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CLINICAL PROBLEM: Most abdominal aortic aneurysms (AAAs) are small with low rupture risk (<1%/y) when diagnosed but slowly expand to ≥55 mm and undergo surgical repair. Patients and clinicians require medications to limit AAA growth and rupture, but drugs effective in animal models have not translated to patients. RECOMMENDATIONS FOR INCREASING TRANSLATION FROM MOUSE MODELS: Use models that simulate human AAA tissue pathology, growth patterns, and rupture; focus on the clinically relevant outcomes of growth and rupture; design studies with the rigor required of human clinical trials; monitor AAA growth using reproducible ultrasound; and perform studies in both males and females. SUMMARY OF STRENGTHS AND WEAKNESSES OF MOUSE MODELS: The aortic adventitial elastase oral ß-aminopropionitrile model has many strengths including simulating human AAA pathology and modeling prolonged aneurysm growth. The Ang II (angiotensin II) model performed less well as it better simulates acute aortic syndrome than AAA. The elastase plus TGFß (transforming growth factor-ß) blocking antibody model displays a high rupture rate, making prolonged monitoring of AAA growth not feasible. The elastase perfusion and calcium chloride models both display limited AAA growth.
Assuntos
Aneurisma da Aorta Abdominal , Ruptura Aórtica , Modelos Animais de Doenças , Animais , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Humanos , Ruptura Aórtica/prevenção & controle , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/patologia , Elastase Pancreática , Camundongos , Aorta Abdominal/patologia , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Feminino , Progressão da Doença , MasculinoRESUMO
BACKGROUND: Doxycycline has been shown to prevent arterial calcification via attenuation of matrix metalloproteinases (MMP) in preclinical models. We assessed the effects of doxycycline on progression of arterial calcification in patients enrolled in the Non-Invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (N-TA3CT). METHODS: Two hundred and sixty-one patients were randomized to 100 mg doxycycline twice daily or placebo. Arterial calcification was measured in abdominal vessels on noncontrast computed tomography scans. Patients with baseline computed tomography scan and 1 or more follow-up scans within the 2-year study were included for analysis. For individual arteries, mean change in iliofemoral artery calcification over time was calculated via linear regression. Serum MMP-3 and MMP-9 levels were measured at baseline and 6 months. RESULTS: Sixty-five patients in the doxycycline and 66 in the placebo arm were included in this analysis. Baseline characteristics between the groups were similar. The unadjusted mean change in iliofemoral calcium score per year trended toward higher values in patients treated with doxycycline compared with placebo (322 ± 399 units/year vs. 217 ± 307 units/year, P = 0.09). After 6 months, changes in serum MMP-3 and MMP-9 levels were not significantly different between study arms. CONCLUSIONS: In patients with small aortic aneurysm, treatment with doxycycline 100 mg twice daily did not decrease circulating levels of the matrix degrading enzymes MMP-3 and 9 or alter the progression of arterial calcification.
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OBJECTIVE: Current management of small abdominal aortic aneurysms (AAAs) primarily involves serial imaging surveillance of maximum transverse diameter (MTD) to estimate rupture risk. Other measurements, such as volume and tortuosity, are less well-studied and may help characterize and predict AAA progression. This study evaluated predictors of AAA volume growth and discusses the role of volume in clinical practice. METHODS: Subjects from the Non-invasive Treatment of Abdominal Aortic Aneurysm Clinical Trial (baseline AAA MTD, 3.5-5.0 cm) with ≥2 computed tomography scans were included in this study (n = 250). Computed tomography scans were conducted approximately every 6 months over 2 years. MTD, volume, and tortuosity were used to model growth. Univariable and multivariable backwards elimination least squares regressions assessed associations with volume growth. RESULTS: Baseline MTD accounted for 43% of baseline volume variance (P < .0001). Mean volume growth rate was 10.4 cm3/year (standard deviation, 8.8 cm3/year) (mean volume change +10.4%). Baseline volume accounted for 30% of volume growth variance; MTD accounted for 13% of volume growth variance. More tortuous aneurysms at baseline had significantly larger volume growth rates (difference, 32.8 cm3/year; P < .0001). Univariable analysis identified angiotensin II receptor blocker use (difference, -3.4 cm3/year; P = .02) and history of diabetes mellitus (difference, -2.8 cm3/year; P = .04) to be associated with lower rates of volume growth. Baseline volume, tortuosity index, current tobacco use, and absence of diabetes mellitus remained significantly associated with volume growth in multivariable analysis. AAAs that reached the MTD threshold for repair had a wide range of volumes: 102 cm3 to 142 cm3 in female patients (n = 5) and 105 cm3 to 229 cm3 in male patients (n = 20). CONCLUSIONS: Baseline AAA volume and MTD were found to be moderately correlated. On average, AAA volume grows about 10% annually. Baseline volume, tortuosity, MTD, current tobacco use, angiotensin II receptor blocker use, and history of diabetes mellitus were predictive of volume growth over time.
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Aneurisma da Aorta Abdominal , Antagonistas de Receptores de Angiotensina , Aneurisma da Aorta Abdominal/complicações , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Feminino , Humanos , Masculino , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: Abdominal aortic aneurysm (AAA) is a common progressive disease and a significant cause of morbidity and mortality. Prior investigations have shown that diabetes mellitus (DM) may be relatively protective of AAA incidence and growth. The Non-invasive Treatment of Aortic Aneurysm Clinical Trial (N-TA3CT) is a contemporary study of small AAA growth that provides a unique opportunity to validate and explore the effect of DM on AAA. Confirming the effect of DM on AAA growth in this study may present opportunities to explore for clues to potential biologic mechanisms as well as inform current patient management. METHODS: This is a secondary analysis examining the association of diabetes and aneurysm growth within N-TA3CT: a placebo-controlled multicenter trial of doxycycline in 261 patients with AAA maximum transverse diameters (MTDs) between 3.5 and 5 cm. The primary outcome is the change in the MTD from baseline as determined by computed tomography (CT) scans obtained during the trial. Secondary outcome is the growth pattern of the AAA. Baseline characteristics and growth patterns were assessed with t tests (continuous) or χ2 tests (categorical). Unadjusted and adjusted longitudinal analyses were performed with a repeated measures linear mixed model to compare AAA growth rates between patients with and without diabetes. RESULTS: Of 261 patients, 250 subjects had sufficient imaging and were included in this study. There were 56 patients (22.4%) with diabetes and 194 (77.6%) without. Diabetes was associated with higher body mass index and increased rates of hypercholesterolemia and coronary artery disease (P < .05). Diabetes was also associated with increased frequency of treatment for atherosclerosis and hypertension including treatment with statin, angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, anti-platelet, and diuretic therapy (P < .05). Baseline MTD was not significantly different between those with (4.32 cm) and without DM (4.30 cm). Median growth rate for patients with diabetes was 0.12 cm/y (interquartile range, 0.07-0.22 cm/y) and 0.19 cm/y (interquartile range, 0.12-0.27 cm/y) in patients without DM, which was significantly different on unadjusted analysis (P < .0001). Diabetes remained significantly associated with AAA growth after adjustment for other relevant clinical factors (coef, -0.057; P < .0001). CONCLUSIONS: Patients with diabetes have more than a 35% reduction in the median growth rates of AAA despite more severe concomitant vascular comorbidities and similar initial sizes of aneurysms. This effect persists and remains robust after adjusted analysis; and slower growth rates may delay the time to reach repair threshold. Rapid growth (>0.5 cm/y) is infrequent in patients with DM.
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Aneurisma da Aorta Abdominal , Diabetes Mellitus , Hipertensão , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/tratamento farmacológico , Aneurisma da Aorta Abdominal/epidemiologia , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/tratamento farmacológico , Diabetes Mellitus/epidemiologia , Humanos , Fatores de Risco , Tomografia Computadorizada por Raios XRESUMO
Importance: Abdominal aortic aneurysms affect more than 3% of US older adults. Objective: To test whether doxycycline reduces the growth of abdominal aortic aneurysm over 2 years as measured by maximum transverse diameter. Design, Setting, and Participants: Parallel, 2-group, randomized clinical trial that was conducted at 22 US clinical centers between May 2013 and January 2017, and enrolled patients 50 years or older with small (3.5-5.0 cm for men, 3.5-4.5 cm for women) infrarenal aneurysms. The final date of follow-up was July 31, 2018. Interventions: Patients were randomized to receive twice daily for 2 years doxycycline 100 mg orally (as capsules) (n = 133) or placebo (n = 128). Main Outcomes and Measures: The primary outcome was change in abdominal aortic aneurysm maximum transverse diameter measured from CT images at baseline and follow-up at 2 years. Patients were assigned ranks based on the maximum transverse diameter (measured or imputed) of the aorta and also if they underwent aneurysm repair or died. The ranks were converted to scores having a normal distribution to facilitate the primary analysis ("normal scores"). Results: Of 261 patients randomized, no follow-up CT scans were obtained on 7 (3%), leaving a final analysis set of 129 patients assigned to doxycycline and 125 to placebo (mean [SD] age, 71.0 years [7.4 years], 35 women [14%]). The outcome normal scores used in the primary analysis were based on maximum transverse diameter (measured or imputed) in 113 patients (88%) in the doxycycline group and 112 patients (90%) in the placebo group; aneurysm repair in 13 (10%) and 9 (7%), and death in 3 (2%) and 4 (3%), respectively. The primary outcome, normal scores reflecting change in aortic diameter, did not differ significantly between the 2 groups, mean change in normal scores, 0.0262 vs -0.0258 (1-sided P = .71). Mean (SD) baseline maximum transverse diameter was 4.3 cm (0.4 cm) for doxycycline and 4.3 cm (0.4 cm) for placebo. At the 2-year follow-up, the change in measured maximum transverse diameter was 0.36 cm (95% CI, 0.31 to 0.40 cm) for 96 patients in the doxycycline group vs 0.36 cm (95% CI, 0.30 to 0.41 cm) for 101 patients in the placebo group (difference, 0.0; 95% CI, -0.07 to 0.07 cm; 2-sided P = .93). No patients were withdrawn from the study because of adverse effects. Joint pain occurred in 84 of 129 patients (65%) with doxycycline and 79 of 125 (63%) with placebo. Conclusions and Relevance: Among patients with small infrarenal abdominal aortic aneurysms, doxycycline compared with placebo did not significantly reduce aneurysm growth at 2 years. These findings do not support the use of doxycycline for reducing the growth of small abdominal aortic aneurysms. Trial Registration: ClinicalTrials.gov Identifier: NCT01756833.
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Antibacterianos/uso terapêutico , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/tratamento farmacológico , Doxiciclina/uso terapêutico , Administração Oral , Idoso , Antibacterianos/efeitos adversos , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/crescimento & desenvolvimento , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/patologia , Doxiciclina/efeitos adversos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão/efeitos dos fármacos , Tomografia Computadorizada por Raios X , Falha de TratamentoRESUMO
OBJECTIVE: Routine computed tomography (CT) imaging in trauma patients has led to increased recognition of blunt vertebral artery injuries (BVIs). We sought to determine the prevalence of strokes, injury progression, and need for intervention in patients with BVI. METHODS: Consecutive patients presenting with BVI during 2 years were identified from the institutional trauma registry. Inpatient records, imaging studies, and follow-up data were reviewed in detail from the electronic medical record. RESULTS: There were 76 BVIs identified in 70 patients (64% male; mean age, 47 ± 19 years); bilateral injuries occurred in 6 patients. Five patients who arrived at the hospital intubated had evidence of posterior circulation infarcts on admission CT, whereas one additional patient had evidence of a posterior circulation infarct attributed to complications of late spinal surgery. Four of the five patients with infarcts on admission CT survived to discharge, but only one had residual stroke symptoms. Minor (grade 1 or grade 2) injuries occurred in 25 (36%) patients; severe (grade 3 or grade 4) injuries occurred in 45 (64%). Twelve patients died of associated injuries (eight with severe BVI, four with minor BVI). Stepwise logistic regression analysis selected age (odds ratio, 1.14; confidence interval, 1.04-1.25; P < .001) and intubation on arrival (odds ratio, 450.4; confidence interval, 17.41-1645.51; P < .001) as independent predictors of hospital stroke and death. Of the 58 surviving to discharge, 31 (53%) returned for follow-up CT scans. Six of 10 (60%) patients with minor injuries had resolution or improvement compared with 3 of 21 (14%) with severe injuries (P = .027). One patient (10%) with a minor BVI and two patients (10%) with severe BVI had radiologic progression, but none were clinically significant. During a mean follow-up of 15 ± 13 months, none of the study patients had treatment (surgical or interventional) for BVI, and there were no delayed strokes. Only five patients in this series had vertebral pseudoaneurysms, which limits conclusions about this type of BVI. CONCLUSIONS: These data suggest that BVI-related strokes are present at the time of admission and do not have clinical sequelae. No late strokes occurred in this series, and no surgical or interventional treatments were required even in the presence of radiographic worsening. The relatively few cases of vertebral pseudoaneurysms in this series limit any conclusions about these specific lesions. However, these data indicate that follow-up imaging of nonaneurysmal BVI is not necessary in adults who are found to be asymptomatic on follow-up.
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Angiografia por Tomografia Computadorizada , Procedimentos Desnecessários , Lesões do Sistema Vascular/diagnóstico por imagem , Dissecação da Artéria Vertebral/diagnóstico por imagem , Artéria Vertebral/diagnóstico por imagem , Ferimentos não Penetrantes/diagnóstico por imagem , Adulto , Idoso , Doenças Assintomáticas , Bases de Dados Factuais , Progressão da Doença , Registros Eletrônicos de Saúde , Feminino , Mortalidade Hospitalar , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prevalência , Prognóstico , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Acidente Vascular Cerebral/mortalidade , Lesões do Sistema Vascular/mortalidade , Lesões do Sistema Vascular/terapia , Artéria Vertebral/lesões , Dissecação da Artéria Vertebral/mortalidade , Dissecação da Artéria Vertebral/terapia , Ferimentos não Penetrantes/mortalidade , Ferimentos não Penetrantes/terapiaRESUMO
OBJECTIVE: Increasing evidence suggests that contractile dysfunction in smooth muscle cells (SMCs) plays a critical role in aortic biomechanical dysfunction and aortic aneurysm and dissection (AAD) development. However, the mechanisms underlying SMC contractile dysfunction in sporadic AAD are poorly understood. In this study, we examined the role of the NLRP3 (nucleotide oligomerization domain-like receptor family, pyrin domain containing 3)-caspase-1 inflammasome, a key inflammatory cascade, in SMC contractile dysfunction in AAD. APPROACH AND RESULTS: We observed significant SMC contractile protein degradation in aortas from patients with sporadic thoracic AAD. The contractile protein degradation was associated with activation of the NLRP3-caspase-1 inflammasome cascade. In SMCs, caspase-1 bound and directly cleaved and degraded contractile proteins, leading to contractile dysfunction. Furthermore, Nlrp3 or caspase-1 deficiency in mice significantly reduced angiotensin II-induced contractile protein degradation, biomechanical dysfunction, and AAD formation in both thoracic and abdominal aortas. Finally, blocking this cascade with the inflammasome inhibitor, glyburide (an antidiabetic medication), reduced angiotensin II-induced AAD formation. CONCLUSIONS: Inflammasome-caspase-1-mediated degradation of SMC contractile proteins may contribute to aortic biomechanical dysfunction and AAD development. This cascade may be a therapeutic target in AAD formation. In addition, glyburide may have protective effects against AAD development.
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Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Torácica/enzimologia , Dissecção Aórtica/enzimologia , Caspase 1/metabolismo , Inflamassomos/metabolismo , Proteínas Musculares/metabolismo , Músculo Liso Vascular/enzimologia , Miócitos de Músculo Liso/enzimologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Vasoconstrição , Idoso , Dissecção Aórtica/genética , Dissecção Aórtica/fisiopatologia , Dissecção Aórtica/prevenção & controle , Angiotensina II , Animais , Aorta Abdominal/efeitos dos fármacos , Aorta Abdominal/enzimologia , Aorta Abdominal/patologia , Aorta Abdominal/fisiopatologia , Aorta Torácica/efeitos dos fármacos , Aorta Torácica/enzimologia , Aorta Torácica/patologia , Aorta Torácica/fisiopatologia , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/prevenção & controle , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/fisiopatologia , Aneurisma da Aorta Torácica/prevenção & controle , Fenômenos Biomecânicos , Caspase 1/deficiência , Caspase 1/genética , Células Cultivadas , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Glibureto/farmacologia , Humanos , Inflamassomos/antagonistas & inibidores , Inflamassomos/genética , Masculino , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Fenótipo , Proteólise , Vasoconstrição/efeitos dos fármacosRESUMO
An embolic event originating from thrombus on an otherwise un-diseased or minimally diseased proximal artery (Phantom Thrombus) is a rare but significant clinical challenge. All patients from a single center with an imaging defined luminal thrombus with a focal mural attachment site on an artery were evaluated retrospectively. We excluded all patients with underlying anatomic abnormalities of the vessel at the attachment site. Six patients with a mean age of 62.5 years were identified over a 2.5-year period. All patients had completed treatment for or had a current diagnosis of malignancy and none were on antiplatelets or other anticoagulants. Four thrombi originated in the aorta proximal to the renal arteries and one originated distal. One thrombus was found in the common carotid artery and one was in an arterialized vein graft. Mean follow-up was 22 months. None of the patients underwent removal or exclusion of the embolic source. With systemic anticoagulation, four of the phantom thrombi were resolved on imaging within 8 weeks, one resolved after 72 weeks. One phantom thrombus reoccurred after 6 months on reduced anticoagulant dosing. There was one acute and one death in follow-up (26 months). One patient required a partial foot amputation secondary to tissue necrosis from the initial thromboembolic event. Arterial thrombi forming on otherwise normal vessels are a distinct clinical entity. In patients with a phantom thrombus, a strategy of therapeutic anticoagulation for management of the embolic source seems to be safe and effective over both the short and intermediate-term.
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Anticoagulantes/administração & dosagem , Artérias/diagnóstico por imagem , Procedimentos Endovasculares/métodos , Trombectomia/métodos , Tromboembolia , Trombose , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Avaliação de Processos e Resultados em Cuidados de Saúde , Administração dos Cuidados ao Paciente/métodos , Seleção de Pacientes , Tromboembolia/complicações , Tromboembolia/diagnóstico , Tromboembolia/etiologia , Tromboembolia/prevenção & controle , Trombose/diagnóstico , Trombose/etiologia , Trombose/terapiaRESUMO
OBJECTIVE: Medical management of acute aortic dissections limited to the descending thoracic aorta (AD-desc) is associated with acceptable outcomes. Uncertainty remains about whether acute type B aortic dissections involving the aortic arch (AD-arch) have an increased risk of retrograde extension into the ascending aorta or other dissection-related complications. This study compared outcomes of AD-arch with AD-desc managed medically. METHODS: Consecutive patients admitted from 2005 to 2014 with acute aortic dissections not involving the ascending aorta were retrospectively analyzed. Primary end points included dissection-related death and operative intervention. RESULTS: The study included 99 patients (63% men; mean age, 60 ± 14 years) with acute aortic dissections. Dissections were limited to the aorta distal to the left subclavian artery (AD-desc) in 79 patients (80%), and 20 (20%) had involvement of the left subclavian (n = 16), left common carotid (n = 1), or innominate (n = 3) arteries (AD-arch). Dissections ended proximal to the celiac artery in 30 patients (30%), between the celiac artery and aortic bifurcation in 36 (36%), and distal to the aortic bifurcation in 33 (33%). During medical management, further proximal extension into the arch occurred in two AD-arch patients and one AD-desc patient (P < .05), but proximal dissection into the ascending aorta occurred in only one AD-arch patient with Marfan disease. Compared with patients with AD-desc, those with AD-arch were younger (53 ± 12.5 vs 62 ± 16 years; P < .01) and had more frequent early interventions (40% vs 19%; P = .047), cardiac complications (35% vs 11%; P < .01), and neurologic events (25% vs 6%; P < .01). Seven AD-arch patients (35%) and nine AD-desc patients (11%) died of dissection-related causes (P < .01). Among survivors, late interventions were performed in four of eight AD-arch patients (50%) and in six of 58 AD-desc patients (10%; P = .02). Medical treatment without intervention was successful in four AD-arch patients (20%) and in 52 AD-desc patients (66%; P < .001). Multivariate logistic regression retained arch involvement as the sole predictor of dissection-related death (odds ratio, 4.2; 95% confidence interval, 1.3-13.4) and failure of medical treatment (odds ratio, 7.7; 95% confidence interval, 2.5-29). The distal extent of dissection had no bearing on outcome. CONCLUSIONS: AD-arch dissections are associated with a higher risk of cardiac and neurologic events, need for early intervention, and dissection-related death than AD-desc dissections. Because further proximal dissections into the ascending aorta were rare in this study, medical management appears to be safe as the initial treatment of AD-arch dissections. However, surgeons should be aware of the increased risk of complications and the potential need for urgent interventions in these patients.
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Aorta Torácica , Aneurisma da Aorta Torácica/terapia , Dissecção Aórtica/terapia , Fármacos Cardiovasculares/uso terapêutico , Doença Aguda , Adulto , Idoso , Dissecção Aórtica/complicações , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/mortalidade , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/cirurgia , Aneurisma da Aorta Torácica/complicações , Aneurisma da Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Torácica/mortalidade , Aortografia/métodos , Fármacos Cardiovasculares/efeitos adversos , Distribuição de Qui-Quadrado , Progressão da Doença , Feminino , Cardiopatias/etiologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Doenças do Sistema Nervoso/etiologia , Razão de Chances , Estudos Retrospectivos , Fatores de Risco , Tennessee , Fatores de Tempo , Tomografia Computadorizada por Raios X , Resultado do Tratamento , Procedimentos Cirúrgicos VascularesRESUMO
Abdominal aortic aneurysm (AAA) is a common vascular disease associated with high mortality rate due to progressive enlargement and eventual rupture. There is currently no established therapy known to alter the rate of aneurysmal expansion. Thus, understanding the processes that initiate and sustain aneurysmal growth is pivotal for the development of medical therapies aimed at halting disease progression. Using an elastase-induced AAA mouse model that recapitulates key features of human AAA, we previously reported that a natural IgG antibody directs alternative pathway complement activation and initiates the inflammatory process that culminates in aneurysmal development. The target of this natural antibody, however, was unknown. Herein we identify a natural IgG that binds to fibrinogen deposited in elastase-perfused aortic tissues, activates the complement lectin pathway (LP), and induces AAA. Moreover, we establish that alterations in the glycosylation patterns of this antibody critically affect its ability to activate the LP in vivo. We find that LP activation precedes the alternative pathway and absence of the LP complement protein mannan-binding lectin abrogates elastase-induced AAA. In human AAA tissues the mouse anti-fibrinogen antibody recognizes epitopes that localize to the same areas that stain positively for mannan-binding lectin, which suggests that the complement LP is engaged in humans as well. Lastly, we demonstrate that circulating antibodies in a subset of AAA patients react against fibrinogen or fibrinogen-associated epitopes in human aneurysmal tissues. Our findings support the concept that an autoimmune process directed at aortic wall self-antigens may play a central role in the immunopathogenesis of AAA.
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Aneurisma da Aorta Abdominal/etiologia , Ativação do Complemento/imunologia , Lectina de Ligação a Manose da Via do Complemento/imunologia , Fibrinogênio/imunologia , Imunoglobulina G/imunologia , Análise de Variância , Animais , Aneurisma da Aorta Abdominal/imunologia , Western Blotting , Ensaio de Imunoadsorção Enzimática , Proteínas da Matriz Extracelular/metabolismo , Imunofluorescência , Humanos , Imunoglobulina G/metabolismo , Imuno-Histoquímica , Imunoprecipitação , Camundongos , Camundongos Endogâmicos C57BL , Elastase PancreáticaAssuntos
Microbiota , Lesões do Sistema Vascular , Angioplastia , Humanos , Hiperplasia , InflamaçãoRESUMO
OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin II (AngII) to form angiotensin-(1-7) (Ang-(1-7)), which generally opposes effects of AngII. AngII infusion into hypercholesterolemic male mice induces formation of abdominal aortic aneurysms (AAAs). This study tests the hypothesis that deficiency of ACE2 promotes AngII-induced AAAs, whereas ACE2 activation suppresses aneurysm formation. APPROACH AND RESULTS: ACE2 protein was detectable by immunostaining in mice and human AAAs. Whole-body deficiency of ACE2 significantly increased aortic lumen diameters and external diameters of suprarenal aortas from AngII-infused mice. Conversely, ACE2 deficiency in bone marrow-derived cells had no effect on AngII-induced AAAs. In contrast to AngII-induced AAAs, ACE2 deficiency had no significant effect on external aortic diameters of elastase-induced AAAs. Because ACE2 deficiency promoted AAA formation in AngII-infused mice, we determined whether ACE2 activation suppressed AAAs. ACE2 activation by administration of diminazene aceturate (30 mg/kg per day) to Ldlr(-/-) mice increased kidney ACE2 mRNA abundance and activity and elevated plasma Ang-(1-7) concentrations. Unexpectedly, administration of diminazene aceturate significantly reduced total sera cholesterol and very low-density lipoprotein-cholesterol concentrations. Notably, diminazene aceturate significantly decreased aortic lumen diameters and aortic external diameters of AngII-infused mice resulting in a marked reduction in AAA incidence (from 73% to 29%). None of these effects of diminazene aceturate were observed in the Ace2(-/y) mice. CONCLUSIONS: These results demonstrate that ACE2 exerts a modulatory role in AngII-induced AAA formation, and that therapeutic stimulation of ACE2 could be a benefit to reduce AAA expansion and rupture in patients with an activated renin-angiotensin system.
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Aneurisma da Aorta Abdominal/etiologia , Aneurisma da Aorta Abdominal/metabolismo , Peptidil Dipeptidase A/metabolismo , Idoso , Angiotensina II/metabolismo , Enzima de Conversão de Angiotensina 2 , Animais , Aneurisma da Aorta Abdominal/patologia , Diminazena/análogos & derivados , Diminazena/farmacologia , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Feminino , Humanos , Hipercolesterolemia/complicações , Hipercolesterolemia/metabolismo , Leucócitos/enzimologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Peptidil Dipeptidase A/deficiência , Peptidil Dipeptidase A/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores de LDL/deficiência , Receptores de LDL/genética , Sistema Renina-AngiotensinaRESUMO
BACKGROUND: The purpose of this study was to further elucidate the role of the vascular smooth muscle cells (SMCs) in abdominal aortic aneurysm (AAA) disease. We hypothesized that that AAA SMCs are unique and actively participate in the process of degrading the aortic matrix. METHODS: Whole-genome expression profiles of SMCs from AAAs, nondilated abdominal aorta (NAA), and carotid endarterectomy (CEA) were compared. We quantified elastolytic activity by culturing SMCs in [(3)H]elastin-coated plates and measuring solubilized tritium in the media after 7 days. Matrix metalloproteinase (MMP)-2 and MMP-9 production was assessed using real-time polymerase chain reaction, zymography, and Western blotting. RESULTS: Each SMC type exhibited a unique gene expression pattern. AAA SMCs had greater elastolytic activity than NAA-SMCs (+68%; P < .001) and CEA-SMCs (+45%; P < .001). Zymography showed an increase of active MMP-2 (62 kD) in media from AAA SMCs. AAA SMCs demonstrated twofold greater expression of MMP-2 messenger (m)RNA (P < .05) and 7.3-fold greater MMP-9 expression (P < .01) than NAA-SMCs. Culture with U937 monocytes caused a synergistic increase of elastolysis by AAA SMCs (41%; P < .001) but not NAA-SMCs or CEA-SMCs (P = .99). Coculture with U937 caused a large increase in MMP-9 mRNA in AAA-SMCs and NAA-SMCs (P < .001). MMP-2 mRNA expression was not affected. Western blots of culture media showed a fourfold increase of MMP-9 (92 kD) protein only in AAA-SMCs/U937 but not in NAA-SMCs/U937 (P < .001) and a large increase in active-MMP2 (62 kD), which was less apparent in NAA-SMCs/U937 media (P < .01). CONCLUSIONS: AAA-SMCs have a unique gene expression profile and a proelastolytic phenotype that is augmented by macrophages. This may occur by a failure of post-transcriptional control of MMP-9 synthesis.
Assuntos
Aneurisma da Aorta Abdominal/genética , Elastina/genética , Expressão Gênica , Músculo Liso Vascular/metabolismo , RNA Mensageiro/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Western Blotting , Células Cultivadas , Elastina/biossíntese , Citometria de Fluxo , Humanos , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/biossíntese , Metaloproteinase 9 da Matriz/genética , Músculo Liso Vascular/patologia , Reação em Cadeia da Polimerase em Tempo RealRESUMO
Aneurysmal arterial disease is a vascular degenerative condition that is distinct from atherosclerotic and other occlusive arterial diseases. There is regionalization of the predisposition to aneurysm formation within the vascular tree, and the pathological process varies with location. Infrarenal abdominal aortic aneurysm (AAA) is the most common manifestation of aneurysmal disease, and smoking is the dominant risk factor. Smoking is a much greater risk factor for AAA than for atherosclerosis. In addition to playing a role in the pathogenesis of AAA, smoking also increases the rate of expansion and risk of rupture of established AAA. The mechanistic relationship between AAA and smoking is being established by the use of enhanced animal models that are dependent on smoke or smoke components. The mechanisms seem to involve durable alterations in vascular smooth muscle cell and inflammatory cell function. This review examines the clinical, epidemiological, and mechanistic evidence implicating smoking as a cause of aneurysms, focusing on AAA.
Assuntos
Aneurisma da Aorta Abdominal/epidemiologia , Fumaça/efeitos adversos , Fumar/efeitos adversos , Fumar/epidemiologia , Animais , Aneurisma da Aorta Abdominal/terapia , Ruptura Aórtica/epidemiologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Incidência , Prevalência , Prognóstico , Medição de Risco , Fatores de Risco , Comportamento de Redução do Risco , Fumaça/análise , Abandono do Hábito de Fumar , Prevenção do Hábito de FumarRESUMO
Androgen has long been recognized for its pivotal role in the sexual dimorphism of cardiovascular diseases, including aortic aneurysms (AAs), a devastating vascular disease with a higher prevalence and fatality rate in men than in women. However, the mechanism by which androgen mediates AAs is largely unknown. Here, we found that male, not female, mice developed AAs when exposed to aldosterone and high salt (Aldo-salt). We revealed that androgen and androgen receptors (ARs) were crucial for this sexually dimorphic response to Aldo-salt. We identified programmed cell death protein 1 (PD-1), an immune checkpoint, as a key link between androgen and AAs. Furthermore, we demonstrated that administration of anti-PD-1 Ab and adoptive PD-1-deficient T cell transfer reinstated Aldo-salt-induced AAs in orchiectomized mice and that genetic deletion of PD-1 exacerbated AAs induced by a high-fat diet and angiotensin II (Ang II) in nonorchiectomized mice. Mechanistically, we discovered that the AR bound to the PD-1 promoter to suppress the expression of PD-1 in the spleen. Thus, our study unveils a mechanism by which androgen aggravates AAs by suppressing PD-1 expression in T cells. Moreover, our study suggests that some patients with cancer might benefit from screenings for AAs during immune checkpoint therapy.