HCY, SDMA, and ADMA. However, only age was an independent predictor for cardiovascular death. Older patients have higher values of HCY and SDMA than younger subjects suggesting age-adjusted cutoff values of HCY and SDMA due to strong age dependency.


Assuntos
Envelhecimento/sangue , Arginina/análogos & derivados , Doenças Cardiovasculares/epidemiologia , Homocisteína/sangue , Claudicação Intermitente/sangue , Extremidade Inferior/irrigação sanguínea , Idoso , Arginina/sangue , Áustria/epidemiologia , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Feminino , Humanos , Incidência , Claudicação Intermitente/complicações , Claudicação Intermitente/mortalidade , Masculino , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida/tendências
9.
J Vasc Surg ; 68(4): 1135-1142.e6, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29615349

RESUMO

BACKGROUND: The prevalence of lower extremity artery disease (LEAD) is high (20%-25%) in the population older than 65 years, but patients are seldom identified until the disease is advanced. Circulating markers of disease activity might provide patients with a key opportunity for timely treatment. We tested the hypothesis that measuring blood-specific fragments generated during degradation of the extracellular matrix (ECM) could provide further insight into the pathophysiologic mechanism of arterial remodeling. METHODS: The protein profile of diseased arteries from patients undergoing infrainguinal limb revascularization was assessed by a liquid chromatography and tandem mass spectrometry, nontargeted proteomic approach. The information retrieved was the basis for measurement of neoepitope fragments of ECM proteins in the blood of 195 consecutive patients with LEAD by specific enzyme-linked immunosorbent assays. RESULTS: Histologic and proteomic analyses confirmed the structural disorganization of affected arteries. Fourteen of 81 proteins were identified as differentially expressed in diseased arteries with respect to healthy tissues. Most of them were related to ECM components, and the difference in expression was used in multivariate analyses to establish that severe arterial lesions in LEAD patients have a specific proteome. Analysis of neoepitope fragments in blood revealed that fragments of versican and collagen type IV, alone or in combination, segregated patients with mild to moderate symptoms (intermittent claudication, Fontaine I-II) from those with severe LEAD (critical limb ischemia, Fontaine III-IV). CONCLUSIONS: We propose noninvasive candidate biomarkers with the ability to be clinically useful across the LEAD spectrum.


Assuntos
Proteínas da Matriz Extracelular/sangue , Matriz Extracelular/química , Artéria Femoral/química , Claudicação Intermitente/sangue , Isquemia/sangue , Extremidade Inferior/irrigação sanguínea , Fragmentos de Peptídeos/sangue , Doença Arterial Periférica/sangue , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Cromatografia Líquida , Colágeno Tipo IV/sangue , Estado Terminal , Ensaio de Imunoadsorção Enzimática , Matriz Extracelular/patologia , Feminino , Artéria Femoral/patologia , Humanos , Claudicação Intermitente/diagnóstico , Isquemia/diagnóstico , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Proteômica/métodos , Espectrometria de Massas em Tandem , Versicanas/sangue
10.
Microvasc Res ; 117: 44-49, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29325705

RESUMO

BACKGROUND: Transcutaneous oxygen pressure (tcpO2) reliability is blunted by an unpredictable transcutaneous gradient through the skin. We hypothesized that the "Decrease from Rest of Oxygen pressure (DROP: subtraction of limb-changes from chest-changes from the respective starting values) would show a good to excellent reliability during Exercise -tcpO2 investigations. METHODS: In three different experiments we tested: The intra-test variability at the peripheral level (Experiment A: 32 patients, 16 at each location), at the chest level (Experiment B: 45 patients) and the test-retest reproducibility within 3 months (Experiment C: 67 patients). We calculated the intra-class coefficient of correlation (ICC) with 95% confidence interval [Lower/upper limit]. ICC between 0.60 and 0.749 indicate a good agreement. ICC above 0.750 indicates an excellent agreement. RESULTS: ICC values for DROP-min were 0.848 [0.723/0.935] at the buttock and 0.920 [0.846/0.967] at the calf levels, in experiment A; ICC were 0.873 [0.799/0.923] at the buttock and 0.898 [0.790/0.953] at the calf levels, in experiment B; 0.806 [0.716/0.871] at then buttock level (n = 67) and 0.807 [0.722/0.868] at the calf in experiment C. CONCLUSIONS: Intra-test and test-retest reliability is excellent using the DROP calculation for exercise-tcpO2 investigations.


Assuntos
Monitorização Transcutânea dos Gases Sanguíneos , Teste de Esforço , Claudicação Intermitente/diagnóstico , Oxigênio/sangue , Doença Arterial Periférica/diagnóstico , Idoso , Biomarcadores/sangue , Feminino , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/fisiopatologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Estudos Retrospectivos
11.
Clin Physiol Funct Imaging ; 38(1): 69-75, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27491344

RESUMO

The aim of this study was to compare the effects of a single session of walking and combined exercise on oxidative stress and vascular function in peripheral arterial disease patients. Thirteen patients with peripheral arterial disease underwent two experimental sessions in random order: walking (ten sets of 2-min walking at the speed corresponding to the onset of claudication pain with 2-min interval between sets) and combined exercise (1 × 10 reps in eight resistance exercises plus five-two-minute sets of walking). Before and after the exercise, vascular function (blood flow, leg vascular resistance and blood-flow postreactive hyperaemia) and oxidative stress (malondialdehyde and plasma nitrite levels) were obtained. Blood flow increased similarly after both sessions, whilst leg vascular resistance decreased similarly after both sessions. Plasma nitrite increased only after the combined exercise. Malondialdehyde decreased after both sessions, and the decrease was greater after combined exercise. As a conclusion, a single session of combined exercise improves blood flow and leg vascular resistance similarly to walking session; however, combined exercise promoted better effects on oxidative stress.


Assuntos
Hemodinâmica , Claudicação Intermitente/terapia , Extremidade Inferior/irrigação sanguínea , Estresse Oxidativo , Doença Arterial Periférica/terapia , Treinamento de Resistência/métodos , Velocidade de Caminhada , Idoso , Índice Tornozelo-Braço , Biomarcadores/sangue , Pressão Sanguínea , Feminino , Humanos , Hiperemia/fisiopatologia , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Nitritos/sangue , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Resistência Vascular
12.
J Am Heart Assoc ; 6(7)2017 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28711864

RESUMO

BACKGROUND: The relative benefit of higher statin dosing in patients with peripheral artery disease has not been reported previously. We compared the effectiveness of low- or moderate-intensity (LMI) versus high-intensity (HI) statin dose on clinical outcomes in patients with peripheral artery disease. METHODS AND RESULTS: We reviewed patients with symptomatic peripheral artery disease who underwent peripheral angiography and/or endovascular intervention from 2006 to 2013 who were not taking other lipid-lowering medications. HI statin use was defined as atorvastatin 40-80 mg or rosuvastatin 20-40 mg. Baseline demographics, procedural data, and outcomes were retrospectively analyzed. Among 909 patients, 629 (69%) were prescribed statins, and 124 (13.6%) were treated with HI statin therapy. Mean low-density lipoprotein level was similar in patients on LMI versus HI (80±30 versus 87±44 mg/dL, P=0.14). Demographics including age (68±12 versus 67±10 years, P=0.25), smoking history (76% versus 80%, P=0.42), diabetes mellitus (54% versus 48%, P=0.17), and hypertension (88% versus 89%, P=0.78) were similar between groups (LMI versus HI). There was a higher prevalence of coronary artery disease (56% versus 75%, P=0.0001) among patients on HI statin (versus LMI). After propensity weighting, HI statin therapy was associated with improved survival (hazard ratio for mortality: 0.52; 95% confidence interval, 0.33-0.81; P=0.004) and decreased major adverse cardiovascular events (hazard ratio: 0.58; 95% confidence interval 0.37-0.92, P=0.02). CONCLUSIONS: In patients with peripheral artery disease who were referred for peripheral angiography or endovascular intervention, HI statin therapy was associated with improved survival and fewer major adverse cardiovascular events compared with LMI statin therapy.


Assuntos
Atorvastatina/administração & dosagem , Dislipidemias/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Claudicação Intermitente/tratamento farmacológico , Isquemia/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Rosuvastatina Cálcica/administração & dosagem , Idoso , Idoso de 80 Anos ou mais , Amputação , Angiografia , Atorvastatina/efeitos adversos , Biomarcadores/sangue , Estado Terminal , Progressão da Doença , Intervalo Livre de Doença , Prescrições de Medicamentos , Dislipidemias/sangue , Dislipidemias/diagnóstico por imagem , Dislipidemias/mortalidade , Procedimentos Endovasculares , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico por imagem , Claudicação Intermitente/mortalidade , Isquemia/sangue , Isquemia/diagnóstico por imagem , Isquemia/mortalidade , Estimativa de Kaplan-Meier , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico por imagem , Doença Arterial Periférica/mortalidade , Padrões de Prática Médica/tendências , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Rosuvastatina Cálcica/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
13.
J Am Soc Hypertens ; 11(9): 553-564, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28735679

RESUMO

Conservative therapy after complete revascularization is increasing in popularity in patients with peripheral artery disease (PAD). The aim of the present study was to find determinants of the improvement of walking abilities and endothelial function in patients with PAD undergoing supervised treadmill training program (STTP). The presented study enclosed 66 patients in the mean age 65.4 ± 7.7 years with PAD who underwent a 3-month length STTP. We assessed the effect of following factors on the change of the flow-mediated dilatation value (ΔFMD), maximal walking time (ΔMWT), and pain-free walking time (ΔPFWT). The evaluation included several biochemical and anthropometric indices with special insight into markers of angiogenesis, including soluble endoglin (sEng), platelet-derived growth factor, and angiopoietin-2. Linear regression analysis for each of the variables and multi-factorial model analysis of variances was adopted to select the most influential determinants. The levels of sEng, a biomarker of several cardiovascular pathologies, were found to significantly predict the greater improvement of maximal walking time and pain-free walking time. Moreover, the linear regression analysis demonstrated, and analysis of variance confirmed that coronary artery disease and peracted endovascular interventions of lower limbs arteries are significant determinants of the better ΔFMD improvement. On the contrary, treatment with ß-blockers and older age were poor predictors of ΔFMD increase. In conclusion, the sEng level could serve as a determinant of walking abilities change after STTP in patients with PAD. The treatment with ß-blockers, the coexistence of coronary artery disease, and peracted endovascular interventions of lower limbs arteries are determinants of endothelial function.


Assuntos
Endoglina/sangue , Claudicação Intermitente/terapia , Doença Arterial Periférica/terapia , Caminhada , Antagonistas Adrenérgicos beta/uso terapêutico , Fatores Etários , Idoso , Angiopoietina-2/sangue , Biomarcadores/sangue , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiopatologia , Terapia por Exercício/métodos , Feminino , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Dor/complicações , Dor/etiologia , Medição da Dor , Doença Arterial Periférica/sangue , Doença Arterial Periférica/fisiopatologia , Fator de Crescimento Derivado de Plaquetas/análise , Prognóstico , Fatores de Tempo , Resultado do Tratamento
14.
Vasa ; 46(1): 37-45, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27960614

RESUMO

BACKGROUND: Individual shear rate therapy (ISRT) has been designed as a novel non-invasive treatment option for peripheral artery disease (PAD) patients and has been shown to improve endothelial function and walking distance. The aim of this study was to elucidate the impact of ISRT on the level of nitric oxide in patient blood plasma and the expression of related molecular markers in peripheral blood mononuclear cells (PBMCs). Molecular diagnostic tests were performed for two ISRT trials. PATIENTS AND METHODS: In ISRT-1 26 healthy subjects underwent one session of treadmill training and one session of ISRT respectively in a cross-over design. In ISRT-2 14 PAD patients with a stable intermittent claudication underwent a 30 hours long-term treatment. Plasma nitrite release as well as the mRNA expression of NOS2 and key regulators of the kallikrein-kinin system were measured in PBMCs at different time points. RESULTS: Short-term ISRT revealed significantly decreased NOS2 expression in PBMCs of healthy volunteers and PAD patients. Long-term ISRT, in turn, demonstrated a significant plasma nitrite increase in PAD patients. CONCLUSIONS: We verified that long-term ISRT stimulates the vascular system and exerts a comparable effect to physical exercise in regards to NO release, which coincide with recent findings regarding an improvement of endothelial function. However, further studies are necessary to investigate the role for circulating leukocytes.
.


Assuntos
Contrapulsação/métodos , Claudicação Intermitente/terapia , Nitritos/sangue , Doença Arterial Periférica/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos Cross-Over , Teste de Esforço , Feminino , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Sistema Calicreína-Cinina/genética , Leucócitos Mononucleares/enzimologia , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/sangue , Óxido Nítrico Sintase Tipo II/genética , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , RNA Mensageiro/sangue , RNA Mensageiro/genética , Estresse Mecânico , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
15.
PLoS One ; 11(9): e0162353, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27611073

RESUMO

Critical limb ischemia (CLI) is the advanced stage of peripheral artery disease (PAD) and associated with an extremely poor clinical outcome. In order to understand the possible role of circulating cytokines and poor outcome associated with CLI we compared the circulating cytokine profile of patients with CLI against patients with intermittent claudication (IC). The levels of 48 circulating cytokines were examined in 226 consecutive patients with peripheral artery disease (PAD) admitted for elective, non-urgent, invasive treatment of IC or CLI. The PAD patient cohort was evenly distributed between subjects with IC (46.5%) and CLI (53.5%). As accustomed in PAD, CLI was associated with higher age, chronic kidney disease and diabetes when compared to IC (P < 0.01 for all). In multivariable linear regression modeling taking into account the baseline differences between IC and CLI groups CLI was independently associated with elevated levels of a large number of cytokines: IL-1ß, IL-1ra, IL-2Rα, IL-4, IL-6, IL-10, IFN-γ, GM-CSF, G-CSF (P < 0.01 for all), and IL-2, IL-7, IL-12, IL-13, IL-17, bFGF, VEGF, SCGF-ß (P < 0.05 for all). The current findings indicate that CLI is associated with a circulating cytokine profile, which resembles serious medical conditions such as severe pancreatitis, sepsis, or even cancer. Compared to IC, CLI is a systemic inflammatory condition, which may explain the extremely poor outcome associated with it.


Assuntos
Citocinas/sangue , Extremidades/irrigação sanguínea , Claudicação Intermitente/sangue , Claudicação Intermitente/etiologia , Isquemia/sangue , Isquemia/complicações , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Coortes , Comorbidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/complicações , Doença Arterial Periférica/diagnóstico
16.
Clin Biochem ; 49(15): 1167-1172, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27208561

RESUMO

OBJECTIVE: Aspirin is a widely used drug for prevention of thrombotic events in cardiovascular patients, but approximately 25% of patients experience insufficient platelet inhibition due to aspirin, and remain in risk of cardiovascular events. This study aimed to investigate the value of circulating miR-92a and platelet size as biomarkers of the individual response to aspirin therapy. METHODS: Blood samples were collected from 50 healthy blood donors without antithrombotic medication and 50 patients with intermittent claudication on daily aspirin therapy. Based on results from the arachidonic acid stimulated aggregation test on Multiplate®analyzer (ASPItest), patients were defined as aspirin resistant (n=10) or aspirin responders (n=40). Plasma levels of miR-92a were evaluated by RT-qPCR analysis and platelet distribution width (PDW) was used to assess platelet size variability. Receiver operating characteristic curves for miR-92a levels and PDW were used to set cut-off values for discrimination between aspirin responding and aspirin resistant patients. RESULTS: When defining aspirin resistance as an ASPItest ≥30U, the optimal cut-off values for discrimination of aspirin responders and aspirin resistant patients were found to be PDW>11.8fL and a relative expression level of miR-92a>4.5. Using these cut-off values we could define a PDW/miR-92a-score with a specificity of 97.5% and a sensitivity of 80.0% in relation to detect aspirin resistance. The corresponding positive and negative predictive values were found to be 88.9% and 95.1%, respectively. CONCLUSION: Aspirin resistance can potentially be identified by miR-92a levels in plasma combined with PDW.


Assuntos
Aspirina/farmacologia , Plaquetas/citologia , MicroRNAs/sangue , Adulto , Estudos de Casos e Controles , Resistência a Medicamentos , Feminino , Humanos , Claudicação Intermitente/sangue , Masculino , Pessoa de Meia-Idade , Agregação Plaquetária
17.
Perfusion ; 31(7): 560-7, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26980004

RESUMO

This observational study aimed to investigate the relationship between renal injury, endothelial function and oxidative stress in claudicants undergoing maximal treadmill exercise. Twenty patients with claudication were identified in whom the urinary N-acetyl-ß-D-glucosaminidase (ß-NAG)/creatinine ratio, plasma oxidative state and endothelial function were tested pre- and post-maximal treadmill walking exercise. Of the 20 participants in this study, the urinary NAG/creatinine (Cr) rose from a pre-exercise level of 8.9, 6.7 to 14.3 (µmol/L/mmol Cr; median, IQR) to 12.9, 9.1 to 17.7 post exercise (p = 0.0003, Mann Whitney U test). Of the 20 participants, eight participants had a rise of the NAG/Cr ratio post exercise whereas 12 did not. Participants with a rise in the NAG/Cr ratio post exercise had a greater ability to increase endothelial reactivity (%; median, IQR; 2.56, 0.1 to 3.7) cf. (0.1, -4.8 to 0.9, p = 0.03); they also walked further (metres; median, IQR; 415, 208 to 908) cf. (170, 100 to 315, p = 0.04), had a lower pre-exercise H2O2 (median, IQR; 1.9, 1.4 to 2.3 cf. 2.7, 2.1 to 3.3; p = 0.04) and a greater rise in H2O2 post exercise (18.8, -1.5 to 129.7 cf., -7.7, -13.9 to -2.0, p = 0.04). The mechanism by which the phenotypically distinct sub-group of patients with intermittent claudication who experience a NAG/Cr rise involves complex interactions between systemic oxidative stress and endothelial function. Implications on cardiovascular risk in this group requires further investigation.


Assuntos
Lesão Renal Aguda/etiologia , Lesão Renal Aguda/urina , Claudicação Intermitente/complicações , Claudicação Intermitente/urina , Estresse Oxidativo , Acetilglucosaminidase/urina , Lesão Renal Aguda/sangue , Lesão Renal Aguda/metabolismo , Idoso , Idoso de 80 Anos ou mais , Creatinina/urina , Endotélio/metabolismo , Exercício , Feminino , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de Risco
18.
Clin Res Cardiol ; 105(8): 666-676, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26830098

RESUMO

BACKGROUND: Inflammation is the driving force in atherosclerosis. One central strategy in the treatment of peripheral arterial disease (PAD) is the promotion of angiogenesis. Here, proangiogenic Tie-2 expressing monocytes (TEM) and circulating angiogenic cells (CAC) play a crucial role. Exercise training (ET) is recommended in PAD patients at Fontaine stage II to promote angiogenesis. METHODS: 40 patients with intermittend claudication (IC) [2 groups: supervised ET (SET) vs. non-supervised ET (nSET), each n = 20] and 20 healthy controls were included in the study. Analysis of TEM and CAC was performed from whole blood by flow-cytometry. TEM were identified via CD45, CD86, CD14, CD16 and analysed for the expression of Tie-2. CAC were identified via their expression of CD45 (CD45dim), CD34 and VEGF-R2 (CD309/KDR). Follow up was performed after mean of 7.65 ± 1.62 months. RESULTS: In comparison to healthy controls, we found increased proportions of CAC (p < 0.0001) and similar TEM numbers in both ET groups. At follow-up (FU) TEM poroportions increased (p < 0.001) and CAC proportions decreased (p < 0.01), but both more significantly in SET (p < 0.001) than nSET (p = 0.01). Only in SET fibrinogen levels decreased and VEGF-A increased (both p < 0.05). Finally, we found in both ET groups a significant increase in absolute walking distance but with a higher individual increase in SET (p < 0.01). TEM and CAC proportions correlated inversely with the absolute walking distance (CAC: r = -0.296, p = 0.02; TEM: r = -0.270, p = 0.04) as well as with ABI (CAC: r = -0.394, p < 0.01; TEM: r = -0.382, p < 0.01). CONCLUSIONS: ET influences the distribution of CAC and TEM proportions. nSET, although still effective in regard to an improved walking distance, is less effective in the influence of proangiogenic cells and inflammatory burden than SET. Our results indicate SET to be a more preferential exercise form, supporting the necessity to establish more SET programs.


Assuntos
Biomarcadores/sangue , Terapia por Exercício , Tolerância ao Exercício , Claudicação Intermitente/terapia , Monócitos/metabolismo , Neovascularização Fisiológica , Doença Arterial Periférica/terapia , Receptor TIE-2/sangue , Idoso , Feminino , Humanos , Mediadores da Inflamação/sangue , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Projetos Piloto , Recuperação de Função Fisiológica , Fatores de Tempo , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangue
19.
Vasc Med ; 21(2): 156-69, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26823456

RESUMO

Antiplatelet agents are recommended for the reduction of major adverse cardiovascular events among all patients with symptomatic peripheral artery disease. However, the optimal antiplatelet regimen and duration of therapy in peripheral artery disease (PAD) remains unclear, largely due to limited and conflicting data in this patient population. This article reviews current data on antithrombotic therapy in PAD and discusses the implications of this data for current practice and future research.


Assuntos
Anticoagulantes/uso terapêutico , Fibrinolíticos/uso terapêutico , Claudicação Intermitente/tratamento farmacológico , Isquemia/tratamento farmacológico , Doença Arterial Periférica/tratamento farmacológico , Inibidores da Agregação de Plaquetas/uso terapêutico , Anticoagulantes/efeitos adversos , Coagulação Sanguínea/efeitos dos fármacos , Estado Terminal , Quimioterapia Combinada , Fibrinolíticos/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/mortalidade , Isquemia/sangue , Isquemia/diagnóstico , Isquemia/mortalidade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/mortalidade , Agregação Plaquetária/efeitos dos fármacos , Inibidores da Agregação de Plaquetas/efeitos adversos , Fatores de Risco , Resultado do Tratamento
20.
Vascular ; 24(3): 264-72, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26567275

RESUMO

OBJECTIVE: This study assesses the impact of treadmill-based SET alone or in combination with resistance training on systemic inflammatory response, in patients with intermittent claudication (IC). METHODS: Thirty-five patients with IC were randomised to 12 weeks of treadmill-only SET (Group 1) or a combination of treadmill and lower-limb resistance SET (Group 2). A panel of pro- and anti-inflammatory markers were assessed before, during and after the SET. RESULTS: Over the duration of SET, homocysteine increased within Group 1 (12.0-15.5 µmol/L, p = 0.003) but not Group 2, (13.7-14.7 µmol/) while neutrophil elastase (NE) increased within Group 2 (174.5-238.2 ng/mL, p = 0.007) but not Group 1 (300.8-312.0 ng/mL). In both groups NE increased following acute exercise at the start of the SET. Differences in cytokine expression was evident between the two groups (in Group 1, pro-inflammatory cytokines interleukin-12 and interferon-gamma decreased following an acute bout of exercise at the end of SET, where as in Group 2 pro-inflammatory cytokines interleukin-6 and 8 were seen to increase after an acute bout of exercise at the end of SET). CONCLUSION: SET in patients with IC influences the complex immune-modulatory state of atherosclerosis through inflammatory pathways that induce both pro-inflammatory and immunosuppressive responses.


Assuntos
Citocinas/sangue , Terapia por Exercício/métodos , Mediadores da Inflamação/sangue , Inflamação/terapia , Claudicação Intermitente/terapia , Doença Arterial Periférica/terapia , Treinamento de Resistência , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Terapia por Exercício/efeitos adversos , Feminino , Humanos , Inflamação/sangue , Inflamação/diagnóstico , Inflamação/fisiopatologia , Claudicação Intermitente/sangue , Claudicação Intermitente/diagnóstico , Claudicação Intermitente/fisiopatologia , Masculino , Pessoa de Meia-Idade , Doença Arterial Periférica/sangue , Doença Arterial Periférica/diagnóstico , Doença Arterial Periférica/fisiopatologia , Projetos Piloto , Austrália do Sul , Fatores de Tempo , Resultado do Tratamento
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