RESUMEN
BACKGROUND: The COMPASS trial demonstrated that in patients with peripheral arterial disease, the combination of rivaroxaban and aspirin compared with aspirin reduces the risk of major adverse limb events, but it is not known whether this combination can also improve symptoms in patients with intermittent claudication. The primary objective of this study is to evaluate the effect of the combination on claudication distance. STUDY DESIGN: Eighty-eight patients with intermittent claudication will be randomized to receive rivaroxaban 2.5â mg twice daily plus aspirin 100â mg once daily or aspirin 100â mg once daily for 24 weeks. The primary outcome is the change in claudication distance from the baseline to 24 weeks, measured by 6â min walking test and treadmill test. The primary safety outcome is the incidence of major bleeding and clinically relevant non-major bleeding according to the International Society on Thrombosis and Hemostasis criteria. SUMMARY: The COMPASS CLAUDICATION trial will provide high-quality evidence regarding the effect of the combination of rivaroxaban and aspirin on claudication distance in patients with peripheral arterial disease.
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Aspirina/uso terapéutico , Claudicación Intermitente/tratamiento farmacológico , Enfermedad Arterial Periférica/tratamiento farmacológico , Método Doble Ciego , Quimioterapia Combinada , Prueba de Esfuerzo , Inhibidores del Factor Xa/uso terapéutico , Femenino , Estudios de Seguimiento , Humanos , Claudicación Intermitente/diagnóstico , Claudicación Intermitente/etiología , Masculino , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/diagnóstico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios Prospectivos , Rivaroxabán/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: Patients with peripheral artery disease (PAD) are at increased risk of major adverse limb events (MALE). Furthermore, MALE have several clinical implications and a poor prognosis, so prevention is a fundamental issue. The main objective of the present meta-analysis of randomized clinical trials is to evaluate the effect of different lipid-lowering therapies on MALE incidence in patients with PAD. METHODS: A meta-analysis of randomized studies that evaluated the use of lipid-lowering therapy in patients with PAD and reported MALE was performed, after searching the PubMed/MEDLINE, Embase, ScieLO, Google Scholar, and Cochrane Controlled Trials databases. A fixed- or random-effects model was used. RESULTS: Five randomized clinical trials including 11,603 patients were identified and considered eligible for the analyses (5903 subjects were allocated to receive lipid-lowering therapy, while 5700 subjects were allocated to the respective placebo/control arms). The present meta-analysis revealed that lipid-lowering therapy was associated with a lower incidence of MALE (OR: 0.76, 95% confidence interval: 0.66-0.87; I2: 28%) compared to placebo/control groups. The sensitivity analysis shows that the results are robust. CONCLUSION: This study demonstrated that the use of lipid-lowering therapy compared with the placebo/control arms was associated with a marked reduction in the risk of MALE. Physicians involved in the monitoring and treatment of patients with PAD must work hard to ensure adequate lipid-lowering medication in these patients.
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Enfermedad Arterial Periférica , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/tratamiento farmacológico , Extremidades , LípidosRESUMEN
ABSTRACT BACKGROUND: Peripheral arterial disease (PAD) is characterized by progressive narrowing of the arterial lumen, resulting from atherosclerotic plaques. Treatment for PAD aims to control atherosclerosis and improve blood flow. Use of antiplatelet agents and anticoagulants has played important roles in helping to prevent occlusions and stenosis. OBJECTIVE: To evaluate the evidence from Cochrane systematic reviews regarding the accuracy, effectiveness and safety of use of anticoagulants and antiplatelets in lower-limb revascularization, in patients with peripheral arterial disease. METHODS: Systematic reviews found through searches in the Cochrane Library were included. Two authors evaluated whether the reviews found were in line with the inclusion criteria for this investigation. A qualitative synthesis of their findings was presented. RESULTS: Three systematic Cochrane reviews were included. Patients who underwent prosthetic bypass surgery probably presented greater benefit from use of antiplatelets, and patients who underwent vein revascularization probably presented greater benefit from use of anticoagulants. Patients who received endovascular treatment benefited from both antiplatelet and anticoagulant treatment. However, the reliability of the results found was impaired because at the time when these reviews were published, there was no mandatory assessment using the GRADE criteria. CONCLUSION: Despite the evidence found, it is necessary for these reviews to be updated in order to evaluate the degree of certainty of the results found.
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Humanos , Preparaciones Farmacéuticas , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Reproducibilidad de los Resultados , Fibrinolíticos/uso terapéuticoRESUMEN
BACKGROUND: Peripheral arterial disease (PAD) is characterized by progressive narrowing of the arterial lumen, resulting from atherosclerotic plaques. Treatment for PAD aims to control atherosclerosis and improve blood flow. Use of antiplatelet agents and anticoagulants has played important roles in helping to prevent occlusions and stenosis. OBJECTIVE: To evaluate the evidence from Cochrane systematic reviews regarding the accuracy, effectiveness and safety of use of anticoagulants and antiplatelets in lower-limb revascularization, in patients with peripheral arterial disease. METHODS: Systematic reviews found through searches in the Cochrane Library were included. Two authors evaluated whether the reviews found were in line with the inclusion criteria for this investigation. A qualitative synthesis of their findings was presented. RESULTS: Three systematic Cochrane reviews were included. Patients who underwent prosthetic bypass surgery probably presented greater benefit from use of antiplatelets, and patients who underwent vein revascularization probably presented greater benefit from use of anticoagulants. Patients who received endovascular treatment benefited from both antiplatelet and anticoagulant treatment. However, the reliability of the results found was impaired because at the time when these reviews were published, there was no mandatory assessment using the GRADE criteria. CONCLUSION: Despite the evidence found, it is necessary for these reviews to be updated in order to evaluate the degree of certainty of the results found.
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Enfermedad Arterial Periférica , Preparaciones Farmacéuticas , Fibrinolíticos/uso terapéutico , Humanos , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Reproducibilidad de los ResultadosRESUMEN
Resumo Contexto A pandemia do Coronavírus 2019 (COVID-19) tem afetado negativamente o comportamento da população. Nesse contexto, o impacto da pandemia da COVID-19 no tratamento medicamentoso dos pacientes com doença arterial periférica (DAP) e claudicação intermitente (CI) permanece obscuro. Objetivos Analisar o impacto da pandemia da COVID-19 no tratamento medicamentoso dos pacientes com DAP e CI. Métodos Neste estudo observacional transversal, 136 pacientes com DAP e CI, recrutados do nosso banco de dados, responderam por telefone um questionário envolvendo as seguintes questões: a) cuidados com a COVID-19; b) saúde global; c) tratamento das doenças. Posteriormente, os pacientes foram divididos em dois grupos, de acordo com a dificuldade para a aquisição dos medicamentos (DAM: dificuldade e SDAM: sem dificuldade), para a comparação da saúde global entre os dois grupos. Resultados Dezessete porcento dos pacientes reportaram dificuldades para a aquisição dos medicamentos durante a pandemia. Uma maior prevalência desses pacientes reportou estar mais triste (56,5% versus 24,8%, p < 0,01) e com mais dificuldades para dormir (56,5% versus 24,8%, p < 0,01) em relação aos pacientes do grupo SDAM. Os grupos não apresentaram diferenças para o declínio na capacidade de caminhada, ansiedade, estresse e depressão (p > 0,05). Conclusões Uma maior prevalência de pacientes do grupo DAM reportou estar mais triste e com mais dificuldade para dormir em comparação ao grupo SDAM durante a pandemia da COVID-19.
Abstract Background The Coronavirus 2019 (COVID-19) pandemic has had a negative impact on the population's behavior. In this context, the effect of the COVID-19 pandemic on drug treatment of patients with peripheral arterial disease (PAD) and intermittent claudication (IC) remains unclear. Objectives To analyze the impact of the COVID-19 pandemic on drug treatment of patients with PAD and IC. Methods In this cross-sectional, observational study, 136 patients with PAD and IC were recruited from our database and answered a questionnaire by telephone involving the following questions: a) precautions related to COVID-19; b) general health status; and c) treatment of diseases. Subsequently, patients were divided into two groups according to difficulty in obtaining their drugs (DOD: difficulty obtaining drugs, or NDOD: no difficulty obtaining drugs) and overall health was compared between groups. Results Seventeen percent of patients reported difficulties with obtaining drugs during the pandemic. A higher proportion of these patients reported being sadder (56.5% vs. 24.8%, P < 0.01) and having more difficulty sleeping (56.5% vs. 24.8%, P < 0.01) than of the patients in the NDOD group (P <0.01). The groups did not differ in terms of impairment of walking capability, anxiety, stress, or depression (P> 0.05). Conclusions A higher proportion of patients in the DOD group reported being sadder and having greater difficulty sleeping compared to the NDOD group during the COVID-19 pandemic.
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Humanos , Masculino , Femenino , Persona de Mediana Edad , Anciano , Aislamiento Social , Cumplimiento de la Medicación , Enfermedad Arterial Periférica/tratamiento farmacológico , COVID-19 , Claudicación Intermitente/tratamiento farmacológico , Ansiedad , Estudios Transversales , Caminata , Depresión , Calidad del Sueño , Accesibilidad a los Servicios de SaludRESUMEN
A hipertensão arterial é o fator mais potente no desenvolvimento da doença vascular aterosclerótica e um fator de risco importante para a doença arterial periférica (DAP) e suas complicações. A DAP é resultante do bloqueio das artérias que fornecem sangue aos membros inferiores, em geral secundário à aterosclerose. Destaca-se o aumento de casos de pacientes com DAP, juntamente com o crescimento da expectativa de vida, variando quantitativamente conforme o sexo e a comorbidade já em curso, tais como: hipertensão, diabetes, tabagismo; dislipidemia, idade, dentre outros. A maioria dos pacientes com DAP são assintomáticos ou não apresenta o sintoma mais presente: claudicação intermitente, mas quando sintomáticos estes podem referir dor, desconforto, queimação ou câimbra em membros inferiores. Para diagnóstico da DAP encontra-se como mais referenciado o índice tornozelo-braquial (ITB) com Doppler, mas também formas de se identificar a doença, por meio da angiotomografia, angioressonância magnética, arteriografia por punção direta, além do exame físico minuncioso, este sim imprescindível. A redução da pressão arterial sistólica (PAS) reduz eventos cardiovasculares e a meta atual para tratamento na DAP é de PA ≤ 140×90 mmHg (em diabéticos, considerar PA diastólica ≤ 85 mmHg). A terapia anti-hipertensiva deve ser administrada a pacientes com hipertensão e DAP para reduzir o risco de IM, AVC, insuficiência cardíaca e morte cardiovascular. O uso de inibidores da enzima conversora da angiotensina (IECA) ou bloqueadores dos receptores da angiotensina (BRA) são eficazes neste propósito e são drogas de escolha na hipertensão. Não há contra indicação aos betabloqueadores nestes pacientes. A cessação do tabagismo, exercícios, terapia com estatinas, terapia antiplaquetária com aspirina ou clopidogrel e, possivelmente, cilostazol em pacientes sem história de insuficiência cardíaca controlam parte dos fatores de risco, auxiliando assim a continuidade da assistência ao paciente com DAP quando da necessidade de angioplastia com stent, uso de balão arterial, cirurgia de by-pass, além da revascularização endovascular
Arterial hypertension is the most potent factor in the development of atherosclerotic vascular disease and an important risk factor for peripheral arterial disease (PAD) and its complications. PAD results from the blockage of the arteries that supply blood to the lower limbs, usually secondary to atherosclerosis. The increase in cases of patients with PAD stands out, together with the increase in life expectancy, varying quantitatively according to sex and comorbidity already underway, such as: hypertension, diabetes, smoking; dyslipidemia, age, among others. Most patients with PAD are asymptomatic or do not have the most common symptom: intermittent claudication, but when symptomatic they may report pain, discomfort, burning or cramps in the lower limbs. For the diagnosis of PAD, the ankle-brachial index (ABI) with Doppler is the most referenced, but also ways to identify the disease, through angiotomography, magnetic resonance angiography, arteriography by direct puncture, in addition to detailed physical examination. The reduction in systolic blood pressure (SBP) reduces cardiovascular events and the current target for treatment in PAD is BP ≤ 140 × 90 mmHg (in diabetics, consider diastolic BP ≤ 85 mmHg). Antihypertensive therapy should be administered to patients with hypertension and PAD to reduce the risk of MI, stroke, heart failure and cardiovascular death. The use of angiotensin-converting enzyme (ACEI) inhibitors or angiotensin receptor blockers (BRA) are effective in this regard and are drugs of choice in hypertension. There is no contraindication to beta-blockers in these patients. Smoking cessation, exercise, statin therapy, antiplatelet therapy with aspirin or clopidogrel and, possibly, cilostazol in patients without a history of heart failure control part of the risk factors, thus helping the continuity of assistance to patients with PAD when the need for stent angioplasty, use of an arterial balloon, bypass surgery, in addition to endovascular revascularization.
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Humanos , Enfermedad Arterial Periférica/tratamiento farmacológico , Factores de Riesgo de Enfermedad Cardiaca , Hipertensión/tratamiento farmacológicoRESUMEN
BACKGROUND: Case studies and reviews have shown that creatine supplementation can affect kidney function. The objective of this study is to verify the effects of 8 weeks of creatine supplementation on renal function (creatinine clearance: primary outcome) in patients with symptomatic peripheral arterial disease. METHODS: Twenty-nine patients, of both genders, were randomized (1:1) in a double-blind manner for administration of Placebo (PLA; n = 15) or creatine monohydrate (Cr; n = 14). The supplementation protocol consisted of 20 g/day for 1 week divided into 4 equal doses (loading phase), followed by single daily doses of 5 g in the subsequent 7 weeks (maintenance phase). Before and after the supplementation period, markers of renal function, serum creatinine, creatinine excretion rate, and creatinine clearance were evaluated. The Generalized Estimation Equation Model was used for comparison between groups. The level of significance was P < 0.05. RESULTS: No significant differences were found between groups before and after the intervention for serum creatinine (Cr: pre 1.00 ± 0.15 mL/dL vs. post 1.07 ± 0.16 mL/dL; PLA: pre 1.30 ± 0.53 mL/dL vs. post 1.36 ± 0.47 mL/dL, P = 0.590), creatinine excretion rate (Cr: pre 81.73 ± 43.80 mg/dL vs. post 102.92 ± 59.57 mg/dL; PLA: pre 74.37 ± 38.90 mg/dL vs. post 86.22 ± 39.94 mg/dL, P = 0.560), or creatinine clearance (Cr; pre 108 ± 59 mL/min/1.73 m2 vs. post 117 ± 52 mL/min/1.73 m2; PLA: pre 88 ± 49 mL/min/1.73 m2 vs. post 82 ± 47 mL/min/1.73 m2, P = 0.366). CONCLUSIONS: Eight weeks of creatine supplementation is safe and does not compromise the renal function of patients with peripheral arterial disease.
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Creatina/administración & dosificación , Suplementos Dietéticos , Tasa de Filtración Glomerular/efectos de los fármacos , Riñón/efectos de los fármacos , Enfermedad Arterial Periférica/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Brasil , Creatina/efectos adversos , Creatinina/sangre , Creatinina/orina , Suplementos Dietéticos/efectos adversos , Método Doble Ciego , Femenino , Humanos , Riñón/fisiopatología , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/fisiopatología , Eliminación Renal/efectos de los fármacos , Factores de Tiempo , Resultado del TratamientoRESUMEN
OBJECTIVES: To determine the indications for the use, potential benefits, and adverse reactions of alprostadil in a group of Colombian patients. METHODS: A retrospective cross-sectional study was conducted in patients diagnosed with critical limb ischemia who received alprostadil in five hospitals in Colombia between September 2011 and July 2017. We reviewed the clinical records of each patient to obtain the sociodemographic and pharmacological variables, clinical stages, complications, comorbidities, reported effectiveness and adverse reactions. RESULTS: Sixty-one patients treated with alprostadil were evaluated; 50.8% of patients were men, and the average age of 72.5 ± 10.7 years. A total of 86.9% of patients were hypertensive, and 65.6% were diabetic. A total of 77.0% presented ulceration, and this condition was considered as a diabetic foot in 57.4% of patients. A total of 81.9% of patients were classified as Fontaine stage 4; 60.7% received therapy as initially indicated, with an average of 19 days of alprostadil use. Regarding the therapy results, 58.0% of the patients with ulcers or trophic lesions showed improvement, 86.2% showed improvement of pain, and the limb was saved in 72.1% of patients. CONCLUSIONS: Critical limb ischemia was presented by patients with advanced age and high cardiovascular risk who were treated during severe and advanced stages where therapeutic options are limited. Treatment with alprostadil achieved satisfactory results with improvement in ulcers, pain, and limb salvage rates in this series of patients.
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Alprostadil/administración & dosificación , Isquemia/tratamiento farmacológico , Extremidad Inferior/irrigación sanguínea , Enfermedad Arterial Periférica/tratamiento farmacológico , Vasodilatadores/administración & dosificación , Administración Intravenosa , Anciano , Anciano de 80 o más Años , Alprostadil/efectos adversos , Colombia , Enfermedad Crítica , Estudios Transversales , Bases de Datos Factuales , Femenino , Humanos , Isquemia/diagnóstico , Isquemia/fisiopatología , Recuperación del Miembro , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/diagnóstico , Enfermedad Arterial Periférica/fisiopatología , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Grado de Desobstrucción Vascular/efectos de los fármacos , Vasodilatadores/efectos adversosRESUMEN
BACKGROUND: Patients with peripheral artery disease (PAD) undergoing a lower-extremity revascularization are at heightened risk for ischemic cardiac and limb events. Although intensification of antithrombotic therapy after revascularization has demonstrated benefit in coronary disease populations, this approach has not been well studied or shown consistent benefit in PAD. Recent trial evidence demonstrated that a treatment strategy of rivaroxaban added to background antiplatelet therapy reduced ischemic risk in patients following recent acute coronary syndromes, as well as in patients with stable atherosclerotic vascular disease. Whether these benefits extend to the population of patients with symptomatic lower-extremity PAD undergoing revascularization is the objective of the VOYAGER PAD trial. STUDY DESIGN: VOYAGER PAD is an international randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of rivaroxaban in symptomatic PAD patients undergoing a peripheral surgical and/or endovascular revascularization. Patients are randomized in a 1:1 ratio to either rivaroxaban 2.5 mg twice daily or placebo, on a background of low-dose aspirin (100 mg daily). In addition, the use of a limited course of P2Y12 inhibition is allowed at the discretion of the site investigator. The primary efficacy end point is a novel composite of myocardial infarction, ischemic stroke, cardiovascular death, acute limb ischemia, and major amputation of vascular etiology. The primary safety end point is major bleeding according to the Thrombolysis in Myocardial Infarction definition. Enrolment began in August 2015 and will complete randomization of at least 6,500 patients by January 2018. This event-driven trial is expected to observe outcomes over a mean patient follow-up of 30 months. CONCLUSIONS: VOYAGER PAD is evaluating the efficacy of rivaroxaban added to background antiplatelet therapy to reduce major cardiovascular and limb ischemic vascular outcomes in the high-risk population of PAD patients undergoing peripheral revascularization.
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Aspirina/administración & dosificación , Procedimientos Endovasculares/métodos , Extremidad Inferior/irrigación sanguínea , Enfermedad Arterial Periférica/tratamiento farmacológico , Rivaroxabán/administración & dosificación , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Inhibidores del Factor Xa/administración & dosificación , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/cirugía , Inhibidores de Agregación Plaquetaria , Antagonistas del Receptor Purinérgico P2Y/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Antiplatelet therapy with clopidogrel is recommended to reduce cardiovascular events in patients with peripheral artery disease (PAD); however, clopidogrel efficacy has not been adequately studied in this patient population. Therefore, we aimed to determine the effects of cilostazol therapy on platelet reactivity among PAD patients on clopidogrel. METHODS: We performed a cross-sectional pilot study of 46 Puerto Rican patients diagnosed with PAD. The cohort was divided based on use of clopidogrel and cilostazol (n=24) or clopidogrel alone (n=22). Platelet function was measured ex vivo using the VerifyNow P2Y12 assay. Genomic DNA was extracted from peripheral blood samples using the QIAamp DNA Blood Midi Kit, which was subjected to candidate variant genotyping (CYP2C19, ABCB1, PON1 and P2RY12) using TaqMan quantitative polymerase chain reaction assays. All analyses were performed using SAS version 9.4 (SAS Institute). RESULTS: Among all enrolled patients, 18 (39%) had high on-treatment platelet reactivity (HTPR). The mean platelet reactivity was 207±53 (range, 78-325) with higher P2Y12 reaction units in the non-cilostazol group, 224±45 vs. 191±55 on the cilostazol group (p=0.03). No significant differences were observed in the clinical or genetic variables between the two groups. A multiple regression analysis determined that history of diabetes mellitus (p=0.03), use of cilostazol (p=0.03) and hematocrit (p=0.02) were independent predictors of platelet reactivity. CONCLUSIONS: In Puerto Rican PAD patients on clopidogrel therapy, history of diabetes mellitus, use of cilostazol and hematocrit are independent predictors of platelet reactivity. Adjunctive cilostazol therapy may enhance clopidogrel efficacy among PAD patients with HTPR.
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Plaquetas/efectos de los fármacos , Enfermedad Arterial Periférica/complicaciones , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/farmacología , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tetrazoles/farmacología , Ticlopidina/análogos & derivados , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anciano , Arildialquilfosfatasa/genética , Cilostazol , Clopidogrel , Estudios Transversales , Citocromo P-450 CYP2C19 , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Humanos , Masculino , Proyectos Piloto , Pruebas de Función Plaquetaria , Receptores Purinérgicos P2Y12/genética , Tetrazoles/uso terapéutico , Ticlopidina/farmacología , Ticlopidina/uso terapéuticoRESUMEN
OBJECTIVE: We have previously shown that exogenous administration of the nuclear protein high mobility group box 1 (HMGB1) improves angiogenesis after tissue ischemia. Antagonizing HMGB1 prolongs muscle necrosis and deters regeneration. In this study, we evaluated HMGB1 expression in peripheral arterial disease (PAD) and the mechanisms that promote its release in a murine model of hindlimb ischemia. Specifically, we investigated how chloroquine (CQ), a commonly employed disease-modifying antirheumatic drug, promotes HMGB1 release from muscle. We hypothesized that CQ could increase HMGB1 locally and systemically, allowing it to mediate recovery from ischemic injury. METHODS: Muscle biopsies were performed on patients undergoing lower extremity surgery for non-PAD-related disease as well as for claudication and critical limb ischemia. Clinical symptoms and ankle-brachial indices were recorded for each patient. HMGB1 was detected in muscle sections using immunohistochemical staining. Unilateral femoral artery ligation was performed on both wild-type and inducible HMGB1 knockout mice. Wild-type mice were administered intraperitoneal CQ 2 weeks before and after femoral artery ligation. Laser Doppler perfusion imaging was used to determine perfusion recovery. Serum and tissue levels of HMGB1 were measured at designated time points. In vitro, cultured C2C12 myoblasts were treated with increasing doses of CQ. HMGB1, autophagosome formation, p62/SQSTM1 accumulation, caspase-1 expression and activity, and lactate dehydrogenase levels were measured in supernatants and cell lysates. RESULTS: Nuclear expression of HMGB1 was prominent in patients with claudication and critical limb ischemia (P < .05) compared with controls. CQ-treated mice had elevated serum HMGB1 and diffuse HMGB1 staining in muscle (P < .01). In wild-type mice, CQ treatment resulted in higher laser Doppler perfusion imaging ratios in the ischemic limb at 7 days (P < .03) and less fat replacement after 2 weeks (P < .03). In cultured myoblasts, CQ induced autophagosome accumulation, inhibited p62/SQSTM-1 degradation, and activated caspase-1. CONCLUSIONS: HMGB1 is prominently expressed in PAD muscle but mostly confined to the nucleus. Our in vivo data suggest that HMGB1 mobilization into the sarcoplasm and serum can be increased with CQ, possibly through caspase-1-mediated pathways. Whereas HMGB1 can be released by many cell types, these studies suggest that the muscle may be an important additional source that is relevant in PAD.
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Cloroquina/farmacología , Arteria Femoral/cirugía , Proteína HMGB1/metabolismo , Claudicación Intermitente/tratamiento farmacológico , Isquemia/tratamiento farmacológico , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Enfermedad Arterial Periférica/tratamiento farmacológico , Anciano , Animales , Autofagia/efectos de los fármacos , Velocidad del Flujo Sanguíneo , Estudios de Casos y Controles , Caspasa 1/metabolismo , Línea Celular , Modelos Animales de Enfermedad , Femenino , Proteína HMGB1/deficiencia , Proteína HMGB1/genética , Humanos , Claudicación Intermitente/metabolismo , Claudicación Intermitente/patología , Isquemia/metabolismo , Isquemia/patología , L-Lactato Deshidrogenasa/metabolismo , Ligadura , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedad Arterial Periférica/metabolismo , Enfermedad Arterial Periférica/patología , Recuperación de la Función , Flujo Sanguíneo Regional , Proteína Sequestosoma-1/metabolismo , Transducción de Señal/efectos de los fármacos , Regulación hacia ArribaRESUMEN
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.
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Atorvastatina/administración & dosificación , Dislipidemias/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/administración & dosificación , Claudicación Intermitente/tratamiento farmacológico , Isquemia/tratamiento farmacológico , Enfermedad Arterial Periférica/tratamiento farmacológico , Rosuvastatina Cálcica/administración & dosificación , Anciano , Anciano de 80 o más Años , Amputación Quirúrgica , Angiografía , Atorvastatina/efectos adversos , Biomarcadores/sangre , Enfermedad Crítica , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Prescripciones de Medicamentos , Dislipidemias/sangre , Dislipidemias/diagnóstico por imagen , Dislipidemias/mortalidad , Procedimientos Endovasculares , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Claudicación Intermitente/sangre , Claudicación Intermitente/diagnóstico por imagen , Claudicación Intermitente/mortalidad , Isquemia/sangre , Isquemia/diagnóstico por imagen , Isquemia/mortalidad , Estimación de Kaplan-Meier , Lípidos/sangre , Masculino , Persona de Mediana Edad , Enfermedad Arterial Periférica/sangre , Enfermedad Arterial Periférica/diagnóstico por imagen , Enfermedad Arterial Periférica/mortalidad , Pautas de la Práctica en Medicina/tendencias , Sistema de Registros , Estudios Retrospectivos , Factores de Riesgo , Rosuvastatina Cálcica/efectos adversos , Factores de Tiempo , Resultado del TratamientoRESUMEN
Peripheral artery disease (PAD) is a multifactorial disease initially triggered by reduced blood supply to the lower extremities due to atherosclerotic obstructions. It is considered a major public health problem worldwide, affecting over 200 million people. Management of PAD includes smoking cessation, exercise, statin therapy, antiplatelet therapy, antihypertensive therapy and surgical intervention. Although these pharmacological and non-pharmacological interventions usually increases blood flow to the ischemic limb, morbidity and mortality associated with PAD continue to increase. This scenario raises new fundamental questions regarding the contribution of intrinsic metabolic changes in the distal affected skeletal muscle to the progression of PAD. Recent evidence suggests that disruption of skeletal muscle mitochondrial quality control triggered by intermittent ischemia-reperfusion injury is associated with increased morbidity in individuals with PAD. The mitochondrial quality control machinery relies on surveillance systems that help maintaining mitochondrial homeostasis upon stress. In this review, we describe some of the most critical mechanisms responsible for the impaired skeletal muscle mitochondrial quality control in PAD. We also discuss recent findings on the central role of mitochondrial bioenergetics and quality control mechanisms including mitochondrial fusion-fission balance, turnover, oxidative stress and aldehyde metabolism in the pathophysiology of PAD, and highlight their potential as therapeutic targets.
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Mitocondrias/efectos de los fármacos , Enfermedad Arterial Periférica/tratamiento farmacológico , Preparaciones Farmacéuticas/administración & dosificación , Animales , Metabolismo Energético/efectos de los fármacos , Humanos , Músculo Esquelético/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
Introducción: El pie diabético es uno de los problemas más grave en la medicina contemporánea que aún no se ha resuelto. Actualmente el Heberprot-P ® constituye una alternativa terapéutica para su solución. Objetivos: Identificar en los pacientes con úlcera de pie diabético el grado de severidad de la enfermedad arterial periférica en función del índice tobillo/brazo y determinar la respuesta al tratamiento con Heberprot-P® según el grado de severidad de la enfermedad arterial periférica. Métodos: Estudio retrospectivo, descriptivo de corte transversal en 156 pacientes diabéticos ingresados entre junio de 2010 a diciembre de 2011 en el Instituto Nacional de Angiología y Cirugía Vascular por presentar una úlcera de pie diabético y recibieron tratamiento con Heberprot-P ®. Las variables estudiadas fueron: sexo, edad, tipo de diabetes y tiempo de evolución de la misma, grado de severidad de la enfermedad arterial periférica según los valores del índice tobillo-brazo, y el porcentaje de granulación a las ocho semanas de tratamiento. Resultados: Se observó una mayor proporción de pacientes con un grado de severidad normal los cuales tuvieron el 92,8 por ciento de respuesta al tratamiento. El 33,3 por ciento de no respuesta presentaba un grado severo de enfermedad arterial periférica. Conclusión: Los pacientes con un grado severo de enfermedad arterial periférica o valores bajos del índice de presiones tobillo-brazo no tienen una respuesta favorable a la administración del Heberprot-P®(AU)
Introduction: Heberprot-P® presently represents a therapeutic alternative for this illness. Objective: To determine the response to Heberprot-P ® treatment in patients with diabetic foot ulcers, depending on the level of severity of the peripheral arterial disease. Methods: Retrospective, descriptive and cross-sectional study of 156 patients with diabetic foot ulcers, who were admitted to the National Institute of Angiology and Vascular Surgery from June 2010 through December 2011. They were treated with Heberprot-P ® during hospitalization. The studied variables were sex, age, type of diabetes and time of progression, level of severity of the peripheral arterial disease according to the ankle-brachial pressure indexes, and the percentage of granulation after eight-week treatment. Results: The proportion of patients with normal level of disease was higher, 92.8 percent of whom positively responded to treatment whereas 7.2 percent did not. Among the patients with severe peripheral arterial disease, 33.3 percent showed no response to this treatment. Conclusion: The patients with severe peripheral arterial disease or low ankle-brachial pressure index do not show favorable response to the administration of Heberprot-P®(AU)
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Humanos , Pie Diabético/tratamiento farmacológico , Enfermedad Arterial Periférica/tratamiento farmacológico , Estudios RetrospectivosRESUMEN
OBJECTIVE: Abnormalities in skeletal muscle structure and function are important contributors to exercise intolerance and functional decline in peripheral arterial disease. In this study, we tested the hypothesis that administration of N-acetylcysteine (NAC) would improve fatigue resistance and ameliorate the histopathological changes in skeletal muscle in a mouse model of peripheral arterial disease. We also anticipated that NAC treatment would lower the levels of biomarkers of oxidative damage in the ischemic muscle. METHODS: Male Balb/c mice were subjected to bilateral ligation of the femoral artery and, after 2 weeks of recovery, received daily intraperitoneal injections of either NAC (150 mg/kg) or saline for 15 days. At the end of the treatment, the extensor digitorium longus (EDL) and soleus muscles were excised for assessment of contractile function in vitro and histological analysis. Free malondialdehyde and protein carbonyl levels were measured in the gastrocnemius muscle. RESULTS: In the soleus muscle, force after 10 minutes of submaximal tetanic stimulation (60 Hz, 300 ms trains, 0.3 trains/s) was higher (P < .05) in NAC-treated animals (45% ± 3% of the initial value; n = 7) when compared with controls (30.3% ± 3%; n = 8). No differences were found in fatigue development between groups in the EDL muscle (ligated NAC, 35.7% ± 1.9%; ligated saline, 37.5% ± 1.1%). In addition, there was a tendency for lower levels of connective tissue deposition in the soleus of animals treated with NAC (n = 6) when compared with those that received only saline (n = 9) (ligated NAC, 16% ± 2% vs ligated saline, 24% ± 2%; P = .057). No differences were found in lipid peroxidation or protein carbonyl levels between ligated saline and ligated NAC groups. CONCLUSIONS: Taken together, these results indicate that treatment with NAC improves fatigue resistance in the soleus but not the EDL muscle in a model of peripheral arterial insufficiency. CLINICAL RELEVANCE: Despite the increasing burden of peripheral arterial disease (PAD) and its detrimental consequences on the quality of life of the patients, few pharmacological therapies have shown to evoke meaningful effects on functional performance in these individuals. N-acetylcysteine is approved for clinical use, has minimal side effects and most important, has shown to consistently improve exercise performance in animals and humans. In this study, we showed, for the first time, that treatment with this drug at a dose amenable for clinical application evoked marked effects on fatigue resistance in the soleus muscle in a mouse model of PAD. These encouraging findings set the stage for translational studies to determine the acute and long-term impact of this drug on walking capacity in patients with PAD.
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Acetilcisteína/farmacología , Antioxidantes/farmacología , Fatiga Muscular/efectos de los fármacos , Músculo Esquelético/irrigación sanguínea , Músculo Esquelético/efectos de los fármacos , Enfermedad Arterial Periférica/tratamiento farmacológico , Animales , Biomarcadores/metabolismo , Colágeno/metabolismo , Tolerancia al Ejercicio/efectos de los fármacos , Arteria Femoral/cirugía , Ligadura , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones Endogámicos BALB C , Contracción Muscular/efectos de los fármacos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Estrés Oxidativo/efectos de los fármacos , Enfermedad Arterial Periférica/metabolismo , Enfermedad Arterial Periférica/patología , Enfermedad Arterial Periférica/fisiopatología , Carbonilación Proteica/efectos de los fármacos , Recuperación de la Función , Factores de TiempoRESUMEN
Peripheral arterial disease (PAD) is a significant cause of morbidity and mortality worldwide. Lifestyle changes, like the cessation of the use of tobacco as well as a modification of dietary and exercise habits, can be the most cost-effective interventions in patients with PAD. Smocking cessation is the most important intervention, since it increases survival in these patients. Antiplatelet therapy is an essential component in the treatment of peripheral arterial disease (PAD) of the lower extremities. In addition to delaying arterial obstructive progression, these agents are most usefull in reducing adverse cardiovascular events such as non-fatal myocardial infarction (MI), stroke and vascular death. Mainstay of treatment continues to be aspirin monotherapy (75-325mg daily). Current treatment for lower extremity PAD is directed towards the relief of symptoms and improvement in QoL. The two agents which have consistently been found to be most efficient in achieving these goals are cilostazol and naftidrofuryl oxalate. Naftidrofuryl oxalate may emerge as the most efficient and cost-effective treatment for symptom relief.
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Enfermedad Arterial Periférica/terapia , Antihipertensivos/uso terapéutico , Cilostazol , Ensayos Clínicos como Asunto , Dieta con Restricción de Grasas , Dieta Reductora , Método Doble Ciego , Quimioterapia Combinada , Drogas en Investigación/uso terapéutico , Terapia por Ejercicio , Humanos , Hipoglucemiantes/uso terapéutico , Hipolipemiantes/uso terapéutico , Metaanálisis como Asunto , Estudios Multicéntricos como Asunto , Nafronil/uso terapéutico , Enfermedad Arterial Periférica/dietoterapia , Enfermedad Arterial Periférica/tratamiento farmacológico , Inhibidores de Agregación Plaquetaria/uso terapéutico , Cese del Hábito de Fumar , Tetrazoles/uso terapéutico , Terapias en Investigación , Pérdida de PesoRESUMEN
BACKGROUND: Flaxseed is an important source of alpha-linolenic acid an essential omega-3 fatty acid. The possibility that a supplementation of the diet with foods rich in alpha-linolenic acid, antioxidants and fiber (like flaxseed) has not been investigated. METHODS/DESIGN: The primary objective is to determine whether consumption of a diet rich in FLAXseed over a one year period has any beneficial cardiovascular effects in patients with Peripheral Arterial Disease (FLAX-PAD study). This is a single center, prospective, double blinded, randomized controlled clinical trial aimed at in 110 patients over 40 years old and with peripheral arterial disease. Patients will receive 30 g of milled flaxseed (or placebo) per day. Primary endpoints are incidence of myocardial infarction and stroke. Secondary measures include: requirement for surgical interventions, exercise and cardiopulmonary performance, cardiac arrhythmias, serum lipid profile, arterial sufficiency, blood pressure, inflammatory profile, platelet function, changes in drug dosage levels, as well as nutrigenomic and biomarker profiles in the blood. Recruitment and baseline examinations started in October 2008. Baseline data of the 110 patients is shown. CONCLUSIONS: FLAX-PAD will generate data on the safety, tolerability, cardiovascular efficacy and genomic response to a diet rich in flaxseed. It will determine the effects on primary and secondary events (stroke, myocardial infarctions, angina pectoris, cardiac arrhythmias) as well as in secondary endpoints (exercise performance, blood pressure and circulating lipid levels) in patients with PAD.