高血压致主动脉夹层机制研究及治疗进展
[1] MUSSA F F,HORTON J D,MORIDZADEH R,et al.
[J].JAMA,2016,316(7):754-763.
[本文引用:2] [2] CLOUGH R E,NIENABER C A .
[J].Nat Rev Cardiol,2015 12(2):103-114.
Acute aortic syndrome (AAS) describes the acute presentation of patients with characteristic 'aortic pain' caused by one of several life threatening thoracic aortic conditions including aortic dissection, intramural hematoma or penetrating atherosclerotic ulcer. Recent advances in imaging and therapeutic techniques have emphasized the importance of early diagnosis of acute aortic syndrome because it is crucial for survival. Not just because the cardiovascular community knows little, the management of AAS remains a therapeutic challenge, while diverse surgical and percutaneous strategies for the treatment of aortic syndromes are continuously evolving. As a result of increasing knowledge and better management strategies in this area, the outcomes of patients treated for acute aortic syndromes have improved. This review discusses the etiology and clinical presentation, but mainly focuses on modern management and both established and emerging therapeutic approaches to acute aortic syndromes.
[本文引用:1] [3] ERBEL R,ALFONSO F,BOILEAU C,et al.
[J].Eur Heart J,2001,22(18):1642-1681.
Erbel R(1), Alfonso F, Boileau C, Dirsch O, Eber B, Haverich A, Rakowski H, Struyven J, Radegran K, Sechtem U, Taylor J, Zollikofer C, Klein WW, Mulder B, Providencia LA; Task Force on Aortic Dissection, European Society of Cardiology.
[本文引用:1] [4] LO R C,BENSLEY R P,HAMDAN A D,et al.
[J].J Vasc Surg,2013,57(5):1261-1268.
Abstract OBJECTIVE: Prior studies of gender differences in abdominal aortic aneurysm (AAA) repair suggest there may be differences in presentation, suitability for endovascular aneurysm repair (EVAR), and outcomes between men and women. METHODS: We used the Vascular Study Group of New England database to identify all patients undergoing EVAR or open AAA repair. We analyzed demographics, comorbidities, and procedural, and perioperative data. Results were compared using the Fisher exact test and the Student t-test. Multivariable logistic regression and Cox proportional hazards modeling were performed to identify predictors of mortality. RESULTS: We identified 4026 patients (78% men) who underwent AAA repair (54% EVAR). Women were less likely than men to undergo EVAR for intact aneurysms (50% vs 60% of intact AAA repair; P .99) repairs. Late survival was worse in women than men only for patients undergoing open repair of ruptured aneurysms (hazard ratio, 1.8; 95% confidence interval, 1.0-3.1; P = .04). After controlling for age, type of repair, urgency at presentation (ie, elective/intact vs ruptured), comorbidities, and other relevant risk factors, gender was not predictive of 30-day or 1-year mortality. CONCLUSIONS: Women with AAAs are being treated at older ages and smaller AAA diameters and are undergoing rupture repair at smaller diameters than men. Women are more likely to experience perioperative complications as a result of less favorable vascular anatomy. Age >80 years, comorbidity, presentation, and type of repair are more important predictors of mortality than gender. Copyright 漏 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
[本文引用:1] [5] MOON M R.
[J].Surg Clin North Am,2009,89(4):869-893.
[本文引用:1] [6] OHLMANN P,FAURE A,MOREL O,et al.
[J].Crit Care Med,2006,34(5):1358-1364.
We sought to determine whether assessing D-Dimer might be helpful for the management of acute aortic dissection (AAD).Single-center retrospective case-control study.University Hospital of Strasbourg France.Patients were 94 consecutive patients admitted to our institution with confirmed AAD and in whom D-Dimer test had been performed at presentation. These patients were matched with 94 controls presenting with clinical suspicion of dissection, which was later ruled out.Patient characteristics and clinical course were analyzed.Ninety-three (99%) patients with AAD had elevated D-Dimer (>400 ng/mL) with a median D-Dimer value of 8610 ng/mL (interquartile range, 2982-20,000 ng/mL). Receiver operating characteristic curves analysis showed that D-Dimer, but not C-reactive protein, troponin, lactate dehydrogenase, or leukocyte count, was predictive of a diagnosis of AAD, with a sensitivity and specificity of 99% and 34%, respectively. D-Dimer concentration positively correlated with the anatomical extension of the dissection to the different segments of the aorta (R = .47, p 5200 ng/mL (odds ratio, 5.38; confidence interval, 1.27-30.87), and female gender (odds ratio, 4.96; confidence interval, 1.39-19.95).D-Dimers are elevated in patients with AAD and provide valuable diagnostic and prognostic information. In patients with acute chest pain and elevated D-Dimer, a diagnosis of AAD should also be considered. D-Dimer might be a useful complementary tool to the current diagnostic work-up of patients with suspected AAD.
[本文引用:1] [7] LANDENHED M,ENGSTROM G,GOTTSATER A,et al.
[J].J Am Heart Assoc,2015,4(1):e001513.
Abstract BACKGROUND: Community screening to guide preventive interventions for acute aortic disease has been recommended in high-risk individuals. We sought to prospectively assess risk factors in the general population for aortic dissection (AD) and severe aneurysmal disease in the thoracic and abdominal aorta. METHODS AND RESULTS: We studied the incidence of AD and ruptured or surgically treated aneurysms in the abdominal (AAA) or thoracic aorta (TAA) in 30 412 individuals without diagnosis of aortic disease at baseline from a contemporary, prospective cohort of middle-aged individuals, the Malm脙露 Diet and Cancer study. During up to 20 years of follow-up (median 16 years), the incidence rate per 100 000 patient-years at risk was 15 (95% CI 11.7 to 18.9) for AD, 27 (95% CI 22.5 to 32.1) for AAA, and 9 (95% CI 6.8 to 12.6) for TAA. The acute and in-hospital mortality was 39% for AD, 34% for ruptured AAA, and 41% for ruptured TAA. Hypertension was present in 86% of individuals who subsequently developed AD, was strongly associated with incident AD (hazard ratio [HR] 2.64, 95% CI 1.33 to 5.25), and conferred a population-attributable risk of 54%. Hypertension was also a risk factor for AAA with a smaller effect. Smoking (HR 5.07, 95% CI 3.52 to 7.29) and high apolipoprotein B/A1 ratio (HR 2.48, 95% CI 1.73 to 3.54) were strongly associated with AAA and conferred a population-attributable risk of 47% and 25%, respectively. Smoking was also a risk factor for AD and TAA with smaller effects. CONCLUSIONS: This large prospective study identified distinct risk factor profiles for different aortic diseases in the general population. Hypertension accounted for more than half of the population risk for AD, and smoking for half of the population risk of AAA. 脗漏 2015 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.
[本文引用:1] [8] FUKUDA S,WATANABE H,IWAKURA K,et al.
[J].Circ J,2015,79(3):524-529.
Physical examination as an initial screening tool to diagnose abdominal aortic aneurysm (AAA) has lost favor over the past 20 years. This multicenter cohort study aimed to determine the prevalence of AAA in elderly Japanese patients with hypertension (HT) and to clarify the diagnostic accuracy of physical examination using a pocket-sized ultrasound imaging device (the 'pocket-echo').Methods60and60Results:A total of 1,731 patients with HT aged >60 years from 20 collaborating institutions were enrolled in this study. Abdominal palpation was performed on physical examination, and the pocket-echo was used to confirm the diagnosis of AAA. The abdominal aorta was well visualized in 1,692 patients (98%). AAA was discovered in 69 patients (4.1%), with advanced age and male sex identified as independent risk factors. The prevalence of AAA increased according to age regardless of sex, and reached 9.2% and 5.7%, respectively, in males and females ≥80 years. Overall, 33 cases of AAA were missed on abdominal palpation (sensitivity, 52%), whereas for AAAs >40 mm, the sensitivity was 75%.We assessed the utility of the pocket-echo and physical examination for diagnosing AAA in Japanese patients with HT aged over 60 years. Our findings highlight the importance of AAA screening programs in high-risk Japanese populations, and confirm the ability of physical examination to detect large, but not small, AAAs. (Circ J 2015; 79: 524-529).
[本文引用:0] [9] JACKEL K,BRASCHLER T,KNECHTLE B.
[J].Praxis (Bern 1994),2015,104(8):411-417.
Abstract in English , German Wir berichteten über einen 65-j01hrigen Patienten, der sich mit einem A. axillaris-Aneurysma und einige Jahre sp01ter mit einer akuten Aortendissektion vom Typ Stanford A pr01sentierte. Nach chirurgischer Akutversorgung der Dissektion der Aorta konnte in der weiteren Abkl01rung keine spezifische 02tiologie gefunden werden. Die h02chstwahrscheinliche Ursache war eine inad01quat eingestellte arterielle Hypertonie. Daher zielt die Nachsorge auf die Therapie jener Risikofaktoren ab, von denen man weiss, dass sie das Wachstum eines Aortenaneurysmas f02rdern k02nnen. We report a 65 year old patient who presented with both an aneurysm of the axillary artery and, some years later, with an acute aortic dissection type Stanford A. After surgical intervention of the dissection in the further workup, no specific etiology could be found. The most likely reason for the two aneurysms was the inadequately treated hypertension. Therefore, follow-up strategies aim to treat the risk factors which are known to promote aneurysm growth.
[本文引用:1] [10] WANG F,XU B,SUN Z,et al.
[J].Neural Regen Res,2013 8(11):1007-1015.
Hemodynamic parameters play an important role in aneurysm formation and growth. However, it is difficult to directly observe a rapidly growing de novo aneurysm in a patient. To investigate possible associations between hemodynamic parameters and the formation and growth of intracranial aneurysms, the present study constructed a computational model of a case with an internal carotid artery aneurysm and an anterior communicating artery aneurysm, based on the CT angiography findings of a patient. To simulate the formation of the anterior communicating artery aneurysm and the growth of the internal carotid artery aneurysm, we then constructed a model that virtually removed the anterior communicating artery aneurysm, and a further two models that also progressively decreased the size of the internal carotid artery aneurysm. Computational simulations of the fluid dynamics of the four models were performed under pulsatile flow conditions, and wall shear stress was compared among the different models. In the three aneurysm growth models, increasing size of the aneurysm was associated with an increased area of low wall shear stress, a significant decrease in wall shear stress at the dome of the aneurysm, and a significant change in the wall shear stress of the parent artery. The wall shear stress of the anterior communicating artery remained low, and was significantly lower than the wall shear stress at the bifurcation of the internal carotid artery or the bifurcation of the middle cerebral artery. After formation of the anterior communicating artery aneurysm, the wall shear stress at the dome of the internal carotid artery aneurysm increased significantly, and the wall shear stress in the upstream arteries also changed significantly. These findings indicate that low wall shear stress may be associated with the initiation and growth of aneurysms, and that aneurysm formation and growth may influence hemodynamic parameters in the local and adjacent arteries.
[本文引用:1] [11] TAGUCHI E,NISHIGAMI K,MIYAMOTO S,et al.
[J].Heart Vessels,2014,29(1):78-82.
Weak aortic media layers can lead to intimal tear (IT) in patients with overt aortic dissection (AD), and aortic plaque rupture is thought to progress to penetrating atherosclerotic ulcer (PAU) with intramural hematoma (IMH). However, the influences of shear stress and atherosclerosis on IT and PAU have not been fully examined. Ninety-eight patients with overt AD and 30 patients with IMH and PAU admitted to our hospital from 2002 to 2007 were enrolled. The greater curvatures of the aorta, including the anterior and right portions of the ascending aorta and anterior portion of the aortic arch, were defined as sites of high shear stress. The other portions of the aorta were defined as sites of low shear stress based on anatomic and hydrodynamic theories. Aortic calcified points (ACPs) were manually counted on computed tomography slices of the whole aorta every 10 mm from the top of the arch to the abdominal bifurcation point. IT was more often observed at sites of high shear stress in overt AD than in PAU (73.5 vs 20.0 %, P < 0.0001). Significantly more ACPs were present in PAU than in overt AD (18.6 卤 8 vs 13.3 卤 10, P = 0.007). The present study suggests that high shear stress and less severe atherosclerosis could induce the occurrence of an IT, thereafter progressing to overt AD, and that low shear stress and more severe atherosclerosis could proceed to PAU with IMH. These findings may help to identify the entrance-tear site.
[本文引用:1] [12] RINAUDO A,PASTA S.
[J].Proc Inst Mech Eng H,2014,228(6):627-638.
The of an ascending is likely caused by excessive hemodynamic loads exerted on the aneurysmal wall. Computational fluid-dynamic analyses were performed on patient-specific ascending obtained from patients with either or tricuspid aortic valve to evaluate hemodynamic and wall shear parameters, imparting aneurysm enlargement. Results showed an accelerated flow along the outer aortic wall with helical flow in the aneurysm center for ascending . In a different way, tricuspid aortic valve ascending exhibited normal systolic flow without substantial secondary pattern. Analysis of wall shear parameters evinced a high and locally varying wall shear stress on the outer aortic wall and high temporal oscillations in wall shear stress (oscillatory shear index) on either left or right side of aneurysmal aorta. These findings may explain the asymmetric dilatation typically observed in ascending . Simulations of a hypertensive scenario revealed an increase in wall shear stress upon 44% compared to normal systemic pressure models. Computational fluid-dynamics-based analysis may allow identification of wall shear parameters portending aneurysm dilatation and hence guide preventative intervention.
[本文引用:1] [13] CASTRO M A,AHUMADA OLIVARES M C,PUTMAN C M,et al.
[J].Med Biol Eng Comput,2014,52(10):827-839.
The aim of this work was to determine whether or not Newtonian rheology assumption in image-based patient-specific computational fluid dynamics (CFD) cerebrovascular models harboring cerebral aneurysms may affect the hemodynamics characteristics, which have been previously associated with aneurysm progression and rupture. Ten patients with cerebral aneurysms with lobulations were considered. CFD models were reconstructed from 3DRA and 4DCTA images by means of region growing, deformable models, and an advancing front technique. Patient-specific FEM blood flow simulations were performed under Newtonian and Casson rheological models. Wall shear stress (WSS) maps were created and distributions were compared at the end diastole. Regions of lower WSS (lobulation) and higher WSS (neck) were identified. WSS changes in time were analyzed. Maximum, minimum and time-averaged values were calculated and statistically compared. WSS characterization remained unchanged. At high WSS regions, Casson rheology systematically produced higher WSS minimum, maximum and time-averaged values. However, those differences were not statistically significant. At low WSS regions, when averaging over all cases, the Casson model produced higher stresses, although in some cases the Newtonian model did. However, those differences were not significant either. There is no evidence that Newtonian model overestimates WSS. Differences are not statistically significant.
[本文引用:1] [14] RAPSOMANIKI E,TIMMIS A,GEORGE J,et al.
[J].Lancet,2014,383(9932):1899-1911.
[本文引用:1] [15] 肖子亚,姚晨玲,顾国嵘.
[J].中华心血管病杂志,2016,44(7):642-645.
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[本文引用:1] [16] WANG X,LEMAIRE S A,CHEN L,et al.
[J].Surgery,2005,138(2):352-359.
Thoracic aortic aneurysmal diseases are characterized by degeneration of elastin within the aortic wall. Although proteinases, such as matrix metalloproteinase, appear to contribute to elastin degradation, little is known about the role of elastic fiber assembly in such diseases. Fibulin-5 is an extracellular protein that is expressed in the vascular basement membrane and regulates elastic fiber assembly by microfibril machinery. In this study, we examined whether thoracic aortic dissection (TAD) is associated with abnormal fibulin-5 expression.Intraoperative aortic samples were obtained from 21 patients with proximal aortic dissection. Control aortic tissue was obtained from 11 organ donors, heart transplant recipients, and patients undergoing coronary artery bypass. An in vitro culture of vascular smooth muscle cells was obtained from 2 TAD patients and 1 control subject. To evaluate elastin expression, we stained tissue sections with Verhoeff-Van Gieson stain. Fibulin-5 messenger RNA (mRNA) expression was determined by quantitative real-time reverse-transcriptase-polymerase chain reaction.Aortic fibulin-5 mRNA and elastin content were decreased in TAD patients, compared with controls (P=.001 and P=.02, respectively). Decreased fibulin-5 expression strongly correlated with decreased amounts and fragmentation of elastin in aortic samples from patients with TAD (r=0.83, P < .0001 and F=20.7, P < .0001 respectively). The fibulin-5 mRNA in aortic vascular smooth muscle cells collected from TAD demonstrated a 38% decrease in expression, compared with the control.Patients with proximal aortic dissection exhibited significantly decreased expression of aortic fibulin-5. Decreased fibulin-5 may contribute to the pathogenesis of aortic dissection by impairing elastic fiber assembly.
[本文引用:1] [17] BAX D V,BERNARD S E,LOMAS A,et al.
[J].J Biol Chem,2003,278(36):34605-34616.
[本文引用:1] [18] HE R,GUO D C,ESTRERA A L,et al.
[J].J Thorac Cardiovasc Surg,2006,131(3):671-678.
Abstract OBJECTIVE: The histopathologic abnormality underlying ascending aortic aneurysm and dissection is medial degeneration, a lesion that is described as the noninflammatory loss of smooth muscle cells and elastic fibers. This study sought to determine whether inflammatory cells are present in medial degeneration and assess any possible contribution of these cells to apoptosis of smooth muscle cells. METHODS: Aortic specimens were obtained from patients undergoing prophylactic surgical repair of an ascending aortic aneurysm (n = 9) and type A dissection (n = 7), along with control patients dying of causes unrelated to aortic disease (n = 5). Immunohistochemical staining was performed to evaluate the presence of lymphocytes and macrophages, and markers of apoptosis were assessed in the aortas of patients with ascending aortic aneurysm and dissection. RESULTS: Immunohistochemical study indicated significantly more CD3 cells in the aortas of patients with aneurysms or dissections than in control aortas (P = .020 and P = .0022, respectively). In addition, aortas of patients with aneurysms or dissections had more CD68 cells (P = .01 and P = .005, respectively). CD3 cells were localized in the media and surrounding the vasa vasorum in the adventitia. Cells yielding a positive result on in situ terminal transferase-mediated deoxyuridine triphosphate nick end-labeling were found in increased numbers in the aortas of patients with aneurysms or dissections relative to control aortas (P = .005 and P = .002, respectively). Furthermore, Fas and FasL were increased in the aortic samples from patients with aneurysms and dissections relative to control aortas. CONCLUSION: The coexistence of inflammatory cells with markers of apoptotic vascular cell death in the media of ascending aortas with aneurysms and type A dissections raises the possibility that activated T cells and macrophages may contribute to the elimination of smooth muscle cells and degradation of the matrix associated with thoracic aortic aneurysms and dissections.
[本文引用:2] [19] LESAUSKAITE V,TANGANELLI P,SASSI C,et al.
[J].Hum Pathol,2001,32(9):1003-1011.
Abstract The etiopathogenesis of thoracic aortic aneurysms is currently an issue of debate. The present study investigated ultrastructural, morphometric, and immunohistochemical aspects of smooth muscle cells (SMCs) in chronic aneurysm of the thoracic aorta (aneurysm group), aortic dilatation associated with valvular disease (valvular group), and dissection of the thoracic aorta (dissection group). Fragments of the ascending aorta that had been taken from the patients during coronary bypass surgery were used as controls. No significant difference was observed in the density of SMCs between the 3 pathologic groups put together and the controls. Only separate analysis of SMC density in each of the pathologic groups showed that the valvular group samples had significantly smaller amounts of SMCs in the internal layer of the media than the dissection group samples and controls. Ultrastructural analysis, in situ end labeling, propidium iodide assay, and DNA laddering did not show apoptosis of SMCs in the samples investigated. Ultrastructure of SMCs characteristic of the synthetic phenotype, together with increased expression of osteopontin in the media of pathologic thoracic aortas indicated the transition of SMCs from the contractile to the synthetic phenotype. Immunohistochemical investigation showed that medial SMCs in the samples taken from aortas of all 3 pathologic groups expressed stronger immunoreactivity for matrix metalloproteinase 1, 2, and 9 and tissue inhibitor of metalloproteinase 1 and 2 than the controls. The present study shows that during the formation of aneurysms, dissection of the thoracic aorta, or aortic dilatation associated with valvular disease, loss of SMCs was not of great importance with respect to their transition from the contractile to the synthetic type in leading to increased production of matrix metalloproteinases. Copyright 2001 by W.B. Saunders Company
[本文引用:1] [20] ELKALIOUBIE A,HAULON S,DUHAMEL A,et al.
[J].Am J Cardiol,2015,116(9):1451-1456.
The high coronary artery disease (CAD) prevalence in patients with abdominal aortic aneurysm (AAA) is well known. However, the inverse relation has been little explored. We present, based on a systematic review and meta-analysis of the published evidence, a critical appraisal of the issue of AAA prevalence and also AAA predictive risk factors in patients with CAD, comparing it with AAA prevalence in subjects without CAD. A total of 22 studies involving 13,388 patients with CAD met the inclusion criteria. Overall, AAA prevalence in patients with CAD was 8.4% (95% confidence interval [CI] 6.9 to 10.3), significantly higher than in subjects without CAD (odds ratio [OR] 2.42, 95% CI 2.08 to 2.81). Pooled analysis revealed that smoking, arterial hypertension, and concomitant carotid artery stenosis were significantly associated with AAA in patients with CAD (OR 1.72, 95% CI 1.14 to 2.61; OR 1.57, 95% CI 1.06 to 2.35; OR 2.14, 95% CI 1.20 to 3.79, respectively). In patients with CAD, AAA prevalence tended to be higher with concomitant peripheral artery disease (OR 2.66, 95% CI 0.82 to 8.61, p= 0.08). In conclusion, AAA prevalence was significantly higher in patients with CAD versus subjects without CAD.
[本文引用:1] [21] HILGERS R H,TODD J Jr,WEBB R C.
[J].J Hypertens,2007,25(8):1687-1697.
The phosphorylation of myosin light chain (MLC) maintains the contracted state of vascular smooth muscle. Dephosphorylation results in relaxation and is determined by the activity of myosin light chain phosphatase (MLCP), which is negatively regulated by Rho kinase. We tested whether an increased Rho kinase activity, and hence a decreased contribution of MLCP, results in an increased contractility of small fourth-order mesenteric arteries (MA) during the early onset of angiotensin II (Ang II)-induced hypertension (Ang II-14d). Calcium sensitivity was similar, but contractile tension in response to [Ca]ex (5 mmol/l) in endothelium-denuded and depolarized MA was greater, in Ang II-14d rats compared to sham-operated normotensive (SHAM) and Ang II-1d. The Rho kinase inhibitor Y-27,632 caused a significantly greater inhibition of the contractile response to various agents (phenylephrine, norepinephrine, U46,619 and K) in MA of Ang II-14d compared to SHAM. Protein expression levels of the GDP/GTP exchange factor PDZ-RhoGEF, which co-immunoprecipitated with RhoA, were increased in MA of Ang II-14d compared to SHAM. RhoA translocation was greater in U46,619 (1 micromol/l)-stimulated MA of Ang II-14d compared to SHAM. Expression levels of Rho kinase beta were higher in MA of Ang II-14d. The MLCP inhibitor calyculin A (100 nmol/l) caused a greater contraction in MA of SHAM compared to Ang II-14d. Phosphorylation of the target subunit of MLCP (MYPT1) was enhanced in U46,619-stimulated MA of Ang II-14d compared to SHAM. This is the first study demonstrating enhanced PDZ-RhoGEF/RhoA/Rho kinase signaling during hypertension at the level of resistance-sized arteries. This enhanced signaling leads to increased MLCP phosphorylation, resulting in vascular hyper-reactivity.
[本文引用:1] [22] 袁重红,杨志昌,王凯玲,等.
[J].医学综述,2014,20(18):3365-3366.
高血压与主动脉夹层的形成有密不可分的联系.众多因素导致的高血压长期作用于血管壁可引起主动脉血管壁发生病变,其结构极易在高血压的进一步影响下被撕裂出现损伤,从而使血液进入血管壁形成血肿,剥离管壁形成主动脉夹层.该文主要阐述血管的结构、血压的形成、调节及高血压的形成、高血压与主动脉内膜撕裂之间的联系,在解剖学与组织学的知识层面上探究并整合高血压与主动脉夹层发病机制间的关系以及容易致病的相关因素及联系.
[本文引用:1] [23] BARBETSEAS J,ALEXOPOULOS N,BRILI S,et al.
[J].Circ J,2008,72(11):1773-1776.
The role of atherosclerosis in thoracic aortic dissection has not been established yet. Transesophageal echocardiography (TEE) is an imaging modality widely used in the diagnostic evaluation of thoracic aortic dissection, and it can detect aortic atherosclerotic plaques and assess their size and specific characteristics.One hundred consecutive patients with thoracic aortic dissection and adequate imaging of the thoracic aorta by TEE were studied. The type of dissection (proximal or distal) and the presence and the degree of aortic atherosclerosis were defined. Proximal aortic dissection (Stanford type A) was found in 64 patients. Patients with proximal dissection were younger than those with distal (type B; 58 /-13 vs 67 /-11 years, p<0.001). The prevalence of arterial hypertension was higher in patients with distal dissection compared with those with proximal. Aortic atherosclerosis was present in less patients with proximal than with distal dissection (67% vs 94%, p<0.002). Logistic regression analysis revealed that patients with severe atherosclerosis were 7.6-fold more probable to have type B than type A dissection (p<0.001).Aortic atherosclerosis is more associated with distal than with proximal aortic dissection.
[本文引用:1] [24] HABASHI J P,DOYLE J J,HOLM T M,et al.
[J].Science,2011,332(6027):361-365.
[本文引用:1] [25] JU X,IJAZ T,SUN H,et al.
[J].Arterioscler Thromb Vasc Biol,2013,33(7):1612-1621.
[本文引用:2] [26] IJAZ T,TILTON R G,BRASIER A R.
[J].J Thorac Dis,2016,8(8):E746-754.
Abstract On April 29, 2015, Son and colleagues published an article entitled 'Granulocyte macrophage colony-stimulating factor (GM-CSF) is required for aortic dissection/intramural haematoma' in Nature Communications. The authors observed that the heterozygous Kruppel-like transcription factor 6 (KLF6) deficiency or absence of myeloid-specific KLF6 led to upregulation of macrophage GM-CSF expression, promoted the development of aortic hematoma/dissection, and stimulated abdominal aortic aneurysm (AAA) formation when the vessel wall was subjected to an inflammatory stimulus. The additional findings of increased adventitial fibrotic deposition, marked infiltration of macrophages, and increased expression of matrix metalloprotease-9 (MMP-9) and IL-6 were blocked with neutralizing GM-CSF antibodies, or recapitulated in normal mice with excess GM-CSF administration. The authors concluded that GM-CSF is a key regulatory molecule in the development of AAA and further suggested that activation of GM-CSF is independent of the transforming growth factor 脦虏 (TGF脦虏)-Smad pathway associated with the Marfan aortic pathology. In this perspective, we expand on this mechanism, drawing from previous studies implicating a similar essential role for IL-6 signaling in macrophage activation, Th17 expansion and aortic dissections. We propose a sequential 'two-hit' model of vascular inflammation involving initial vascular injury followed by recruitment of Ly6C(hi) macrophages. Aided by fibroblast interactions inflammatory macrophages produce amplification of IL-6 and GM-CSF expression that converge on a common, pathogenic Janus kinase (JAK)-signal transducers and activations of transcription 3 (STAT3) signaling pathway. This pathway stimulates effector functions of macrophages, promotes differentiation of Th17 lymphocytes and enhances matrix metalloproteinase expression, ultimately resulting in deterioration of vascular wall structural integrity. Further research evaluating the impact of interventions modulating this common JAK-STAT3 pathway may yield new therapeutic interventions for late stages of vascular expansion in inflammation driven aortic disease.
[本文引用:1] [27] KHAN J A,ABDUL RAHMAN M N,MAZARI F A,et al.
[J].Ann Vasc Surg,2012,26(3):322-329.
The influence of intraluminal thrombus (ILT) on the proteolytic environment within the wall of an abdominal aortic aneurysm (AAA) is unknown. This is the first study to examine the correlation between ILT thickness and the levels of matrix metalloproteinases (MMPs) and their natural inhibitors (tissue inhibitors of matrix metalloproteinases [TIMPs]) within the adjacent AAA wall.Thirty-five patients undergoing elective repair of AAAs were studied. A single full-thickness infrarenal aortic sample was obtained uniformly from the arteriotomy site from each patient. All samples were snap frozen and analyzed for total and active MMP 2, 8, and 9 and TIMP 1 and 2. Thrombus thickness at the specimen site was measured on the preoperative contrast computed tomographic angiograms.There was a statistically significant correlation between ILT thickness, concentration of TIMP 1, and active concentration of MMP 9. MMP 2 (active and total) and TIMP 2 demonstrated a positive correlation with ILT thickness, although not statistically significant.In this novel study, we found a significant positive correlation of ILT thickness with active MMP 9 and TIMP 1 concentration in the adjacent AAA wall, and this may have implications for AAA expansion and eventual rupture.
[本文引用:1] [28] XIONG W,KNISPEL R,MACTAGGART J,et al.
[J].J Biol Chem,2009,284(3):1765-1771.
During arterial aneurysm formation, levels of the membrane-anchored matrix metalloproteinase, MT1-MMP, are elevated dramatically. Although MT1-MMP is expressed predominately by infiltrating macrophages, the roles played by the proteinase in abdominal aortic aneurysm (AAA) formation in vivo remain undefined. Using a newly developed chimeric mouse model of AAA, we now demonstrate that macrophage-derived MT1-MMP plays a dominant role in disease progression. In wild-type mice transplanted with MT1-MMP-null marrow, aneurysm formation induced by the application of CaCl2 to the aortic surface was almost completely ablated. Macrophage infiltration into the aortic media was unaffected by MT1-MMP deletion, and AAA formation could be reconstituted when MT1-MMP / macrophages, but not MT1-MMP / lymphocytes, were infused into MT1-MMP-null marrow recipients. In vitro studies using macrophages isolated from either WT/MT1-MMP-/- chimeric mice, MMP-2-null mice, or MMP-9-null mice demonstrate that MT1-MMP alone plays a dominant role in macrophage-mediated elastolysis. These studies demonstrate that destruction of the elastin fiber network during AAA formation is dependent on macrophage-derived MT1-MMP, which unexpectedly serves as a direct-acting regulator of macrophage proteolytic activity.
[本文引用:1] [29] SARACINI C,BOLLI P,STICCHI E,et al.
[J].J Vasc Surg,2012,55(1):171-179.
Abdominal aortic aneurysm (AAA) has a multifactorial etiology and the relevance of genetic factors is getting increasing interest, in particular those related to the destructive remodeling of extracellular matrix.We performed a candidate gene association study of polymorphisms in genes coding matrix metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs), and elastin (ELN) in AAA. DNA samples from 423 AAA patients and 423 controls were genotyped for 12 polymorphisms in 10 genes: MMP1 (-1607G/GG), MMP2 (-735C/T; -1306C/T; -1575 G/A), MMP3 (5A/6A), MMP9 (-1562C/T), MMP10 (A180G), MMP-12 (-82A/G), MMP-13 (-77A/G), TIMP1 (C434T), TIMP3 (-1296T/C), and ELN (G1355A).Genotype distribution was significantly different between patients and controls for the following polymorphisms: -1306C/T MMP2; 5A/6A MMP3; -77A/G MMP-13; G1355A ELN; and C434T TIMP1. In a multivariable logistic regression analysis adjusted for traditional cardiovascular risk factors and chronic obstructive pulmonary disease, -1306C/T MMP2 (odds ratios [OR] = 0.55 [95% confidence interval, CI .34-.85], P < .007) and G1355A ELN (OR = 0.64 ([95% CI .41-.99], P = .046) polymorphisms resulted in independent protective factors for abdominal aortic aneurysm (AAA), whereas 5A/6A MMP3 (OR = 1.82 [95% CI 1.04-3.12], P = .034) and -77 A/G MMP-13 (OR = 2.14 [95% CI 1.18-3.86], P = .012) polymorphisms resulted in independent risk factors for AAA. In a multivariable logistic regression analysis adjusted for traditional cardiovascular factors and chronic obstructive pulmonary disease, the prevalence of the contemporary presence of three or four genetic risk conditions was a strong and independent determinant of AAA disease (OR = 2.96, 95% CI 1.67-5.24, P < .0001). For those polymorphisms independently associated with AAA in this study (-1306C/T MMP2, 5A/6A MMP3, -77A/G MMP-13, and G1355A ELN polymorphisms), we performed a meta-analysis of the available data (this paper and literature data). We found a significant association with an increased risk of AAA for MMP3 (AAA patients n = 1258, controls n = 1406: OR = 1.48 [95% CI = 1.23-1.78], I(2) = 0%) and MMP-13 (AAA patients n = 800, controls n = 843: OR = 1.37 [95% CI = 1.04-1.82], I(2) = 25%) polymorphisms and a trend that did not reach the statistical significance, toward a decreased risk of AAA for MMP2 (AAA patients n = 1090, controls n = 1077: OR = 0.83 [95% CI = .60-1.15], I(2) =7 1%) and ELN (AAA patients n = 904, controls n = 1069: OR = 0.79 [95% CI = .53-1.18], I(2) = 72%) polymorphisms.These findings suggest that polymorphisms in MMP2, MMP3, MMP-13, and ELN genes may independently contribute to the pathogenesis of AAA.
[本文引用:1] [30] DEGUARA J,BURNAND K G,BERG J,et al.
[J].Hum Mol Genet,2007,16(24):3002-3007.
Matrix metalloproteinase 3 (MMP3), is over expressed in the wall of abdominal aortic aneurysms (AAA), while inactivation of the gene expressing this enzyme is associated with reduced aneurysm formation in an experimental model. The 5A allele of the 5A/6A polymorphism in the promoter region of the MMP3 gene is associated with enhanced MMP3 expression. This study aimed to determine whether the presence of the 5A allele in the MMP3 promoter is a risk factor for AAA, and if this allele is associated with an increased expression of MMP3 in the aneurysm wall. We compared the frequencies of the 5A and 6A alleles in AAA (n = 405), aortic occlusive disease (AOD) (n = 123) and controls (n = 405). The 5A allele frequency was higher in AAA compared with controls (odds ratio - OR 1.32, P = 0.005) and AOD (OR 1.684, P = 0.0004), but was similar in AOD compared to controls (OR 0.78, P = 0.1). The ORs of the 5A/6A and the 5A/5A genotypes were 1.35 and 1.79, compared with 6A homozygotes. Although wall from 5A homozygotes contained 17% more MMP3 mRNA than homozygotes (P = 0.049) the significance of this was lost when adjusted for age and sex (P = 0.069), and size (P = 0.30). Wall from 5A homozygotes did however contain over 45% more MMP3 protein than heterozygotes (P = 0.009 when corrected for age and sex and P = 0.043 when corrected for aneurysm size). It appears that an abnormality in the MMP3 gene is part of the genetic profile that predisposes to aneurysmal disease.
[本文引用:1] [31] MARTIN-ALONSO M,GARCIA-REDONDO A B,GUO D,et al.
[J].Circ Res,2015,117(2):e13-26.
[本文引用:1] [32] SONG Y,XIE Y,LIU F,et al.
[J].BMC Cardiovasc Disord,2013,13:34.
Background Aortic dissection(AD) is an acute process of large blood vessels characterized by dangerous pathogenic conditions and high disability and high mortality. The pathogenesis of AD remains debated. Matrix metalloproteinase-12 (MMP-12) participates in many pathological processes such as abdominal aortic aneurysm, atherosclerosis, emphysema and cancer. However, this elastase has rarely been assessed in the presence of AD. The aim of the present study was to investigate the expression of MMP-12 in aortic tissue so as to offer a better understanding of the possible mechanisms of AD. Methods The protein expression levels of MMP-12 were analyzed and compared in aorta tissue and the blood serum samples by reverse transcription polymerase chain reaction(RT-PCR), Western blotting, immuno-histochemistry, fluorescence resonance energy transfer ( FRET ) activity assay and enzyme-linked immuno sorbent assay ( ELISA ), respectively. Ascending aorta tissue specimens were obtained from 12 patients with an acute Stanford A-dissection at the time of aortic replacement, and from 4 patients with coronary artery disease (CAD) undergoing coronary artery bypass surgery. Meanwhile, serum samples were harvested from 15 patients with an acute Stanford A-dissection and 10 healthy individuals who served as the control group. Results MMP-12 activity could be detected in both AD and CAD groups, but the level in the AD group was higher than those in the CAD group (P < 0.05). MMP-12 proteolysis existed in both serum samples of the AD and healthy groups, and the activity level in the AD group was clearly higher than in the healthy group (P < 0.05). For AD patients, MMP-12 activity in serum was higher than in the aorta wall (P < 0.05). MMP-12 activity in the aortic wall tissue can be inhibited by MMP inhibitor v (P < 0.05). Conclusion The present study directly demonstrates that MMP-12 proteolytic activity exists within the aorta specimens and blood samples from aortic dissection patients. MMP-12 might be of potential relevance as a clinically diagnostic tool and therapeutic target in vascular injury and repair.
[本文引用:1] [33] REN P,ZHANG L,XU G,et al.
[J].Ann Thorac Surg,2013,95(2):570-577.
ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) is a recently identified family of extracellular metalloproteinases that has been shown to participate in tissue destruction. We hypothesized that ADAMTS-1 and ADAMTS-4 expression is increased in aortic tissues from patients with thoracic aortic aneurysms and dissections.We examined ADAMTS-1 and ADAMTS-4 expression in human descending thoracic aortic aneurysms (n = 14), chronic descending thoracic aortic dissections (n = 16), and descending thoracic aortas from age-matched control organ donors (n = 12). In these tissues, we also evaluated the degradation of versican, a proteoglycan substrate of ADAMTS-1 and ADAMTS-4. In cultured macrophages, we examined whether ADAMTS-4 functions in macrophage infiltration by using a transwell assay.ADAMTS-1 and ADAMTS-4 protein and mRNA expression was significantly higher in thoracic aortic aneurysm and dissection tissues than in control aortic tissues. Double immunofluorescence staining showed the expression of ADAMTS-1 and ADAMTS-4 in smooth muscle cells and macrophages. Consistent with the upregulation of ADAMTS-1 and ADAMTS-4 in thoracic aortic aneurysm and dissection tissues, versican was degraded significantly more in these tissues than in control aortic tissues. In cultured macrophages, transforming growth factor-尾 increased ADAMTS-4 protein levels and induced macrophage invasion, and the knockdown of ADAMTS-4 reduced cell invasion.Increased expression of ADAMTS proteins may promote thoracic aortic aneurysm progression by degrading versican and facilitating macrophage invasion.
[本文引用:1] [34] WU Z,DAI F,REN W,et al.
[J].Am J Transl Res,2016,8(1):28-36. [本文引用:1] [35] LI B,WANG Z,HU Z,et al.
[J].Ann Vasc Surg,2017,40 :262-273.
Ang II could regulate the expression of miR143/145 gene cluster and the phenotypic switching of VSMCs via the p38 MAPK signaling pathway. This may play an important role in the pathogenesis of AD.
[本文引用:1] [36] BERTOLI-AVELLA A M,GILLIS E,MORISAKI H,et al.
[J].J Am Coll Cardiol,2015,65(13):1324-1336.
Abstract BACKGROUND: Aneurysms affecting the aorta are a common condition associated with high mortality as a result of aortic dissection or rupture. Investigations of the pathogenic mechanisms involved in syndromic types of thoracic aortic aneurysms, such as Marfan and Loeys-Dietz syndromes, have revealed an important contribution of disturbed transforming growth factor (TGF)-0205 signaling. OBJECTIVES: This study sought to discover a novel gene causing syndromic aortic aneurysms in order to unravel the underlying pathogenesis. METHODS: We combined genome-wide linkage analysis, exome sequencing, and candidate gene Sanger sequencing in a total of 470 index cases with thoracic aortic aneurysms. Extensive cardiological examination, including physical examination, electrocardiography, and transthoracic echocardiography was performed. In adults, imaging of the entire aorta using computed tomography or magnetic resonance imaging was done. RESULTS: Here, we report on 43 patients from 11 families with syndromic presentations of aortic aneurysms caused by TGFB3 mutations. We demonstrate that TGFB3 mutations are associated with significant cardiovascular involvement, including thoracic/abdominal aortic aneurysm and dissection, and mitral valve disease. Other systemic features overlap clinically with Loeys-Dietz, Shprintzen-Goldberg, and Marfan syndromes, including cleft palate, bifid uvula, skeletal overgrowth, cervical spine instability and clubfoot deformity. In line with previous observations in aortic wall tissues of patients with mutations in effectors of TGF-0205 signaling (TGFBR1/2, SMAD3, and TGFB2), we confirm a paradoxical up-regulation of both canonical and noncanonical TGF-0205 signaling in association with up-regulation of the expression of TGF-0205 ligands. CONCLUSIONS: Our findings emphasize the broad clinical variability associated with TGFB3 mutations and highlight the importance of early recognition of the disease because of high cardiovascular risk. Copyright 0008 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
[本文引用:1] [37] ZHANG Y E .
[J].Cold Spring Harb Perspect Biol,2017,9(2):a022129.
Transforming growth factor 尾 (TGF-尾) and structurally related factors use several intracellular signaling pathways in addition to Smad signaling to regulate a wide array of cellular functions. These non-Smad signaling pathways are activated directly by ligand-occupied receptors to reinforce, attenuate, or otherwise modulate downstream cellular responses. This review summarizes the current knowledge of the mechanisms by which non-Smad signaling pathways are directly activated in response to ligand binding, how activation of these pathways impinges on Smads and non-Smad targets, and how final cellular responses are affected in response to these noncanonical signaling modes.
[本文引用:1] [38] FENG J,GE S,ZHANG L,et al.
[J].Eur J Histochem,2016,60(4):2711.
The vascular smooth muscle cell (VSMC) phenotypic switch is a key pathophysiological change in various cardiovascular diseases, such as aortic dissection (AD), with a high morbidity. Polycystin-1 (PC1) is significantly downregulated in the VSMCs of AD patients. PC1 is an integral membrane glycoprotein and kinase that regulates different biological processes, including cell proliferation, apoptosis, and cell polarity. However, the role of PC1 in intracellular signaling pathways remains poorly understood. In this study, PC1 downregulation in VSMCs promoted the expression of SM22伪, ACTA2 and calponin 1 (CNN1) proteins. Furthermore, PC1 downregulation in VSMCs upregulated phospho-MEK, phospho-ERK and myc, but did not change phospho-JNK and phospho-p38. These findings suggest that the MEK/ERK/myc signaling pathway is involved in PC1-mediated human VSMC phenotypic switch. Opposite results were observed when an ERK inhibitor was used in VSMCs downregulated by PC1. When the C-terminal domain of PC1 (PC1 C-tail) was overexpressed in VSMCs, the expression levels of phosphor-ERK, myc, SM22伪, ACTA2 and CNN1 proteins were downregulated. The group with the overexpressed mutant protein (S4166A) in the PC1 C-tail showed similar results to the group with the downregulated PC1 in VSMCs. These results suggest that the Ser at the 4166 site in PC1 is crucial in the PC1 mediated MEK/ERK/myc signaling pathway, which might be the key pathophysiological cause of AD.
[本文引用:1] [39] ZHU S B,ZHU J,ZHOU Z Z,et al.
[J].Am J Transl Res,2015,7(12):2764-2774.
The vascular smooth muscle cell (VSMC) phenotypic switch is considered to be the key pathophysiological change in various cardiovascular diseases, such as aortic dissection, atherosclerosis, and hypertension. The results in this study showed that TGF-β1 promotes the proliferation, migration and morphological changes of VSMC.TGF-β1 promoted the expressions of PI3K, P-PI3K, AKT, P-AKT, ID2, and OPN protein and suppressed the expressions of α-SMA and SM22α protein; the opposite results were observed for TGF-β1 inhibitor group, AKT inhibitor group and Combined inhibitors group. After the stimulation of TGF-β1 signaling, the mRNA levels of PI3K, AKT, ID2, and OPN were the highest, while the mRNA levels of α-SMA and SM22α were the lowest; the opposite results were found in the same groups above. These results suggested the PI3K/AKT/ID2 signaling pathway is involved in TGF-β1-mediated human aortic VSMC phenotypic switching, that is from a contractile to synthetic phenotype, and Combined inhibitors was more effective in inhibiting the phenotypic switch than a single inhibitor. The Combined inhibitors experiments may provide new avenues for the prevention and treatment of thoracic aortic dissection (TAD) that are based on the pathological effects of phenotypic switching.
[本文引用:1] [40] LIU W,WANG B,WANG T,et al.
[J].Cell Physiol Biochem,2016,38(4):1391-1405.
Background/Aims: Acute aortic dissection (AAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimulations, oxidative stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to AAD formation. This study aimed to clarify role of oxidative stress in the pathogenesis of AAD and whether the antioxidant ursodeoxycholic acid (UDCA) attenuates AAD formation. Methods: Angiotensin II (Ang II) was infused in 8-months male ApoE-/- mice for one week to establish a model of AAD. UDCA (10 mg/kg/day) was administered via intragastric gavage for 3 consecutive days before AngII infusion and also during the AngII infusion for another consecutive 7 days. Results: Ang II-infusion resulted in the incidence of AAD at a rate of 35% (13/37) and UDCA markedly reduced the incidence of AAD to 16% (6/37), accompanied with reduced maximal aortic diameter measured at the suprarenal region of the abdominal aorta. Additionally, UDCA pretreatment prevented Ang II induced generations of reactive oxygen species (ROS) and apoptosis of vascular smooth muscle cells (VSMCs) both in vivo and in. vitro Mechanistically, we found UDCA markedly increased Nrf2 expression in VSMCs and prevented Ang II induced expression of NADPH subunits (p47, p67 and gp91) in Nrf2-dependent manner and rescued the activity of redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT), thereby inhibiting apoptosis of VSMCs. Conclusion: These results demonstrate that UDCA prevented AAD formation by reducing apoptosis of VSMCs caused by oxidative stress in Nrf2 dependent manner and suggest that UDCA might have clinical potential to suppress AAD formation. u00a9 2016 The Author(s) Published by S. Karger AG, Basel
[本文引用:1] [41] HUANG J,FENG Y,CHEN X,et al.
[J].Apoptosis,2017,22(4):479-490.
The proto-oncogene Myc is well known for its roles in promoting cell growth, proliferation and apoptosis. However, in this study, we found from a genetic screen that Myc inhibits, rather than promotes, cell death triggered by c-Jun N-terminal kinase (JNK) signaling in Drosophila . Firstly, expression of Drosophila Myc (dMyc) suppresses, whereas loss of dMyc enhances, ectopically activated JNK signaling-induced cell death. Secondly, dMyc impedes physiologically activated JNK pathway-mediated cell death. Thirdly, loss of dMyc triggers JNK pathway activation and JNK-dependent cell death. Finally, the mammalian cMyc gene, when expressed in Drosophila , impedes activated JNK signaling-induced cell death. Thus, besides its well-studied apoptosis promoting function, Myc also antagonizes JNK-mediated cell death in Drosophila , and this function is likely conserved from fly to human.
[本文引用:1] [42] SON B K,SAWAKI D,TOMIDA S,et al.
[J].Nat Commun,2015,6:6994.
Abstract Aortic dissection and intramural haematoma comprise an aortopathy involving separation of the aortic wall. Underlying mechanisms of the condition remain unclear. Here we show that granulocyte macrophage colony-stimulating factor (GM-CSF) is a triggering molecule for this condition. Transcription factor Kr脙录ppel-like factor 6 (KLF6)-myeloid-specific conditional deficient mice exhibit this aortic phenotype when subjected to aortic inflammation. Mechanistically, KLF6 downregulates expression and secretion of GM-CSF. Administration of neutralizing antibody against GM-CSF prevents the condition in these mice. Conversely, administration of GM-CSF in combination with aortic inflammation to wild-type mice is sufficient to induce the phenotype, suggesting the general nature of effects. Moreover, patients with this condition show highly increased circulating levels of GM-CSF, which is also locally expressed in the dissected aorta. GM-CSF is therefore a key regulatory molecule causative of this aortopathy, and modulation of this cytokine might be an exploitable treatment strategy for the condition.
[本文引用:1] [43] CUI R R,LI S J,LIU L J,et al.
[J].Cardiovasc Res,2012,96(2):320-329.
Medial artery calcification is a common macroangiopathy that initiates from a cell-regulated process similar to osteogenesis. Although the mechanisms governing this process remain unclear, epigenomic regulation by specific microRNAs might play a role in vascular smooth muscle cell (VSMC) calcification. In this study, we aimed to investigate whether miR-204 participates in the regulation of VSMC calcification.We found that miR-204 was suppressed in mouse aortic VSMCs during 尾-glycerophosphate-induced calcification, whereas Runx2 protein levels were elevated. Overexpression of miR-204 by transfection of miR-204 mimics decreased Runx2 protein levels and alleviated 尾-glycerophosphate-induced osteoblastic differentiation of VSMCs, whereas miR-204 inhibition by transfection of miR-204 inhibitors significantly elevated Runx2 protein levels and enhanced osteoblastic differentiation of VSMCs, suggesting the role of miR-204 as an endogenous attenuator of Runx2 in VSMC calcification. Luciferase reporter assays revealed Runx2 as the direct target of miR-204 by overexpression of miR-204 on the wild-type or mutant 3'-UTR sequences of Runx2 in VSMCs. In vivo overexpression of miR-204 by injection of miR-204 agomirs in Kunming mice attenuated vitamin D3-induced medial artery calcification.Our study has shown that down-regulation of miR-204 may contribute to 尾-glycerophosphate-induced VSMC calcification through regulating Runx2. miR-204 represents an important new regulator of VSMC calcification and a potential therapeutic target in medial artery calcification.
[本文引用:1] [44] LIAO X B,ZHANG Z Y,YUAN K,et al.
[J].Endocrinology,2013,154(9):3344-3352.
Abstract Arterial calcification is a key pathologic component of vascular diseases such as atherosclerosis, coronary artery disease, and peripheral vascular disease. A hallmark of this pathological process is the phenotypic transition of vascular smooth muscle cells (VSMCs) to osteoblast-like cells. Several studies have demonstrated that microRNAs (miRNAs) regulate osteoblast differentiation, but it is unclear whether miRNAs also regulate VSMC-mediated arterial calcification. In the present study, we sought to characterize the role of miR-133a in regulating VSMC-mediated arterial calcification. Northern blotting analysis of VSMCs treated with 尾-glycerophosphate demonstrated that miR-133a was significantly decreased during osteogenic differentiation. Overexpression of miR-133a inhibited VSMC transdifferentiation into osteoblast-like cells as evidenced by a decrease in alkaline phosphatase activity, osteocalcin secretion, Runx2 expression, and mineralized nodule formation. Conversely, the knockdown of miR-133a using an miR-133a inhibitor promoted osteogenic differentiation of VSMCs by increasing alkaline phosphatase activity, osteocalcin secretion, and Runx2 expression. Runx2 was identified as a direct target of miR-133a by a cotransfection experiment in VSMCs with luciferase reporter plasmids containing wild-type or mutant 3'-untranslated region sequences of Runx2. Furthermore, the pro-osteogenic effects of miR-133a inhibitor were abrogated in Runx2-knockdown cells, and the inhibition of osteogenic differentiation by pre-miR-133a was reversed by overexpression of Runx2, providing functional evidence that the effects of miR-133a in osteogenic differentiation were mediated by targeting Runx2. These results demonstrate that miR-133a is a key negative regulator of the osteogenic differentiation of VSMCs.
[本文引用:1] [45] LI H,ZHANG X,WANG F,et al.
[J].Circulation,2016,134(10):734-751.
[本文引用:1] [46] BUSCH A,BUSCH M,SCHOLZ C J,et al.
[J].Int J Mol Sci,2016,17(1):pii:E81.
Limited comprehension of aneurysm pathology has led to inconclusive results from clinical trials. miRNAs are key regulators of post-translational gene modification and are useful tools in elucidating key features of aneurysm pathogenesis in distinct entities of abdominal and popliteal aneurysms. Here, surgically harvested specimens from 19 abdominal aortic aneurysm (AAA) and 8 popliteal artery aneurysm (PAA) patients were analyzed for miRNA expression and histologically classified regarding extracellular matrix (ECM) remodeling and inflammation. DIANA-based computational target prediction and pathway enrichment analysis verified our results, as well as previous ones. miRNA-362, -19b-1, -194, -769, -21 and -550 were significantly down-regulated in AAA samples depending on degree of inflammation. Similar or inverse regulation was found for miR-769, 19b-1 and miR-550, -21, whereas miR-194 and -362 were unaltered in PAA. In situ hybridization verified higher expression of miR-550 and -21 in PAA compared to AAA and computational analysis for target genes and pathway enrichment affirmed signal transduction, cell-cell-interaction and cell degradation pathways, in line with previous results. Despite the vague role of miRNAs for potential diagnostic and treatment purposes, the number of candidates from tissue signature studies is increasing. Tissue morphology influences subsequent research, yet comparison of distinct entities of aneurysm disease can unravel core pathways.
[本文引用:1] [47] CALWAY T,KIM G H.
[J].J Cardiovasc Pharmacol Ther,2015,20(2):131-143.
Abstract Cardiovascular diseases are one of the most common causes of death in humans and are responsible for billions of dollars in health care expenditures. As the molecular basis of cardiac diseases continues to be explored, there remains the hope for identification of more effective therapeutics. MicroRNAs (miRNAs) are recognized as important regulators of numerous biological pathways and stress responses, including those found in cardiovascular diseases. MicroRNA signatures of cardiovascular diseases can provide targets for miRNA adjustment and offer the possibility of changing gene and protein expression to treat certain pathologies. These adjustments can be conferred using advances in oligonucleotide delivery methods, which can target single miRNAs, families of miRNAs, and certain tissue types. In this review, we will discuss the use of miRNAs in vivo and recent advances in their use for cardiovascular disease in mammalian models. 脗漏 The Author(s) 2014.
[本文引用:1] [48] MAEGDEFESSEL L,AZUMA J,TSAO P S.
[J].Trends Cardiovasc Med,2014,24(1):1-6.
Tremendous efforts have been initiated to elucidate the molecular and pathophysiological characteristics of abdominal aortic aneurysm (AAA) disease, which is a significant contributor to morbidity and mortality in the Western world. Recently, a novel class of small noncoding RNAs, called microRNAs, was identified as important transcriptional and posttranscriptional inhibitors of gene expression thought to simultaneously “fine tune” the translational output of multiple target messenger RNAs (mRNAs) by promoting mRNA degradation or inhibiting translation. Several research groups were able to identify the miR-29 family, and miR-29b in particular, as crucial regulators of—not only vascular fibrosis—but also cardiac-, kidney-, liver-, and skin-fibrosis. The current review briefly points out data indicating a causal role for miR-29 in various diseases, while focusing on its potential benefit during AAA initiation and propagation.
[本文引用:1] [49] MERK D R,CHIN J T,DAKE B A,et al.
[J].Circ Res,2012,110(2):312-324.
Marfan syndrome (MFS) is a systemic connective tissue disorder notable for the development of aortic root aneurysms and the subsequent life-threatening complications of aortic dissection and rupture. Underlying fibrillin-1 gene mutations cause increased transforming growth factor-β (TGF-β) signaling. Although TGF-β blockade prevents aneurysms in MFS mouse models, the mechanisms through which excessive TGF-β causes aneurysms remain ill-defined.We investigated the role of microRNA-29b (miR-29b) in aneurysm formation in MFS.Using quantitative polymerase chain reaction, we discovered that miR-29b, a microRNA regulating apoptosis and extracellular matrix synthesis/deposition genes, is increased in the ascending aorta of Marfan (Fbn1(C1039G/ )) mice. Increased apoptosis, assessed by increased cleaved caspase-3 and caspase-9, enhanced caspase-3 activity, and decreased levels of the antiapoptotic proteins, Mcl-1 and Bcl-2, were found in the Fbn1(C1039G/ ) aorta. Histological evidence of decreased and fragmented elastin was observed exclusively in the Fbn1(C1039G/ ) ascending aorta in association with repressed elastin mRNA and increased matrix metalloproteinase-2 expression and activity, both targets of miR-29b. Evidence of decreased activation of nuclear factor κB, a repressor of miR-29b, and a factor suppressed by TGF-β, was also observed in Fbn1(C1039G/ ) aorta. Furthermore, administration of a nuclear factor κB inhibitor increased miR-29b levels, whereas TGF-β blockade or losartan effectively decreased miR-29b levels in Fbn1(C1039G/ ) mice. Finally, miR-29b blockade by locked nucleic acid antisense oligonucleotides prevented early aneurysm development, aortic wall apoptosis, and extracellular matrix deficiencies.We identify increased miR-29b expression as key to the pathogenesis of early aneurysm development in MFS by regulating aortic wall apoptosis and extracellular matrix abnormalities.
[本文引用:1] [50] ZAMPETAKI A,ATTIA R,MAYR U,et al.
[J].Circ Res,2014,115(10):857-866.
Abdominal aortic aneurysms constitute a degenerative process in the aortic wall. Both the miR-29 and miR-15 families have been implicated in regulating the vascular extracellular matrix.Our aim was to assess the effect of the miR-15 family on aortic aneurysm development.Among the miR-15 family members, miR-195 was differentially expressed in aortas of apolipoprotein E-deficient mice on angiotensin II infusion. Proteomics analysis of the secretome of murine aortic smooth muscle cells, after miR-195 manipulation, revealed that miR-195 targets a cadre of extracellular matrix proteins, including collagens, proteoglycans, elastin, and proteins associated with elastic microfibrils, albeit miR-29b showed a stronger effect, particularly in regulating collagens. Systemic and local administration of cholesterol-conjugated antagomiRs revealed better inhibition of miR-195 compared with miR-29b in the uninjured aorta. However, in apolipoprotein E-deficient mice receiving angiotensin II, silencing of miR-29b, but not miR-195, led to an attenuation of aortic dilation. Higher aortic elastin expression was accompanied by an increase of matrix metalloproteinases 2 and 9 in mice treated with antagomiR-195. In human plasma, an inverse correlation of miR-195 was observed with the presence of abdominal aortic aneurysms and aortic diameter.We provide the first evidence that miR-195 may contribute to the pathogenesis of aortic aneurysmal disease. Although inhibition of miR-29b proved more effective in preventing aneurysm formation in a preclinical model, miR-195 represents a potent regulator of the aortic extracellular matrix. Notably, plasma levels of miR-195 were reduced in patients with abdominal aortic aneurysms suggesting that microRNAs might serve as a noninvasive biomarker of abdominal aortic aneurysms.
[本文引用:1] [51] SPIN J M,TSAO P S.
[J].Circ Res,2014,115(10):812-813.
Author information: (1)From the Division of Cardiovascular Medicine, Stanford University School of Medicine, CA. (2)From the Division of Cardiovascular Medicine, Stanford University School of Medicine, CA. ptsao@stanford.edu.
[本文引用:1] [52] JI R,CHENG Y,YUE J,et al.
[J].Circ Res,2007,100(11):1579-1588.
[本文引用:1] [53] MAEGDEFESSEL L,AZUMA J,TOH R,et al.
[J].Sci Transl Med,2012,4(122):122.
Abstract Identification and treatment of abdominal aortic aneurysm (AAA) remains among the most prominent challenges in vascular medicine. MicroRNAs are crucial regulators of cardiovascular pathology and represent possible targets for the inhibition of AAA expansion. We identified microRNA-21 (miR-21) as a key modulator of proliferation and apoptosis of vascular wall smooth muscle cells during development of AAA in two established murine models. In both models (AAA induced by porcine pancreatic elastase or infusion of angiotensin II), miR-21 expression increased as AAA developed. Lentiviral overexpression of miR-21 induced cell proliferation and decreased apoptosis in the aortic wall, with protective effects on aneurysm expansion. miR-21 overexpression substantially decreased expression of the phosphatase and tensin homolog (PTEN) protein, leading to increased phosphorylation and activation of AKT, a component of a pro-proliferative and antiapoptotic pathway. Systemic injection of a locked nucleic acid-modified antagomir targeting miR-21 diminished the pro-proliferative impact of down-regulated PTEN, leading to a marked increase in the size of AAA. Similar results were seen in mice with AAA augmented by nicotine and in human aortic tissue samples from patients undergoing surgical repair of AAA (with more pronounced effects observed in smokers). Modulation of miR-21 expression shows potential as a new therapeutic option to limit AAA expansion and vascular disease progression.
[本文引用:1] [54] FU X M,ZHOU Y Z,CHENG Z,et al.
[J].Biomed Res Int,2015,2015:831641.
Abstract An aortic aneurysm (AA) is a common disease with potentially life-threatening complications. Despite significant improvements in the diagnosis and treatment of AA, the associated morbidity and mortality remain high. MicroRNAs (miRNAs, miR) are small noncoding ribonucleic acids that negatively regulate gene expression at the posttranscriptional level by inhibiting mRNA translation or promoting mRNA degradation. miRNAs are recently reported to be critical modulators for vascular cell functions such as cell migration, contraction, differentiation, proliferation, and apoptosis. Increasing evidences suggest crucial roles of miRNAs in the pathogenesis and progression of cardiovascular diseases such as coronary artery disease, heart failure, arterial hypertension, and cardiac arrhythmias. Recently, some miRNAs, such as miR-24, miR-155, miR-205, miR-712, miR-21, miR-26a, miR-143/145, miR-29, and miR-195, have been demonstrated to be differentially expressed in the diseased aortic tissues and strongly associated with the development of AA. In the present paper, we reviewed the recent available literature regarding the role of miRNAs in the pathogenesis of AA. Moreover, we discuss the potential use of miRNAs as diagnostic and prognostic biomarkers and novel targets for development of effective therapeutic strategies for AA.
[本文引用:1] [55] CHENG Y,LIU X,YANG J,et al.
[J].Circ Res,2009,105(2):158-166.
[本文引用:1] [56] LEEPER N J,RAIESDANA A,KOJIMA Y,et al.
[J].J Cell Physiol,2011,226(4):1035-1043.
DOI:10.1002/jcp.22422 URL
[本文引用:1] [57] VAN SOLINGEN C,DE BOER H C,BIJKERK R,et al.
[J].Cardiovasc Res,2011,92(3):449-455.
Abstract AIMS: MicroRNA-126 (miR-126), which is enriched in endothelial cells, plays a role in angiogenesis. Based on the seed sequence, miR-126 can also be predicted to regulate vasculogenesis by modulating the endothelial expression of stromal cell-derived factor-1 (SDF-1). METHODS AND RESULTS: Using miR-reporter constructs, we first validated that miR-126 inhibits SDF-1 expression in endothelial cells in vitro. Next, we investigated the potential relevance of this observation with respect to the mobilization of progenitor cells. For this, we studied the migration of human CD34 progenitor cells towards chemotactic factors present in endothelial cell-conditioned medium. Antagomir-induced silencing of miR-126 elevated SDF-1 expression by human umbilical vein endothelial cells and enhanced migration of the CD34 cells. In a murine model of hind limb ischaemia, a striking increase in the number of circulating Sca-1( )/Lin(-) progenitor cells in antagomir-126-treated mice was observed when compared with scramblemir-treated controls. Immunohistochemical staining of capillaries in the post-ischaemic gastrocnemius muscle of miR-126-silenced mice revealed elevated SDF-1 expressing CD31-positive capillaries, whereas a mobilizing effect of miR-126 inhibition was not detected in healthy control animals. CONCLUSION: miR-126 can regulate the expression of SDF-1 in endothelial cells. In the context of an ischaemic event, systemic silencing of miR-126 leads to the mobilization of Sca-1( )/Lin(-) progenitor cells into the peripheral circulation, potentially in response to elevated SDF-1 expression by endothelial cells present in the ischaemic tissue.
[本文引用:1] [58] KIN K,MIYAGAWA S,FUKUSHIMA S,et al.
[J].J Am Heart Assoc,2012,1(5):e000745.
Background Atherosclerotic abdominal aortic aneurysm (AAA) is a progressive, gradual aortic rupture that results in death in the absence of surgical intervention. Key factors that regulate initiation and progression of AAA are unknown, making targeted interventions difficult. MicroRNAs play a fundamental role in atherosclerosis, and atherosclerotic coronary artery disease is characterized by tissue??? and plasma???specific microRNA signatures. However, little is known about microRNAs involved in AAA pathology. This study examined tissue and plasma microRNAs specifically associated with AAA. Methods and Results AAA and normal wall tissues were sampled from patients undergoing AAA repair (n=13; mean age, 68??6 years) and aortic valve replacement surgery (n=7; mean age, 66??4 years), respectively. MicroRNA expression was assessed by high???throughput microRNA arrays and validated by real???time polymerase chain reaction for individual microRNAs that showed significant expression differences in the initial screening. MicroRNAs related to fibrosis (miR???29b), inflammation (miR???124a, miR???146a, miR???155, and miR???223), and endothelium (miR???126, let???7 family members, and miR???21) were significantly upregulated in AAA tissue. Significant negative correlations were seen in expression levels of monocyte chemoattractant protein???1 and miR???124a, ???146a, and ???223; tumor necrosis factor????? and miR???126 and ???223; and transforming growth factor????? and miR???146a. Expression of microRNAs, such as miR???29b, miR???124a, miR???155, and miR???223, that were upregulated in AAA tissue was significantly reduced in plasma of patients with AAA (n=23; mean age, 72??9 years) compared to healthy controls (n=12; mean age, 51??11 years) and patients with coronary artery disease (n=17; mean age, 71??9 years). Conclusions The expression of some microRNAs was specifically upregulated in AAA tissue, warranting further studies on the microRNA function in AAA pathogenesis and on the possibility of using a microRNA biomarker for AAA diagnosis.
[本文引用:1] [59] MAEGDEFESSEL L,SPIN J M,RAAZ U,et al.
[J].Nat Commun,2014,5:5214.
08 2014 Macmillan Publishers Limited.Identification and treatment of abdominal aortic aneurysm (AAA) remain among the most prominent challenges in vascular medicine. MicroRNAs (miRNAs) are crucial regulators of cardiovascular pathology and represent intrigu
[本文引用:1] [60] SON D J,KUMAR S,TAKABE W,et al.
[J].Nat Commun,2013,4:3000.
MicroRNAs (miRNAs) regulate cardiovascular biology and disease, but the role of flow-sensitive microRNAs in atherosclerosis is still unclear. Here we identify miRNA-712 (miR-712) as a mechanosensitive miRNA upregulated by disturbed flow (d-flow) in endothelial cells, in vitro and in vivo. We also show that miR-712 is derived from an unexpected source, pre-ribosomal RNA, in an exoribonuclease-dependent but DiGeorge syndrome critical region 8 (DGCR8)-independent manner, suggesting that it is an atypical miRNA. Mechanistically, d-flow-induced miR-712 downregulates tissue inhibitor of metalloproteinase 3 (TIMP3) expression, which in turn activates the downstream matrix metalloproteinases (MMPs) and a disintegrin and metalloproteases (ADAMs) and stimulate pro-atherogenic responses, endothelial inflammation and permeability. Furthermore, silencing miR-712 by anti-miR-712 rescues TIMP3 expression and prevents atherosclerosis in murine models of atherosclerosis. Finally, we report that human miR-205 shares the same 'seed sequence' as murine-specific miR-712 and also targets TIMP3 in a flow-dependent manner. Targeting these mechanosensitive 'athero-miRs' may provide a new treatment paradigm in atherosclerosis.
[本文引用:1] [61] KIM C W,KUMAR S,SON D J,et al.
[J].Arterioscler Thromb Vasc Biol,2014,34(7):1412-1421.
Abdominal aortic aneurysm (AAA) is characterized as a progressive dilation and degradation of the aortic wall, associated with activation of matrix metalloproteinases (MMPs) and inflammation. Emerging evidence indicates a role for microRNAs (miRNAs) in AAA pathogenesis, but it is unclear whether abdominal aortic endothelial miRNAs play a role in the disease process. We aimed to identify miRNAs in the abdominal aortic endothelium that play a critical role in AAA development. The mouse model of AAA induced by angiotensin II infusion was used in this study. Through a miRNA array and validation study, we initially identified the murine-specific miR-712 and subsequently its human/murine homolog miR-205 as angiotensin II-induced miRNAs in the abdominal aortic endothelium in vivo and in vitro. Mechanistically, miR-712 stimulated MMP activity in the aortic wall by directly targeting 2 MMP inhibitors: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion-inducing cysteine-rich protein with kazal motifs (RECK). Silencing of miR-712 and miR-205 by using anti-miR-712 and anti-miR-205, respectively, significantly decreased the aortic MMP activity and inflammation, preventing AAA development in angiotensin II-infused ApoE(-/-) mice. Further, upregulation of 4 angiotensin II-sensitive miRNAs, miR-205, -21, -133b, and -378, identified in this murine study were confirmed in human AAA samples compared with nondiseased control. Our results demonstrate that angiotensin II-sensitive miR-712 and its human homolog miR-205 downregulate TIMP3 and RECK, which in turn stimulate aortic MMP activity and inflammation, leading to AAA development. Targeting these miRNAs may be a novel therapeutic strategy to prevent AAA.
[本文引用:1] [62] MANCIA G,FAGARD R,NARKIEWICZ K,et al.
[J].J Hypertens,2013,31(7):1281-1357.
[本文引用:1] [63] GROENINK M,DEN HARTOG A W,FRANKEN R,et al.
[J].Eur Heart J,2013,34(45):3491-3500.
Abstract AIM: Patients with Marfan syndrome have an increased risk of life-threatening aortic complications, mostly preceded by aortic dilatation. Treatment with losartan, an angiotensin-II receptor-1 blocker, may reduce aortic dilatation rate in Marfan patients. METHODS AND RESULTS: In this multicentre, open-label, randomized controlled trial with blinded assessments, we compared losartan treatment with no additional treatment in operated and unoperated adults with Marfan syndrome. The primary endpoint was aortic dilatation rate at any predefined aortic level after 3 years of follow-up, as determined by magnetic resonance imaging. A total of 233 participants (47% female) underwent randomization to either losartan (n = 116) or no additional treatment (n = 117). Aortic root dilatation rate after 3.1 00± 0.4 years of follow-up was significantly lower in the losartan group than in controls (0.77 00± 1.36 vs. 1.35 00± 1.55 mm, P = 0.014). Aortic dilatation rate in the trajectory beyond the aortic root was not significantly reduced by losartan. In patients with prior aortic root replacement, aortic arch dilatation rate was significantly lower in the losartan group when compared with the control group (0.50 00± 1.26 vs. 1.01 00± 1.31 mm, P = 0.033). No significant differences in separate clinical endpoints or the composite endpoint (aortic dissection, elective aortic surgery, cardiovascular death) between the groups could be demonstrated. CONCLUSION: In adult Marfan patients, losartan treatment reduces aortic root dilatation rate. After aortic root replacement, losartan treatment reduces dilatation rate of the aortic arch.
[本文引用:1] [64] CHIU H H,WU M H,WANG J K,et al.
[J].Mayo Clin Proc,2013,88(3):271-276.
To assess the tolerability and efficacy of the investigational use of the angiotensin II receptor blocker losartan added to 尾-blockade (BB) to prevent progressive aortic root dilation in patients with Marfan syndrome (MFS).Between May 1, 2007, and September 31, 2011, 28 patients with MFS (11 males [39%]; mean 卤 SD age, 13.1卤6.3 years) with recognized aortic root dilation (z score >2.0) and receiving BB (atenolol or propranolol) treatment were enrolled. They were randomized to receive BB (BB: 13 patients) or 尾-blockade and losartan (BB-L: 15 patients) for 35 months.In the BB-L group, aortic root dilation was reduced with treatment, and the annual dilation rate of the aortic root was significantly lower than that of the BB group (0.10 mm/yr vs 0.89 mm/yr; P=.02). The absolute aortic diameters at the sinus of Valsalva, annulus, and sinotubular junction showed similar trends, with a reduced rate of dilation in the BB-L group (P=.02, P=.03, and P=.03, respectively). Five patients (33%) treated with BB-L were noted to have a reduced aortic root diameter. However, the differences between the groups regarding changes in aortic stiffness and cross-sectional compliance were not statistically significant.This randomized, open-label, active controlled trial mostly based on a pediatric population demonstrated for the first time that losartan add-on BB therapy is safe and provides more effective protection to slow the progression of aortic root dilation than does BB treatment alone in patients with MFS.clinicaltrials.gov Identifier: NCT00651235.
[本文引用:1] [65] BRADY A R,THOMPSON S G,FOWKES F G,et al.
[J].Circulation,2004,110(1):16-21.
[本文引用:1] [66] JOVIN I S,DUGGAL M,EBISU K,et al.
[J].Am J Cardiol,2012,109(7):1050-1054.
Abstract The potential of medical therapy to influence the courses and outcomes of patients with thoracic aortic aneurysms is not known. The aim of this study was to determine whether statin intake is associated with improved long-term outcomes in these patients. A total of 649 patients with thoracic aortic aneurysms were studied, of whom 147 were taking statins at their first presentation and 502 were not. After a median follow-up period of 3.6 years, 30 patients (20%) taking statins had died, compared with 167 patients (33%) not taking statins (hazard ratio 0.68, 95% confidence interval 0.46 to 1, p = 0.049); 87 patients (59%) taking statins reached the composite end point of death, rupture, dissection, or repair compared with 378 patients (75%) not taking statins (hazard ratio 0.72, 95% confidence interval 0.57 to 0.91, p = 0.006). After adjustments for co-morbidities, the association between statin therapy and the composite end point was driven mainly by a reduction in aneurysm repairs (hazard ratio 0.57 95% confidence interval 0.4 to 0.83, p = 0.003). On Kaplan-Meier analysis, the survival rate of patients taking statins was significantly better (p = 0.047). In conclusion, the intake of stains was associated with an improvement in long-term outcomes in this cohort of patients with thoracic aortic aneurysms. This was driven mainly by a reduction in aneurysm repairs. Copyright 脙聜脗漏 2012 Elsevier Inc. All rights reserved.
[本文引用:1] [67] DE BRUIN J L,BAAS A F,HEYMANS M W,et al.
[J].J Vasc Surg,2014,59(1):39-44.
Abstract BACKGROUND: The relationship between numerous risk factors and perioperative mortality after cardiovascular surgery has been studied extensively. While improved perioperative survival and fewer cardiovascular events have been related to statin therapy, its effect on long-term survival after aneurysm repair remains to be elucidated. The aim of this study is to determine the effect of statin therapy on long-term survival after open and endovascular aneurysm repair and to identify other cardiovascular and patient-related risk factors in this respect. METHODS: A post-hoc analysis of a randomized trial comparing open and endovascular abdominal aortic aneurysm repair was performed. In this multicenter trial, 351 patients were randomly assigned to undergo either open abdominal aortic aneurysm repair or endovascular repair. Patients who were on lipid-lowering medication at their inclusion in the trial (n = 135) were compared with those who were not (n = 216). RESULTS: During 6 years of follow-up, 118 (33.6%) patients died after randomization. Statin therapy, baseline characteristics, Society for Vascular Surgery/International Society for Cardiovascular Surgery risk factors, aneurysm size, reinterventions, antiplatelet or anticoagulant agents, and 脦虏-blockers were used to identify prognostic factors influencing survival. After identification of significant factors in a Kaplan-Meier analysis, a multivariable Cox regression analysis was applied. Statin therapy at inclusion in the trial was independently associated with better overall survival after open or endovascular aneurysm repair (hazard ratio [HR], 0.5; 95% confidence interval [CI], 0.3-0.8; P = .004). Statins were especially associated with fewer cardiovascular deaths (HR, 0.4; 95% CI, 0.2-0.9; P = .025). Several risk factors were associated with poor survival after open and endovascular aneurysm repair: age >70 (HR, 3.4; 95% CI, 2.2-5.0; P .05). CONCLUSIONS: Despite the limitations of a post-hoc analysis of a prospectively maintained trial, we conclude that statin therapy at the beginning of the trial is independently associated with improved long-term survival after open or endovascular aneurysm repair, while age above 70 years, a history of cardiovascular disease, and tobacco use are associated with decreased long-term survival. TRIAL REGISTRATION: ClinicalTrials.gov NCT00421330 . Copyright 脗漏 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.
[本文引用:1] [68] STEIN L H,BERGER J,TRANQUILLI M,et al.
[J].Am J Cardiol,2013,112(8):1240-1245.
Abstract Pharmacologic interventions for thoracic aneurysms remain poorly characterized. The results of a pilot study by our group suggested improved outcomes among patients with thoracic aortic aneurysm who were taking statins. In the present study, we undertook a comprehensive analysis of a larger cohort of patients from the Database of the Aortic Institute at Yale-New Haven Hospital. A total of 1,560 patients met the inclusion criteria. The adverse events (i.e., death, dissection, or rupture) and surgery rates for patients with (n0002= 369, 24%) and without (n0002= 1,191, 76%) statin therapy were compared. We evaluated 3 anatomic components of the aorta: root, ascending and arch, and descending and thoracoabdominal aortic aneurysms. A smaller proportion of the statin group had adverse events: overall, 7% versus 15%; ascending and arch, 6% versus 15%; and descending and thoracoabdominal aortic aneurysms, 8% versus 20%. Also, a smaller proportion of statin patients required surgery: overall, 48% versus 60%; ascending and arch, 51% versus 62%; and descending and thoracoabdominal aortic aneurysms, 36% versus 59% (p <0.001 to 0.01). The protective effect of statins was seen in all segments, except the aortic root. Log-rank evaluation of the interval to an adverse event or surgery was longer among statin-treated patients (p <0.001). Logistic regression analysis found statin use, angiotensin receptor blocker use, and chronic obstructive pulmonary disease were associated with decreased adverse events, and statin use, angiotensin receptor blocker use, 0205-blocker therapy, and age were associated with a decreased odds of requiring surgery. Multiple logistic regression analysis found only statins were associated with a decreased odds of an adverse event and that statins, coronary artery disease, and chronic obstructive pulmonary disease were associated with a decreased odds of undergoing surgery. In conclusion, these findings provide a medicinal option for the arsenal of treatment options for patients with aneurysms of the thoracic aorta. Copyright 0008 2013 Elsevier Inc. All rights reserved.
[本文引用:1] [69] ERBEL R,ABOYANS V,BOILEAU C,et al.
[J].Eur Heart J,2014,35(41):2873-2926.
[本文引用:1]
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