RESUMO
INTRODUCTION: Immune-related adverse events (irAEs) due to immune checkpoint inhibitors may lead to discontinuation and treatment-related death. Acute aortitis is a rare but severe irAE. CASE PRESENTATION: A 67-year-old man with recurrent lower gingival carcinoma received nivolumab therapy. Twenty-three months later, he experienced chest compression, which resulted in syncope. Following a whole-body computed tomography (CT) scanning, which revealed diffuse thickening of the aorta, and systemic assessments of the causes of aortitis, he was diagnosed with acute aortitis due to irAE. Nivolumab discontinuation and oral steroids improved CT findings. However, 11 months after nivolumab discontinuation, he developed an aortic aneurysmal rupture. Endovascular aortic repair rescued him. A durable anti-cancer response was still observed 4 months after the aortic rupture. CONCLUSION: Although severe irAE, such as acute aortitis, occurred, the patient may still achieve a durable response. A broad examination and prompt treatment of irAE can help improve the patient's survival.
Assuntos
Ruptura Aórtica , Aortite , Carcinoma , Humanos , Masculino , Idoso , Nivolumabe/efeitos adversos , Aortite/induzido quimicamente , Aortite/diagnóstico por imagem , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/cirurgia , Tomografia Computadorizada por Raios XRESUMO
Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (P<0.0001 by log-rank test) in 8-week-old male homozygotes of osteoprotegerin gene-knockout mice given subcutaneous administration of Ang II for 28 days, with an incidence of 21% fatal aortic rupture and 23% aortic dissection, than in age-matched wild-type mice. Ang II-infused aorta of wild-type mice showed that osteoprotegerin immunoreactivity was present with proteoglycan. The absence of osteoprotegerin was associated with decreased medial and adventitial thickness and increased numbers of elastin breaks as well as with increased periostin expression and soluble receptor activator of nuclear factor-kappa B ligand concentrations. PEGylated human recombinant osteoprotegerin administration decreased all-cause mortality (P<0.001 by log-rank test), the incidence of fatal aortic rupture (P=0.08), and aortic dissection (P<0.001) with decreasing numbers of elastin breaks, periostin expressions, and soluble receptor activator of nuclear factor-kappa B ligand concentrations in Ang II-infused osteoprotegerin gene-knockout mice. Conclusions These data suggest that osteoprotegerin protects against aortic rupture and dissection in Ang II-induced hypertension by inhibiting receptor activator of nuclear factor-kappa B ligand activity and periostin expression.
Assuntos
Dissecção Aórtica , Ruptura Aórtica , Hipertensão , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Angiotensina II/farmacologia , Animais , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/genética , Ruptura Aórtica/prevenção & controle , Modelos Animais de Doenças , Elastina , Hipertensão/induzido quimicamente , Hipertensão/complicações , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Osteoprotegerina/genética , Osteoprotegerina/metabolismo , Ligante RANK/genética , Ligante RANK/metabolismoRESUMO
OBJECTIVE: Aortic aneurysm and dissection are major life-threatening complications of Marfan syndrome. Avoiding factors that promote aortic damage is critical in managing the care of these patients. Findings from clinical and animal studies raise concerns regarding fluoroquinolone use in patients at risk for aortic aneurysm and dissection. Therefore, we examined the effects of ciprofloxacin on aortic aneurysm and dissection development in Marfan mice. METHODS: Eight-week-old Marfan mice (Fbn1C1041G/+) were given ciprofloxacin (100 mg/kg/d; n = 51) or vehicle (n = 59) for 4 weeks. Mice were monitored for 16 weeks. Aortic diameters were measured by using ultrasonography, and aortic structure was examined by using histopathologic and immunostaining analyses. RESULTS: Vehicle-treated Fbn1C1041G/+ mice showed progressive aortic enlargement, with aortic rupture occurring in 5% of these mice. Compared with vehicle-treated Fbn1C1041G/+ mice, ciprofloxacin-treated Fbn1C1041G/+ mice showed accelerated aortic enlargement (P = .01) and increased incidences of aortic dissection (25% vs 47%, P = .03) and rupture (5% vs 25%, P = .005). Furthermore, ciprofloxacin-treated Fbn1C1041G/+ mice had higher levels of elastic fiber fragmentation, matrix metalloproteinase expression, and apoptosis than did vehicle-treated Fbn1C1041G/+ mice. CONCLUSIONS: Ciprofloxacin accelerates aortic root enlargement and increases the incidence of aortic dissection and rupture in Marfan mice, partially by suppressing lysyl oxidase expression and further compromising the inherited defect in aortic elastic fibers. Our findings substantiate that ciprofloxacin should be avoided in patients with Marfan syndrome.
Assuntos
Antibacterianos/toxicidade , Aorta/efeitos dos fármacos , Aneurisma Aórtico/induzido quimicamente , Dissecção Aórtica/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Ciprofloxacina/toxicidade , Fibrilina-1/genética , Remodelação Vascular/efeitos dos fármacos , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Dissecção Aórtica/patologia , Animais , Aorta/metabolismo , Aorta/ultraestrutura , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Ruptura Aórtica/genética , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Apoptose/efeitos dos fármacos , Dilatação Patológica , Progressão da Doença , Tecido Elástico/efeitos dos fármacos , Tecido Elástico/metabolismo , Tecido Elástico/ultraestrutura , Proteínas da Matriz Extracelular/metabolismo , Feminino , Predisposição Genética para Doença , Masculino , Metaloproteinases da Matriz/metabolismo , Camundongos Knockout , Fenótipo , Proteína-Lisina 6-Oxidase/metabolismoRESUMO
BACKGROUND: The perfused elastase AAA model and subcutaneous Angiotensin II infusion AAA model are widely used murine AAA models. We modified these two current models and developed a new murine model to study aneurysm formation and rupture. METHODS: The murine abdominal aorta was treated with elastase. Angiotensin II was infused at a dose of 1,000 ng/kg/min via an osmotic pump placed subcutaneously. A saline osmotic pump was used as the control. The aortas were harvested from the mice 4 weeks later, or earlier if mice died. The abdominal aorta was inspected using ultrasound and microscopy for aneurysm formation and/or signs of rupture. The aneurysm outcome was measured using aortic expansion and proinflammatory cytokine expression. It was also compared with the established conventional elastase perfusion and angiotensin II infusion abdominal aortic aneurysm models. RESULTS: By day 28 after surgery, all abdominal aortas of mice treated in the modified group had dilated and progressed to abdominal aortic aneurysms with 60% ruptured aneurysms, whereas none of the control aortas treated with saline became aneurysmal. In mice treated with elastase solution alone, 100% developed aneurysms and only one had a ruptured aneurysm. In mice given angiotensin II infusion alone, 37.5% developed aneurysms and none had a ruptured aneurysm. Histological examination of the modified murine abdominal aortic aneurysm rupture model was identical to that observed in the conventional elastase model. Quantitative polymerase chain reaction analysis revealed similarly increased levels of proinflammatory cytokines. CONCLUSIONS: We modified two current murine abdominal aortic aneurysm models to develop a murine abdominal aortic aneurysm model with consistent aneurysm formation and high rupture incidence, which can be used for studying abdominal aortic aneurysm rupture and treatment.
Assuntos
Angiotensina II , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Elastase Pancreática , Remodelação Vascular , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/fisiopatologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Ruptura Aórtica/fisiopatologia , Citocinas/metabolismo , Dilatação Patológica , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Fatores de TempoRESUMO
Aortic dissection (AD) is a life-threatening vascular disease with limited treatment strategies. Here, we show that loss of the GWAS-identified SH2B3 gene, encoding lymphocyte adaptor protein LNK, markedly increases susceptibility to acute AD and rupture in response to angiotensin (Ang) II infusion. As early as day 3 following Ang II infusion, prior to the development of AD, Lnk-/- aortas display altered mechanical properties, increased elastin breaks, collagen thinning, enhanced neutrophil accumulation, and increased MMP-9 activity compared with WT mice. Adoptive transfer of Lnk-/- leukocytes into Rag1-/- mice induces AD and rupture in response to Ang II, demonstrating that LNK deficiency in hematopoietic cells plays a key role in this disease. Interestingly, treatment with doxycycline prevents the early accumulation of aortic neutrophils and significantly reduces the incidence of AD and rupture. PrediXcan analysis in a biobank of more than 23,000 individuals reveals that decreased expression of SH2B3 is significantly associated with increased frequency of AD-related phenotypes (odds ratio 0.81). Thus, we identified a role for LNK in the pathology of AD in experimental animals and humans and describe a new model that can be used to inform both inherited and acquired forms of this disease.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/deficiência , Proteínas Adaptadoras de Transdução de Sinal/genética , Aorta/patologia , Dissecção Aórtica/genética , Ruptura Aórtica/genética , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/patologia , Angiotensina II/administração & dosagem , Animais , Aorta/efeitos dos fármacos , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/patologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Masculino , Camundongos , Camundongos KnockoutRESUMO
BACKGROUND AND AIMS: Angiotensin II (Ang II) infusion promotes the development of aortic aneurysms and accelerates atherosclerosis in ApoE-/- mice. In order to elucidate the role of hematopoietic cells in these pathologies, irradiation and bone marrow transplantation (BMT) are commonly utilized. The aim of this study was to investigate the effects of irradiation and BMT on abdominal and thoracic aortic aneurysm formation and acute leukocyte recruitment in the aortic root and descending aorta, in an experimental mouse model of aortic aneurysm formation. METHODS: ApoE-/- mice were either lethally irradiated and reconstituted with ApoE-/- bone marrow or non-irradiated. Following engraftment, mice were treated with Ang II to induce aortic inflammation and accelerate atherosclerosis. RESULTS: Ang II infusion (0.8â¯mg/kg/day) in BMT mice resulted in reduced aortic aneurysms and atherosclerosis with decreased leukocyte infiltration in the aorta compared to non-BMT mice, when receiving the same dose of Ang II. Furthermore, the reduced aortic infiltration in BMT mice was accompanied by increased levels of monocytes in the spleen and bone marrow. A dose of 3â¯mg/kg/day Ang II was required to achieve a similar incidence of aneurysm formation as achieved with 0.8â¯mg/kg/day in non-BMT mice. CONCLUSIONS: This study provides evidence that BMT can alter inflammatory cell recruitment in experimental mouse models of aortic aneurysm formation and atherosclerosis and suggests that irradiation and BMT have a considerably more complex effect on vascular inflammation, which should be evaluated.
Assuntos
Angiotensina II , Aneurisma da Aorta Abdominal/prevenção & controle , Aneurisma da Aorta Torácica/prevenção & controle , Aortite/prevenção & controle , Aterosclerose/prevenção & controle , Transplante de Medula Óssea , Irradiação Corporal Total , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aorta Torácica/metabolismo , Aorta Torácica/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/genética , Ruptura Aórtica/metabolismo , Ruptura Aórtica/prevenção & controle , Aortite/induzido quimicamente , Aortite/genética , Aortite/metabolismo , Aterosclerose/induzido quimicamente , Aterosclerose/genética , Aterosclerose/metabolismo , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/efeitos da radiação , Macrófagos/transplante , Masculino , Camundongos Knockout para ApoE , Monócitos/metabolismo , Monócitos/efeitos da radiação , Monócitos/transplante , Placa AteroscleróticaRESUMO
OBJECTIVE: The mechanisms underlying formation of arterial aneurysms remain incompletely understood. Because inflammation is a common feature during the progressive degeneration of the aortic wall, we studied the role of the costimulatory molecule CD40L, a major driver of inflammation, in aneurysm formation. APPROACH AND RESULTS: Transcriptomics data obtained from human abdominal aortic aneurysms and normal aortas revealed increased abundance of both CD40L and CD40 in media of thrombus-free and thrombus-covered human abdominal aortic aneurysms samples. To further unravel the role of CD40L in aneurysm formation, apolipoprotein E-deficient (Apoe-/-) and Cd40l-/-Apoe-/- mice were infused with angiotensin II for 7 and 28 days. Only a minority of Cd40l-/-Apoe-/- mice (33% and 17%) developed (dissecting) aneurysms compared with 75% and 67% of Apoe-/- littermates after 7 and 28 days of infusion, respectively. Total vessel area of the aorta at the suprarenal level was 52% smaller in angiotensin II-infused Cd40l-/-Apoe-/- mice compared with that in angiotensin II-infused Apoe-/- mice. Chimeric Apoe-/- mice repopulated with Cd40l-/-Apoe-/- bone marrow afforded a similar protection against dissecting aneurysm formation. Moreover, lack of CD40L protected mice from fatal aneurysm rupture. T helper cell and macrophage accumulation in aneurysmal tissue was reduced in Cd40l-/-Apoe-/- mice with a concomitant decrease in expression of proinflammatory chemo- and cytokines. In addition, aneurysms of Cd40l-/-Apoe-/- mice displayed reduced abundance of matrix metalloproteinase-13 and an increase in tissue inhibitor of metalloproteinase-3 while activity of matrix metalloproteinase-2 and matrix metalloproteinase-9 was diminished. CONCLUSIONS: Deficiency of (hematopoietic) CD40L protects against dissecting aneurysm formation and reduces the incidence of fatal rupture. This is associated with a decreased accumulation and activation of inflammatory cells and a dampened protease activity in the arterial wall.
Assuntos
Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/prevenção & controle , Dissecção Aórtica/prevenção & controle , Ruptura Aórtica/prevenção & controle , Ligante de CD40/deficiência , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Angiotensina II , Animais , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/genética , Ruptura Aórtica/metabolismo , Ligante de CD40/genética , Quimiocinas/genética , Quimiocinas/metabolismo , Citocinas/genética , Citocinas/metabolismo , Dilatação Patológica , Modelos Animais de Doenças , Humanos , Masculino , Metaloproteinase 13 da Matriz/genética , Metaloproteinase 13 da Matriz/metabolismo , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/genética , Metaloproteinase 9 da Matriz/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Inibidor Tecidual de Metaloproteinase-3/genética , Inibidor Tecidual de Metaloproteinase-3/metabolismoRESUMO
OBJECTIVE: The pathogenesis of aortic aneurysm (AA) is associated with chronic inflammation in the aortic wall with increased levels of matrix metalloproteinases (MMPs). Clarithromycin (CAM) has been reported to suppresses MMP activity. In this study, we investigated whether CAM could prevent the formation and rupture of AA. METHODS: Male apolipoprotein E-deficient mice (28-30 weeks of age) were infused with angiotensin II for 28 days. CAM (100 mg/kg/d) or saline (as a control) was administered orally to the mice every day (CAM group, n = 13; control group, n = 13). After the administration period, the aortic diameter, elastin content, macrophage infiltration, MMP levels, and levels of inflammatory cytokines, including nuclear factor κB (NF-κB), were measured. RESULTS: The aortic diameter was significantly suppressed in the CAM group (P < .001). No rupture death was observed in the CAM group in contrast to five deaths (38%) in the control group (P < .01). CAM significantly suppressed the degradation of aortic elastin (56.3% vs 16.5%; P < .001) and decreased the infiltration of inflammatory macrophages (0.05 vs 0.16; P < .01). Compared with the controls, the enzymatic activity of MMP-2 and MMP-9 was significantly reduced in the CAM group (MMP-2, 0.15 vs 0.56 [P < .01]; MMP-9, 0.12 vs 0.60 [P < .01]), and the levels of interleukin 1ß (346.6 vs 1066.0; P < .05), interleukin 6 (128.4 vs 346.2; P < .05), and phosphorylation of NF-κB were also decreased (0.3 vs 2.0; P < .01). CONCLUSIONS: CAM suppressed the progression and rupture of AA through the suppression of inflammatory macrophage infiltration, a reduction in MMP-2 and MMP-9 activity, and the inhibition of elastin degradation associated with the suppression of NF-κB phosphorylation.
Assuntos
Aorta/efeitos dos fármacos , Aneurisma Aórtico/prevenção & controle , Ruptura Aórtica/prevenção & controle , Claritromicina/administração & dosagem , Administração Oral , Angiotensina II , Animais , Aorta/metabolismo , Aorta/patologia , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/metabolismo , Aneurisma Aórtico/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Células Cultivadas , Modelos Animais de Doenças , Elastina/metabolismo , Mediadores da Inflamação/metabolismo , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Metaloproteinases da Matriz Secretadas/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , NF-kappa B/metabolismo , Fosforilação , Remodelação Vascular/efeitos dos fármacosRESUMO
OBJECTIVE: The purpose of this study was to establish a reliable, chronic model of abdominal aortic aneurysm (AAA). METHODS: Wild-type 8-week-old C56BL/6 male mice (n = 120) were equally divided into three groups: (1) BAPN group: 0.2% 3-aminopropionitrile fumarate salt (BAPN) drinking water was provided to mice 2 days before surgery until the end of study. Sham aneurysm induction surgery was performed using 5 µL of heat deactivated elastase. (2) Elastase group: mice were given regular drinking water without BAPN. During aneurysm induction surgery, 5 µL of the active form of elastase (10.3 mg protein/mL, 5.9 U/mg protein) was applied on top of the infrarenal abdominal aorta adventitia for 5 minutes. (3) BAPN+elastase group: mice were given BAPN drinking water and the active form of elastase application, as above. On postoperative days 7, 14, 21, 28, and 100, aortic samples were collected for histology, cytokine array, and gelatin zymography after aortic diameter measurement. RESULTS: Compared with the elastase group, the BAPN+elastase group had a higher AAA formation rate (93% vs 65%; P < .01) with more advanced AAAs (25 of 42 vs 1 of 40 for stage II and III; P < .001). Aneurysms from the BAPN+elastase group demonstrated persistent long-term growth (221.5% ± 36.6%, 285.8% ± 78.6%, and 801% ± 160% on days 21, 28, and 100, respectively; P < .001), with considerable thrombus formation (54%) and rupture (31%) at the advanced stages of AAA development. Cytokine levels (pro-matrix metalloproteinase 9, interleukin-1ß, interleukin-6, chemokine [C-C motif] ligand 5, triggering receptor expressed on myeloid cells 1, monocyte chemotactic protein 1, and tissue inhibitor of metalloproteinase 1) in the BAPN+elastase group were higher than in the elastase group on day 7. After day 7, cytokine levels returned to baseline, with the exception of elevated matrix metalloproteinase 2 activity. By histology, CD3-positive T cells in the BAPN+elastase group were elevated on days 28 and 100. CONCLUSIONS: A combination of oral BAPN administration and periaortic elastase application induced a chronic, advanced-stage AAA with characteristics of persistent aneurysm growth, thrombus formation, and spontaneous rupture. Future studies should use this model, especially for examining tissue remodeling during the late stages of aneurysm development.
Assuntos
Aminopropionitrilo/análogos & derivados , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Elastase Pancreática , Animais , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/induzido quimicamente , Doença Crônica , Citocinas/sangue , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Mediadores da Inflamação/sangue , Masculino , Camundongos Endogâmicos C57BL , Trombose/induzido quimicamente , Fatores de TempoRESUMO
BACKGROUND: To create a novel procedure that will decrease the mortality of experimental animals in the intraarterial infusion of elastase abdominal aortic aneurysm (AAA) model. METHODS: Novel models were created by means of direct puncture in the infrarenal abdominal aortic aorta, intraluminal elastase in the 1-cm segment of abdominal aorta. Femoral artery cannula approach and infusing with elastase was considered as the traditional group and that infusing with saline solution as the control group. Survival rate, morphology and histology of aneurysms, and inflammation mediators were calculated. RESULTS: Among the 36 rats, the average length from testicular arteries to left iliolumbar artery was 1.18 ± 0.22 cm, and 77.8% of them were longer than 1 cm. Procedure time was significantly shorter in novel group than that in 2 other groups (P = 0.006; P < 0.0001). During 24 hr postoperation, no death was observed in the novel group. Within 4 wk, survival rate in the control group was 60.6% and 80.8% in the novel group whereas 41.0% in the traditional group. Till the second week, all rats in the traditional and novel group had formed AAAs. And then, the survival rates and rupture rates of AAA between the 2 groups were similar within the following 2 wk (P = 0.487; P = 0.539). Inflammation degree and elastase content in intima media of aneurysms were similar (P = 0.720). However, Tumor necrosis factor alpha and Interleukin-1 beta levels were significantly lower in the novel group than those in the traditional group (P < 0.0001; P < 0.0001). CONCLUSIONS: A novel rat AAA model was created by intraluminal elastase infusion through direct puncture the infrarenal aorta. This model is efficient and reliable, with a high survival rate and with similar morphology and histology of aortic aneurysms.
Assuntos
Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Elastase Pancreática/administração & dosagem , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/sangue , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/patologia , Biomarcadores/sangue , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Mediadores da Inflamação/sangue , Infusões Intra-Arteriais , Interleucina-1beta/sangue , Masculino , Ratos Sprague-Dawley , Fatores de Tempo , Fator de Necrose Tumoral alfa/sangue , UltrassonografiaRESUMO
Background KLF15 (Krüppel-like factor 15) was reported to be involved in a lot of cardiovascular diseases. Little is known about its role in initiation and development of aortic dissection (AD). Methods Samples of the human aorta were collected during AD surgery and aortic valve replacement. Lentivirus was used for in vitro and in vivo KLF15 overexpression in BAPN (ß-aminopropionitrile)-induced rat AD models. The survival times were recorded and compared between the two groups. Autopsy was used for confirming aorta rupture in rat models. qPCR analyses were used for detecting gene expression whereas Western blot and immunostaining were used for detecting protein expression when necessary. Results KLF15 expression was much lower in the aorta walls of AD group patients than the control group subjects. The survival curve showed that the survival time of AD models was prolonged after KLF15 overexpression. qPCR and Western blot showed that connective tissue growth factors (CTGFs) were significantly downregulated in the rat aortas. After KLF15 overexpression in aortic adventitial fibroblasts, the KLF15 mRNA was increased whereas CTGF and its target gene collagens I and III were downregulated. Immunofluorescence staining also showed a decrease in CTGF, collagen I, and III. Lenti-control did not induce a significant change of KLF15, CTGF, collagen I, and III expressions. Conclusions KLF15 is involved in the mechanism of AD formation in human. Overexpression of KLF15 can partially rescue the aorta remodeling and AD formation in animal models. Our research highlighted a potential of KLF15 to serve as a new therapy target of AD.
Assuntos
Aminopropionitrilo , Aorta/metabolismo , Aneurisma Aórtico/prevenção & controle , Ruptura Aórtica/prevenção & controle , Fator de Crescimento do Tecido Conjuntivo/metabolismo , Terapia Genética/métodos , Fatores de Transcrição Kruppel-Like/biossíntese , Remodelação Vascular , Animais , Aorta/patologia , Aneurisma Aórtico/induzido quimicamente , Aneurisma Aórtico/genética , Aneurisma Aórtico/metabolismo , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/genética , Ruptura Aórtica/metabolismo , Células Cultivadas , Colágeno Tipo I/metabolismo , Colágeno Tipo III/metabolismo , Dilatação Patológica , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Humanos , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Masculino , Proteínas Nucleares/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais , Fatores de Tempo , Transfecção , Regulação para CimaRESUMO
RATIONALE: In-hospital outcomes are generally acceptable in patients with type B dissection; however, some patients present with undesirable complications, such as aortic expansion and rupture. Excessive inflammation is an independent predictor of adverse clinical outcomes. OBJECTIVE: We have investigated the underlying mechanisms of catastrophic complications after acute aortic dissection (AAD) in mice. METHODS AND RESULTS: When angiotensin II was administered in lysyl oxidase inhibitor-preconditioned mice, AAD emerged within 24 hours. The dissection was initiated at the proximal site of the descending thoracic aorta and propagated distally into an abdominal site. Dissection of the aorta caused dilatation, and ≈70% of the mice died of aortic rupture. AAD triggered CXCL1 and granulocyte-colony stimulating factor expression in the tunica adventitia of the dissected aorta, leading to elevation of circulating CXCL1/granulocyte-colony stimulating factor levels. Bone marrow CXCL12 was reduced. These chemokine changes facilitated neutrophil egress from bone marrow and infiltration into the aortic adventitia. Interference of CXCL1 function using an anti-CXCR2 antibody reduced neutrophil accumulation and limited aortic rupture post AAD. The tunica adventitia of the expanded dissected aorta demonstrated high levels of interleukin-6 (IL-6) expression. Neutrophils were the major sources of IL-6, and CXCR2 neutralization significantly reduced local and systemic levels of IL-6. Furthermore, disruption of IL-6 effectively suppressed dilatation and rupture of the dissected aorta without any influence on the incidence of AAD and neutrophil mobilization. CONCLUSIONS: Adventitial CXCL1/granulocyte-colony stimulating factor expression in response to AAD triggers local neutrophil recruitment and activation. This leads to adventitial inflammation via IL-6 and results in aortic expansion and rupture.
Assuntos
Túnica Adventícia/metabolismo , Aorta Torácica/metabolismo , Aneurisma da Aorta Torácica/metabolismo , Dissecção Aórtica/metabolismo , Ruptura Aórtica/metabolismo , Quimiocina CXCL1/metabolismo , Fator Estimulador de Colônias de Granulócitos/metabolismo , Ativação de Neutrófilo , Infiltração de Neutrófilos , Neutrófilos/metabolismo , Doença Aguda , Túnica Adventícia/diagnóstico por imagem , Idoso , Aminopropionitrilo/análogos & derivados , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/tratamento farmacológico , Angiotensina II , Animais , Anticorpos Monoclonais/farmacologia , Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/tratamento farmacológico , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/prevenção & controle , Aortografia , Quimiocina CXCL12/metabolismo , Quimiotaxia de Leucócito , Dilatação Patológica , Modelos Animais de Doenças , Feminino , Humanos , Mediadores da Inflamação/metabolismo , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/metabolismo , Interleucina-8/sangue , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Ativação de Neutrófilo/efeitos dos fármacos , Infiltração de Neutrófilos/efeitos dos fármacos , Neutrófilos/efeitos dos fármacos , Neutrófilos/transplante , Receptores de Interleucina-8B/antagonistas & inibidores , Receptores de Interleucina-8B/metabolismo , Transdução de Sinais , Fatores de TempoRESUMO
OBJECTIVE: To determine whether F-fluorodeoxyglucose (F-FDG) micro-positron emission tomography (micro-PET) can predict abdominal aortic aneurysm (AAA) rupture. BACKGROUND: An infrarenal AAA model is needed to study inflammatory mechanisms that drive rupture. F-FDG PET can detect vascular inflammation in animal models and patients. METHODS: After exposing Sprague-Dawley rats to intra-aortic porcine pancreatic elastase (PPE) (12 U/mL), AAA rupture was induced by daily, subcutaneous, ß-aminopropionitrile (BAPN, 300 mg/kg, N = 24) administration. Negative control AAA animals (N = 15) underwent daily saline subcutaneous injection after PPE exposure. BAPN-exposed animals that did not rupture served as positive controls [nonruptured AAA (NRAAA) 14d, N = 9]. Rupture was witnessed using radiotelemetry. Maximum standard uptakes for F-FDG micro-PET studies were determined. Aortic wall PAI-1, uPA, and tPA concentrations were determined by western blot analyses. Interleukin (IL)-1ß, IL-6, IL-10, and MIP-2 were determined by Bio-Plex bead array. Neutrophil and macrophage populations per high-power field were quantified. Matrix metalloproteinase (MMP) activities were determined by zymography. RESULTS: When comparing ruptured AAA (RAAA) to NRAAA 14d animals, increased focal F-FDG uptakes were detected at subsequent sites of rupture (P = 0.03). PAI-1 expression was significantly less in RAAA tissue (P = 0.01), with comparable uPA and decreased tPA levels (P = 0.02). IL-1ß (P = 0.04), IL-6 (P = 0.001), IL-10 (P = 0.04), and MIP-2 (P = 0.02) expression, neutrophil (P = 0.02) and macrophage presence (P = 0.002), and MMP9 (P < 0.0001) activity were increased in RAAA tissue. CONCLUSIONS: With this AAA rupture model, increased prerupture F-FDG uptake on micro-PET imaging was associated with increased inflammation in the ruptured AAA wall. F-FDG PET imaging may be used to monitor inflammatory changes before AAA rupture.
Assuntos
Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Ruptura Aórtica/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos , Aminopropionitrilo , Animais , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Biomarcadores/metabolismo , Modelos Animais de Doenças , Masculino , Tomografia por Emissão de Pósitrons/métodos , Ratos , Ratos Sprague-DawleyRESUMO
OBJECTIVE: Endoleak after endovascular aortic aneurysm repair (EVAR) can affect the durability of the repair and lead to continued sac expansion, rupture, and the need for further endovascular or open surgical interventions. The purpose of this study was to determine whether chronic anticoagulation therapy with warfarin is associated with an increased incidence of endoleak and thus increased need for reintervention after EVAR. METHODS: We reviewed the records of 401 consecutive patients who underwent EVAR at a single institution from 2003 until 2011. Patients on warfarin were compared with a control group not on warfarin. Primary endpoints included reintervention, defined as rupture, explant, or angiography; death from any cause; and a composite outcome of reintervention or death. The presence of an endoleak at last follow-up, identified by computed tomography or ultrasound scan, and increase of more than 5 mm in aneurysm sac size were secondary endpoints. Cox proportional hazards models were used to estimate the effect of warfarin use on the primary and secondary outcomes, controlling for age, gender, obesity, specific comorbidities, antiplatelet drugs, statin use, and urgency of EVAR. RESULTS: Three hundred sixty-three patients with a median follow-up period of 29 months had sufficient data for analysis. Warfarin use was not associated with an increased risk of any of the primary endpoints. Controlling for covariates and length of observation via proportional hazards models, the effect of warfarin remained insignificant. It was found, however, on regression analysis, that adverse outcomes were more prevalent after emergency EVAR and in patients deemed unfit for open surgical repair. CONCLUSIONS: Chronic oral anticoagulation does not appear to affect the incidence of endoleak after EVAR, nor does it impact the need for reintervention or degree of sac regression. We feel that warfarin may be safely used in post-EVAR patients. It appears that adverse long-term outcomes are more likely after emergency EVAR and in patients deemed unfit for open surgery.
Assuntos
Anticoagulantes/administração & dosagem , Aneurisma Aórtico/cirurgia , Implante de Prótese Vascular , Procedimentos Endovasculares , Varfarina/administração & dosagem , Idoso , Anticoagulantes/efeitos adversos , Aneurisma Aórtico/diagnóstico , Aneurisma Aórtico/mortalidade , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/mortalidade , Ruptura Aórtica/cirurgia , Aortografia/métodos , Implante de Prótese Vascular/efeitos adversos , Implante de Prótese Vascular/mortalidade , Esquema de Medicação , Procedimentos Cirúrgicos Eletivos , Emergências , Endoleak/induzido quimicamente , Endoleak/mortalidade , Endoleak/cirurgia , Procedimentos Endovasculares/efeitos adversos , Procedimentos Endovasculares/mortalidade , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Maine/epidemiologia , Masculino , Análise Multivariada , Valor Preditivo dos Testes , Modelos de Riscos Proporcionais , Reoperação , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Ultrassonografia Doppler Dupla , Varfarina/efeitos adversosRESUMO
A 63-year-old male patient with a type B aortic dissection after the use of tadalafil, a phosphodiesterase type 5 inhibitor, is presented. The possible role of a novel predisposing factor--sexual activity combined with tadalafil--is reviewed. This report and three other cases add a new dimension to the known predisposing factors such as chronic systemic hypertension, hereditary connective tissue diseases- and congenital aortic valve diseases. However, the precise role of phosphodiesterase type 5 inhibitors in the pathophysiology of aortic dissection remains unknown.
Assuntos
Aorta Torácica/patologia , Aneurisma da Aorta Torácica/induzido quimicamente , Dissecção Aórtica/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Carbolinas/efeitos adversos , Inibidores da Fosfodiesterase 5/efeitos adversos , Doença Aguda , Dissecção Aórtica/cirurgia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/cirurgia , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/cirurgia , Implante de Prótese Vascular , Carbolinas/uso terapêutico , Emergências , Procedimentos Endovasculares , Disfunção Erétil/tratamento farmacológico , Hemotórax/etiologia , Humanos , Masculino , Pessoa de Meia-Idade , Inibidores da Fosfodiesterase 5/uso terapêutico , Choque/etiologia , Stents , Tadalafila , Tomografia Computadorizada por Raios XRESUMO
It is reported a ruptured descending thoracic aortic aneurysm in a 25-year-old systemic lupus erythematosus woman who underwent 19 years steroid therapy. She was treated with 2 endovascular stent-grafts, discharged from hospital 13 days after the procedure in good health. Three months later she returned with hemorrhagic shock due to high digestive hemorrhage secondary to an aortic-esophageal fistula. She underwent to an open emergency surgery, and died during the post-operative period.
Assuntos
Aneurisma da Aorta Torácica/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Esteroides/efeitos adversos , Adulto , Aneurisma da Aorta Torácica/cirurgia , Ruptura Aórtica/cirurgia , Fístula Esofágica/complicações , Evolução Fatal , Feminino , Hemorragia/etiologia , Humanos , Stents , Fístula Vascular/complicaçõesRESUMO
It is reported a ruptured descending thoracic aortic aneurysm in a 25-year-old systemic lupus erythematosus woman who underwent 19 years steroid therapy. She was treated with 2 endovascular stent-grafts, discharged from hospital 13 days after the procedure in good health. Three months later she returned with hemorrhagic shock due to high digestive hemorrhage secondary to an aortic-esophageal fistula. She underwent to an open emergency surgery, and died during the post-operative period.
Paciente de 25 anos, do sexo feminino, portadora de lúpus eritematoso sistêmico, fazendo uso de corticoesteroide havia 19 anos, deu entrada em unidade de emergência com aneurisma roto de aorta torácica descendente. Foi submetida a tratamento endovascular com 2 stents, recebeu alta hospitalar no 13º dia de pós-operatório, em boas condições de saúde. Três meses depois, retornou em choque hemorrágico secundário a hemorragia digestiva alta. Feito o diagnóstico de fístula aorto-esofágica, foi submetida à cirurgia aberta de emergência, indo a óbito durante o período pós-operatório.
Assuntos
Adulto , Feminino , Humanos , Aneurisma da Aorta Torácica/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Esteroides/efeitos adversos , Aneurisma da Aorta Torácica/cirurgia , Ruptura Aórtica/cirurgia , Fístula Esofágica/complicações , Evolução Fatal , Hemorragia/etiologia , Stents , Fístula Vascular/complicaçõesRESUMO
A 53-year-old man was admitted to our hospital with thoracic back pain and weight loss. Computed tomography revealed inflammatory aortic aneurysm (IAA) of the descending aorta. Sealed rupture of the aneurysm occurred while the patient was under corticosteroid therapy. Endovascular aneurysm repair (EAR) was performed without postoperative complications. Periaortic fibrosis was remarkably decreased three months later while the patient was under prednisolone (20 mg) administration. We believe that EAR could become a practical alternative to open surgical repair. The possibility of an aneurysm rupturing during corticosteroid therapy for IAA should be considered.
Assuntos
Corticosteroides/efeitos adversos , Aneurisma da Aorta Torácica/diagnóstico , Ruptura Aórtica/diagnóstico , Endotélio Vascular/patologia , Procedimentos Cirúrgicos Vasculares , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/cirurgia , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/cirurgia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/cirurgia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Development and rupture of aortic aneurysms involve a combination of complex biological processes. Rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist, has been shown to have a broad spectrum of effects in vivo. The hypothesis that rosiglitazone would reduce aneurysm expansion or rupture was tested in the angiotensin II (Ang II)-induced hypercholesterolemic mouse model. METHODS AND RESULTS: Apolipoprotein E-deficient mice, 12 months of age, were allocated to 4 groups. Three groups were infused with Ang II (1 microg . min(-1) . kg(-1)), and the fourth was infused with saline. Rosiglitazone was given 1 week before infusion and 1 week after infusion. At day 28, aortic size was measured, and tissues were collected for analyses. Both pretreatment and posttreatment with rosiglitazone inhibited the occurrence of fatal rupture (11 of 30 versus 0 of 30 versus 0 of 15; P=0.0013) and reduced maximal dilatation of the aorta (4.6+/-0.13 versus 2.4+/-0.48 versus 2.15+/-0.46 mm2; P<0.0001). Blood glucose, total cholesterol, body weight, and atherosclerosis did not differ between groups. Pretreatment with rosiglitazone inhibited the Ang II-induced expression of angiotensin type 1a Ang II receptor while having no effect on the angiotensin type 2 Ang II receptor, in addition to reducing Ang II-induced expression of E-selectin, tumor necrosis factor-alpha, and interleukin-6. CONCLUSIONS: Pretreatment or posttreatment with RGZ reduced aortic expansion and rupture in this mouse model. Reduction of lesions in animals pretreated with rosiglitazone is concomitant with decreased expression of inflammatory mediators. Further studies are needed to elucidate the precise mechanism.
Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Ruptura Aórtica/prevenção & controle , Hipoglicemiantes/farmacologia , Tiazolidinedionas/farmacologia , Angiotensina II/efeitos adversos , Angiotensina II/farmacologia , Animais , Aneurisma da Aorta Abdominal/sangue , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/sangue , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/genética , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Colesterol/sangue , Modelos Animais de Doenças , Selectina E/sangue , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/induzido quimicamente , Hipercolesterolemia/genética , Hipercolesterolemia/patologia , Hipercolesterolemia/prevenção & controle , Interleucina-6/sangue , Camundongos , Camundongos Knockout , PPAR gama/agonistas , PPAR gama/genética , PPAR gama/metabolismo , Receptores de Angiotensina/sangue , Rosiglitazona , Fator de Necrose Tumoral alfa/sangueRESUMO
Cigarette smoking has been strongly associated with abdominal aortic aneurysm (AAA), but the components of tobacco smoke involved in AAA have not been identified. Benzo(a)pyrene (BaP) is an important constituent in cigarette smoke capable of induction of alterations strikingly similar to the pathological changes seen during AAA development. We therefore hypothesized that BaP exposure contributes to the development of AAA. In this study, C57/B6J mice were treated with vehicle, angiotensin II (AngII) (0.72 mg/kg/day), BaP (10 mg/kg/week), or the combination of AngII and BaP, for 5 weeks, and then examined for incidence of AAA and pathological changes of the aortic wall. Results showed that incidence of AAA formation in C57/B6J mice treated with BaP and AngII was significantly higher than that in AngII-treated mice (7 of 12 compared to 2 of 12). Further, five mice in the group treated with AngII/BaP and one in the group treated with AngII exhibited AAA rupture and hematoma. BaP caused macrophage infiltration, disarray of elastic lamella, and loss of vascular smooth muscle cells (VSMCs). We conclude that BaP aggravates AAA formation and rupture in C57/B6J mice by promoting macrophage infiltration, degeneration of elastic lamella, and loss of VSMCs in the aortic wall.