RESUMO
Abdominal aortic aneurysm (AAA) pathogenesis is distinguished by vessel wall inflammation. Cyclooxygenase (COX)-2 and microsomal prostaglandin E synthase-1, key components of the most well-characterized inflammatory prostaglandin pathway, contribute to AAA development in the 28-day angiotensin II infusion model in mice. In this study, we used this model to examine the role of the prostaglandin E receptor subtype 4 (EP4) and genetic knockdown of COX-2 expression (70% to 90%) in AAA pathogenesis. The administration of the prostaglandin receptor EP4 antagonist AE3-208 (10 mg/kg per day) to apolipoprotein E (apoE)-deficient mice led to active drug plasma concentrations and reduced AAA incidence and severity compared with control apoE-deficient mice (P < 0.01), whereas COX-2 genetic knockdown/apoE-deficient mice displayed only a minor, nonsignificant decrease in incidence of AAA. EP4 receptor protein was present in human and mouse AAA, as observed by using Western blot analysis. Aortas from AE3-208-treated mice displayed evidence of a reduced inflammatory phenotype compared with controls. Atherosclerotic lesion size at the aortic root was similar between all groups. In conclusion, the prostaglandin E(2)-EP4 signaling pathway plays a role in the AAA inflammatory process. Blocking the EP4 receptor pharmacologically reduces both the incidence and severity of AAA in the angiotensin II mouse model, potentially via attenuation of cytokine/chemokine synthesis and the reduction of matrix metalloproteinase activities.
Assuntos
Aneurisma da Aorta Abdominal/fisiopatologia , Receptores de Prostaglandina E Subtipo EP4/fisiologia , Adulto , Angiotensina II , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/prevenção & controle , Ruptura Aórtica/prevenção & controle , Aterosclerose/patologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Técnicas de Silenciamento de Genes , Humanos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Pessoa de Meia-Idade , Naftalenos/farmacologia , Naftalenos/uso terapêutico , Fenilbutiratos/farmacologia , Fenilbutiratos/uso terapêutico , Receptores de Prostaglandina E Subtipo EP4/antagonistas & inibidores , Receptores de Prostaglandina E Subtipo EP4/deficiência , Receptores de Prostaglandina E Subtipo EP4/metabolismo , Transdução de Sinais/fisiologia , UltrassonografiaRESUMO
Patients with peripheral artery disease (PAD), consistent with others with atherosclerotic occlusive disorders, have autonomic dysfunction (as measured by low heart rate variability [HRV]) that predisposes them to sympathetically mediated cardiac arrhythmias and sudden death. Exercise therapy has been shown to increase HRV in patients with coronary artery disease by increasing parasympathetic modulation of heart rate. This study quantified the circulatory and autonomic effects of a progressive, 12-week home-based, low-intensity (pain-free walking) exercise program in PAD and intermittent claudication. Participants (N = 33, mean age 67.8 8.1 years) were randomly assigned to either a walking group (n = 18), whose members performed a structured, 12-week, progressive walking program 5 days/week for 12 weeks, or a comparison group (n = 15), whose members performed usual activities. Circulatory measures (heart rate, blood pressure, and rate pressure product) and autonomic measures (HRV) were obtained at the beginning (Week 1) and end (Week 12) of the study. Minimal change in circulatory measures occurred. However, spectral analysis of HRV revealed that autonomic function improved significantly in members of the walking group; specifically, there was an increase in parasympathetic and a decrease in sympathetic modulation. Members of the walking group also significantly increased maximal walking distance. These findings suggest that a structured, low-intensity, high-frequency walking program improves autonomic function by increasing HRV in patients with PAD.
Assuntos
Sistema Nervoso Autônomo/fisiopatologia , Pressão Sanguínea/fisiologia , Terapia por Exercício/métodos , Exercício Físico/fisiologia , Frequência Cardíaca/fisiologia , Claudicação Intermitente/fisiopatologia , Doença Arterial Periférica/fisiopatologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
OBJECTIVE: The purpose of this study was to establish the risk of rupture as related to size of abdominal aortic aneurysm (AAA), gender, and expansion of the aneurysm. METHODS: Between 1976 and 2001, 476 patients with conditions considered unfit for surgery with AAA 5.0 cm or more were followed with computed tomographic scans every 6 months until rupture, surgery, death, or deletion from follow-up. Surgery was performed for rupture (n = 22), improved medical condition (n = 37), increase in size (n = 95), symptoms (n = 17), and other reasons (n = 24). RESULTS: Fifty ruptures occurred during the follow-up period. The average risk of rupture (and standard error) in male patients with 5.0-cm to 5.9-cm AAA was 1.0% (0.01%) per year, in female patients with 5.0-cm to 5.9-cm AAA was 3.9% (0.15%) per year, in male patients with 6.0-cm or greater AAA was 14.1% (0.18%) per year, and in female patients with 6.0-cm or greater AAA was 22.3% (0.95%) per year. CONCLUSION: The risk of rupture in male patients with AAA 5.0 to 5.9 cm is low. The four-time higher risk of rupture in female patients with AAA 5.0 to 5.9 cm suggests a lower threshold for surgery be considered in fit women. The data regarding risk of rupture in patients with AAA 6.0 cm or more may allow more appropriate decision analysis for surgery in patients with unfit conditions with large AAA.
Assuntos
Aneurisma Roto/diagnóstico por imagem , Aneurisma Roto/etiologia , Aneurisma/complicações , Aneurisma/diagnóstico por imagem , Idoso , Aneurisma/terapia , Aneurisma Roto/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Razão de Chances , Análise de Regressão , Medição de Risco , Fatores de Risco , Índice de Gravidade de Doença , Fatores Sexuais , Taxa de Sobrevida , Fatores de Tempo , Tomografia Computadorizada por Raios XRESUMO
PURPOSE: We present extended follow-up findings of the Kingston prospective sizing program for patients with abdominal aortic aneurysm (AAA) smaller than 5.0 cm in diameter, with gender-specific analysis. METHODS: From 1976 to 2001, 895 patients (688 men, 207 women) with AAA smaller than 5.0 cm were entered, regardless of fitness, in a prospective sizing program in which computed tomography scans were obtained every 6 months. Operations were performed in fit patients with an increase in AAA size to 5 cm (n = 190), AAA expansion greater than 0.5 cm in 6 months (n = 27), or for other reasons (n = 33). Follow-up continued until AAA rupture, surgery, death, or removal from the program. RESULTS: No AAA smaller than 5.0 cm ruptured during prospective follow-up. There was a statistically significant increase in expansion rate relative to size at entry, with the highest mean expansion rate of 0.52 cm/y for AAA 4.5 to 4.9 cm in diameter. There was no significant difference in AAA expansion rate between men and women. The frequency of surgery was inversely related to age at entry, but was positively related to AAA size at entry, with patients with AAA 4.5 to 4.9 cm at entry 6.8 times more likely (95% confidence interval, 4.3-10.7) to undergo surgery than those with AAA 3.0 to 3.4 cm at entry. Women were older than men at entry, and age at entry in those undergoing surgery was significantly greater in women. CONCLUSIONS: The study confirms the results of the United Kingdom Small Aneurysm Trial and the Aneurysm Detection and Management Study, that is, that risk for rupture is extremely unlikely with AAA smaller than 5.0 cm, which enables safe follow-up surveillance programs in both men and women with AAA smaller than 5.0 cm.