RESUMO
Objective: Thoracic endovascular aortic repair (TEVAR) for type B aortic dissection (TBAD) aims to induce false lumen (FL) thrombosis by sealing intimal tears between the true (TL) and the FL, and blocking the inflow into the FL. Incomplete thrombosis of the FL is correlated with poor clinical outcome. We hypothesize that the number of major and minor branches arising from the FL affects FL patency and may negatively influence TEVAR induced FL thrombosis. Methods: Computed tomography (CT)-scans from 89 patients diagnosed with TBAD [best medical treatment (BMT) n = 52, TEVAR n = 37] from two high-volume vascular surgery centers were analyzed retrospectively. Analysis included evaluation of the FL patency status, the number, location and size of intimal tears, and the presence of minor and major side branches originating from the FL. Multiple regression analysis was conducted to evaluate obtained parameters as predictors for FL thrombosis status. Results: In univariate analysis, the strongest correlation for FL patency was found for the number of major (R = 0.79) and minor (R = 0.86) side branches originating from the FL. When applying a multiple linear regression model, the number of major (normalized beta 0.37; P < 0.001) and minor (normalized beta 0.41; P < 0.01) side branches arising from the FL were valid predictors for the axial length of the patent and non-patent FL, and additionally determined the length of the patent FL at 12-month follow-up in patients that underwent TEVAR. Conclusions: Our data suggest that the number of minor side branches that originate from the FL in TBAD is an important determinant of FL patency, to a greater degree than previously assumed.
RESUMO
The compliance of the proximal aortic wall is a major determinant of cardiac afterload. Aortic compliance is often estimated based on cross-sectional area changes over the pulse pressure, under the assumption of a negligible longitudinal stretch during the pulse. However, the proximal aorta is subjected to significant axial stretch during cardiac contraction. In the present study, we sought to evaluate the importance of axial stretch on compliance estimation by undertaking both an in silico and an in vivo approach. In the computational analysis, we developed a 3-D finite element model of the proximal aorta and investigated the discrepancy between the actual wall compliance to the value estimated after neglecting the longitudinal stretch of the aorta. A parameter sensitivity analysis was further conducted to show how increased material stiffness and increased aortic root motion might amplify the estimation errors (discrepancies between actual and estimated distensibility ranging from - 20 to - 62%). Axial and circumferential aortic deformation during ventricular contraction was also evaluated in vivo based on MR images of the aorta of 3 healthy young volunteers. The in vivo results were in good qualitative agreement with the computational analysis (underestimation errors ranging from - 26 to - 44%, with increased errors reflecting higher aortic root displacement). Both the in silico and in vivo findings suggest that neglecting the longitudinal strain during contraction might lead to severe underestimation of local aortic compliance, particularly in the case of women who tend to have higher aortic root motion or in subjects with stiff aortas.
Assuntos
Aorta/fisiologia , Adolescente , Adulto , Aorta/diagnóstico por imagem , Fenômenos Biomecânicos , Complacência (Medida de Distensibilidade) , Simulação por Computador , Feminino , Humanos , Angiografia por Ressonância Magnética , Imageamento por Ressonância Magnética , Masculino , Modelos Cardiovasculares , Movimento (Física) , PressãoRESUMO
Aortic aneurysms and dissections are silent and lethal conditions, whose pathogenesis remains incompletely understood. Although angiotensin II (AngII)-infused ApoE-/- mice have been widely used to study aortic aneurysm and dissection, early morphofunctional alterations preceding the onset of these conditions remain unknown. The goal of this study was to unveil early morphofunctional changes underlying the onset of aneurysm and dissection. At 3 days post-AngII infusion, suprarenal abdominal aorta presented significant volumetric dilatation and microstructural damage. Ex vivo assessment of vascular reactivity of the suprarenal dissection-prone aorta and its side branches, showed an endothelial and contractile dysfunctions that were severe in the suprarenal aorta, moderate distally, and absent in the side branches, mirroring the susceptibility to dissection of these different vascular segments. Early and specific morphofunctional changes of the suprarenal aorta may contribute to the regional onset of aortic aneurysm and dissection by exacerbating the biomechanical burden arising from its side branches.
Assuntos
Angiotensina II , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/patologia , Dissecção Aórtica/patologia , Remodelação Vascular , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/diagnóstico por imagem , Dissecção Aórtica/fisiopatologia , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/fisiopatologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Aneurisma da Aorta Abdominal/fisiopatologia , Aortografia , Angiografia por Tomografia Computadorizada , Dilatação Patológica , Modelos Animais de Doenças , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Músculo Liso Vascular/patologia , Músculo Liso Vascular/fisiopatologia , Fatores de Tempo , Vasoconstrição , Microtomografia por Raio-XRESUMO
GOAL: We introduce a novel approach to estimate cardiac output (CO) and central systolic blood pressure (cSBP) from noninvasive measurements of peripheral cuff-pressure and carotid-to-femoral pulse wave velocity (cf-PWV). METHODS: The adjustment of a previously validated one-dimensional arterial tree model is achieved via an optimization process. In the optimization loop, compliance and resistance of the generic arterial tree model as well as aortic flow are adjusted so that simulated brachial systolic and diastolic pressures and cf-PWV converge towards the measured brachial systolic and diastolic pressures and cf-PWV. The process is repeated until full convergence in terms of both brachial pressures and cf-PWV is reached. To assess the accuracy of the proposed framework, we implemented the algorithm on in vivo anonymized data from 20 subjects and compared the method-derived estimates of CO and cSBP to patient-specific measurements obtained with Mobil-O-Graph apparatus (central pressure) and two-dimensional transthoracic echocardiography (aortic blood flow). RESULTS: Both CO and cSBP estimates were found to be in good agreement with the reference values achieving an RMSE of 0.36 L/min and 2.46 mmHg, respectively. Low biases were reported, namely -0.04 ± 0.36 L/min for CO predictions and -0.27 ± 2.51 mmHg for cSBP predictions. SIGNIFICANCE: Our one-dimensional model can be successfully "tuned" to partially patient-specific standards by using noninvasive, easily obtained peripheral measurement data. The in vivo evaluation demonstrated that this method can potentially be used to obtain central aortic hemodynamic parameters in a noninvasive and accurate way.
Assuntos
Velocidade do Fluxo Sanguíneo/fisiologia , Pressão Sanguínea/fisiologia , Débito Cardíaco/fisiologia , Testes de Função Cardíaca/métodos , Processamento de Sinais Assistido por Computador , Adulto , Algoritmos , Determinação da Pressão Arterial/métodos , Artérias Carótidas/fisiologia , Feminino , Artéria Femoral/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelagem Computacional Específica para o Paciente , Análise de Onda de Pulso/métodosRESUMO
Animal models of aortic aneurysm and dissection can enhance our limited understanding of the etiology of these lethal conditions particularly because early-stage longitudinal data are scant in humans. Yet, the pathogenesis of often-studied mouse models and the potential contribution of aortic biomechanics therein remain elusive. In this work, we combined micro-CT and synchrotron-based imaging with computational biomechanics to estimate in vivo aortic strains in the abdominal aorta of angiotensin-II-infused ApoE-deficient mice, which were compared with mouse-specific aortic microstructural damage inferred from histopathology. Targeted histology showed that the 3D distribution of micro-CT contrast agent that had been injected in vivo co-localized with precursor vascular damage in the aortic wall at 3 days of hypertension, with damage predominantly near the ostia of the celiac and superior mesenteric arteries. Computations similarly revealed higher mechanical strain in branching relative to non-branching regions, thus resulting in a positive correlation between high strain and vascular damage in branching segments that included the celiac, superior mesenteric, and right renal arteries. These results suggest a mechanically driven initiation of damage at these locations, which was supported by 3D synchrotron imaging of load-induced ex vivo delaminations of angiotensin-II-infused suprarenal abdominal aortas. That is, the major intramural delamination plane in the ex vivo tested aortas was also near side branches and specifically around the celiac artery. Our findings thus support the hypothesis of an early mechanically mediated formation of microstructural defects at aortic branching sites that subsequently propagate into a macroscopic medial tear, giving rise to aortic dissection in angiotensin-II-infused mice.
Assuntos
Angiotensina II/administração & dosagem , Aorta/patologia , Estresse Mecânico , Animais , Aorta/diagnóstico por imagem , Ruptura Aórtica/diagnóstico por imagem , Ruptura Aórtica/patologia , Simulação por Computador , Meios de Contraste/química , Análise de Elementos Finitos , Imageamento Tridimensional , Masculino , Camundongos Endogâmicos C57BLRESUMO
Mathematical models of the arterial tree constitute a valuable tool to investigate the hemodynamics of aging and pathology. Rendering such models as patient specific could allow for the assessment of central hemodynamic variables of clinical interest. However, this task is challenging, particularly with respect to the tuning of the local area compliance that varies significantly along the arterial tree. Accordingly, in this study, we demonstrate the importance of taking into account the differential effects of aging on the stiffness of central and peripheral arteries when simulating a person's hemodynamic profile. More specifically, we propose a simple method for effectively adapting the properties of a generic one-dimensional model of the arterial tree based on the subject's age and noninvasive measurements of aortic flow and brachial pressure. A key element for the success of the method is the implementation of different mechanisms of arterial stiffening for young and old individuals. The designed methodology was tested and validated against in vivo data from a population of n = 20 adults. Carotid-to-femoral pulse wave velocity was accurately predicted by the model (mean error = 0.14 m/s, SD = 0.77 m/s), with the greatest deviations being observed for older subjects. In regard to aortic pressure, model-derived systolic blood pressure and augmentation index were both in good agreement (mean difference of 2.3 mmHg and 4.25%, respectively) with the predictions of a widely used commercial device (Mobil-O-Graph). These preliminary results encourage us to further validate the method in larger samples and consider its potential as a noninvasive tool for hemodynamic monitoring.NEW & NOTEWORTHY We propose a technique for adapting the parameters of a validated one-dimensional model of the arterial tree using noninvasive measurements of aortic flow and brachial pressure. Emphasis is given on the adjustment of the arterial tree distensibility, which incorporates the nonuniform effects of aging on central and peripheral vessel elasticity. Our method could find application in the derivation of important hemodynamic indices, paving the way for novel diagnostic tools.
Assuntos
Envelhecimento , Aorta/fisiologia , Hemodinâmica , Modelos Cardiovasculares , Rigidez Vascular , Adulto , Fatores Etários , Idoso , Pressão Arterial , Artéria Braquial/fisiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Reprodutibilidade dos TestesRESUMO
In computational aortic biomechanics, aortic and arterial tissue are typically modelled as a homogeneous layer, making abstraction not only of the layered structure of intima, media and adventitia but also of the microstructure that exists within these layers. Here, we present a novel method to visualize the microstructure of the tunica media along the entire circumference of the vessel. To that end, we developed a pressure-inflation device that is compatible with synchrotron-based phase-contrast imaging. Using freshly excised left common carotid arteries from n = 12 mice, we visualized how the lamellae and interlamellar layers inflate as the luminal pressure is increased from 0 to 120 mm Hg in quasi-static steps. A graph-based segmentation algorithm subsequently allowed us to automatically segment each of the three lamellae, resulting in a three-dimensional geometry that represents lamellae, interlamellar layers and adventitia at nine different pressure levels. Our results demonstrate that the three elastic lamellae unfold and stretch simultaneously as luminal pressure is increased. In the long term, we believe that the results presented in this work can be a first step towards a better understanding of the mechanics of the arterial microstructure.
Assuntos
Pressão Sanguínea/fisiologia , Artéria Carótida Primitiva , Modelos Cardiovasculares , Síncrotrons , Rigidez Vascular/fisiologia , Animais , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Primitiva/fisiologia , Masculino , Camundongos , Camundongos Knockout para ApoERESUMO
In order to show the advantage and potential of propagation-based phase-contrast synchrotron imaging in vascular pathology research, we analyzed aortic medial ruptures in BAPN/AngII-infused mice, a mouse model for aortic dissection. Ascending and thoraco-abdominal samples from n = 3 control animals and n = 10 BAPN/AngII-infused mice (after 3, 7 and 14 days of infusion, total of 24 samples) were scanned. A steep increase in the number of ruptures was already noted after 3 days of BAPN/AngII-infusion. The largest ruptures were found at the latest time points. 133 ruptures affected only the first lamella while 135 ruptures affected multiple layers. Medial ruptures through all lamellar layers, leading to false channel formation and intramural hematoma, occurred only in the thoraco-abdominal aorta and interlamellar hematoma formation in the ascending aorta could be directly related to ruptures of the innermost lamellae. The advantages of this technique are (i) ultra-high resolution that allows to visualize the individual elastic lamellae in the aorta; (ii) quantitative and qualitative analysis of medial ruptures; (iii) 3D analysis of the complete aorta; (iv) high contrast for qualitative information extraction, reducing the need for histology coupes; (v) earlier detection of (micro-) ruptures.
Assuntos
Aorta Abdominal/patologia , Aorta Torácica/patologia , Aneurisma da Aorta Abdominal/patologia , Dissecção Aórtica/patologia , Ruptura Aórtica/patologia , Dissecção Aórtica/diagnóstico por imagem , Angiotensina II/administração & dosagem , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Torácica/diagnóstico por imagem , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Ruptura Aórtica/diagnóstico por imagem , Modelos Animais de Doenças , Imageamento Tridimensional , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Contraste de Fase/métodos , SíncrotronsRESUMO
In order to advance the state-of-the-art in computational aortic biomechanics, we investigated the influence of (i) a non-uniform wall thickness, (ii) minor aortic side branches and (iii) a non-uniform axial stretch distribution on the location of predicted hotspots of principal strain in a mouse model for dissecting aneurysms. After 3 days of angiotensin II infusion, a murine abdominal aorta was scanned in vivo with contrast-enhanced micro-CT. The animal was subsequently sacrificed and its aorta was scanned ex vivo with phase-contrast X-ray tomographic microscopy (PCXTM). An automatic morphing framework was developed to map the non-pressurized, non-stretched PCXTM geometry onto the pressurized, stretched micro-CT geometry. The output of the morphing model was a structural FEM simulation where the output strain distribution represents an estimation of the wall deformation, not only due to the pressurization, but also due to the local axial stretch field. The morphing model also included minor branches and a mouse-specific wall thickness. A sensitivity study was then performed to assess the influence of each of these novel features on the outcome of the simulations. The results were supported by comparing the computed hotspots of principal strain to hotspots of early vascular damage as detected on PCXTM. Non-uniform axial stretch, non-uniform wall thickness and minor subcostal arteries significantly alter the locations of calculated hotspots of maximal principal strain. Even if experimental data on these features are often not available in clinical practice, one should be aware of the important implications that simplifications in the model might have on the final simulated result.
Assuntos
Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/fisiologia , Angiotensina II/farmacologia , Animais , Aorta Abdominal/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout para ApoE , Tomografia por Raios X/métodosRESUMO
AIMS: Angiotensin II-infused ApoE-/- mice are a popular mouse model for preclinical aneurysm research. Here, we provide insight in the often-reported but seldom-explained variability in shape of dissecting aneurysms in these mice. METHODS AND RESULTS: N = 45 excised aortas were scanned ex vivo with phase-contrast X-ray tomographic microscopy. Micro-ruptures were detected near the ostium of celiac and mesenteric arteries in 8/11 mice that were sacrificed after 3 days of angiotensin II-infusion. At later time points (after 10, 18, and 28 days) the variability in shape of thoraco-abdominal lesions (occurring in 31/34 mice) was classified into 7 different categories based on the presence or absence of a medial tear (31/31), an intramural hematoma (23/31) or a false channel (11/23). Medial tears were detected both in the thoracic and the abdominal aorta and were most prevalent at the left and ventral aspects of celiac and mesenteric arteries. The axial length of the hematoma strongly correlated to the total number of ruptured branch ostia (r2 = 0.78) and in 22/23 mice with a hematoma the ostium of the left suprarenal artery had ruptured. Supraceliac diameters at baseline were significantly lower for mice that did not develop an intramural hematoma, and the formation of a false channel within that intramural hematoma depended on the location, rather than the length, of the medial tear. CONCLUSION: Based on our observations we propose an elaborate hypothesis that explains how aortic side branches (i) affect the initiation and propagation of medial tears and the subsequent adventitial dissection and (ii) affect the variability in shape of dissecting aneurysms. This hypothesis was partially validated through the live visualization of a dissecting aneurysm that formed during micro-CT imaging, and led us to the conclusion that angiotensin II-infused mice are more clinically relevant for the study of aortic dissections than for the study of abdominal aortic aneurysms.
Assuntos
Angiotensina II , Aorta Abdominal/patologia , Aorta Torácica/patologia , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Torácica/patologia , Dissecção Aórtica/patologia , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/genética , Dissecção Aórtica/metabolismo , Animais , Aorta Abdominal/diagnóstico por imagem , Aorta Abdominal/metabolismo , Aorta Torácica/diagnóstico por imagem , Aorta Torácica/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/genética , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Torácica/induzido quimicamente , Aneurisma da Aorta Torácica/genética , Aneurisma da Aorta Torácica/metabolismo , Aortografia/métodos , Angiografia por Tomografia Computadorizada , Modelos Animais de Doenças , Progressão da Doença , Hematoma/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fatores de Tempo , Ultrassonografia Doppler de Pulso , Remodelação Vascular , Microtomografia por Raio-XRESUMO
OBJECTIVE: Current experimental models of abdominal aortic aneurysm (AAA) do not accurately reproduce the major features of human AAA. We hypothesized that blockade of TGFß (transforming growth factor-ß) activity-a guardian of vascular integrity and immune homeostasis-would impair vascular healing in models of nondissecting AAA and would lead to sustained aneurysmal growth until rupture. APPROACH AND RESULTS: Here, we test this hypothesis in the elastase-induced AAA model in mice. We analyze AAA development and progression using ultrasound in vivo, synchrotron-based ultrahigh resolution imaging ex vivo, and a combination of biological, histological, and flow cytometry-based cellular and molecular approaches in vitro. Systemic blockade of TGFß using a monoclonal antibody induces a transition from a self-contained aortic dilatation to a model of sustained aneurysmal growth, associated with the formation of an intraluminal thrombus. AAA growth is associated with wall disruption but no medial dissection and culminates in fatal transmural aortic wall rupture. TGFß blockade enhances leukocyte infiltration both in the aortic wall and the intraluminal thrombus and aggravates extracellular matrix degradation. Early blockade of IL-1ß or monocyte-dependent responses substantially limits AAA severity. However, blockade of IL-1ß after disease initiation has no effect on AAA progression to rupture. CONCLUSIONS: Endogenous TGFß activity is required for the healing of AAA. TGFß blockade may be harnessed to generate new models of AAA with better relevance to the human disease. We expect that the new models will improve our understanding of the pathophysiology of AAA and will be useful in the identification of new therapeutic targets.
Assuntos
Anticorpos Monoclonais/toxicidade , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/induzido quimicamente , Ruptura Aórtica/induzido quimicamente , Elastase Pancreática , Fator de Crescimento Transformador beta/antagonistas & inibidores , Remodelação Vascular/efeitos dos fármacos , Animais , Aorta Abdominal/imunologia , Aorta Abdominal/metabolismo , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Ruptura Aórtica/imunologia , Ruptura Aórtica/metabolismo , Ruptura Aórtica/patologia , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Quimiotaxia de Leucócito/efeitos dos fármacos , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Matriz Extracelular/patologia , Interleucina-1beta/metabolismo , Cinética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síncrotrons , Trombose/induzido quimicamente , Trombose/metabolismo , Trombose/patologia , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Ultrassonografia , Cicatrização/efeitos dos fármacosRESUMO
BACKGROUND: Low and oscillatory wall shear stresses (WSS) near aortic bifurcations have been linked to the onset of atherosclerosis. In previous work, we calculated detailed WSS patterns in the carotid bifurcation of mice using a Fluid-structure interaction (FSI) approach. We subsequently fed the animals a high-fat diet and linked the results of the FSI simulations to those of atherosclerotic plaque location on a within-subject basis. However, these simulations were based on boundary conditions measured under anesthesia, while active mice might experience different hemodynamics. Moreover, the FSI technique for mouse-specific simulations is both time- and labor-intensive, and might be replaced by simpler and easier Computational Fluid Dynamics (CFD) simulations. The goal of the current work was (i) to compare WSS patterns based on anesthesia conditions to those representing active resting and exercising conditions; and (ii) to compare WSS patterns based on FSI simulations to those based on steady-state and transient CFD simulations. METHODS: For each of the 3 computational techniques (steady state CFD, transient CFD, FSI) we performed 5 simulations: 1 for anesthesia, 2 for conscious resting conditions and 2 more for conscious active conditions. The inflow, pressure and heart rate were scaled according to representative in vivo measurements obtained from literature. RESULTS: When normalized by the maximal shear stress value, shear stress patterns were similar for the 3 computational techniques. For all activity levels, steady state CFD led to an overestimation of WSS values, while FSI simulations yielded a clear increase in WSS reversal at the outer side of the sinus of the external carotid artery that was not visible in transient CFD-simulations. Furthermore, the FSI simulations in the highest locomotor activity state showed a flow recirculation zone in the external carotid artery that was not present under anesthesia. This recirculation went hand in hand with locally increased WSS reversal. CONCLUSIONS: Our data show that FSI simulations are not necessary to obtain normalized WSS patterns, but indispensable to assess the oscillatory behavior of the WSS in mice. Flow recirculation and WSS reversal at the external carotid artery may occur during high locomotor activity while they are not present under anesthesia. These phenomena might thus influence plaque formation to a larger extent than what was previously assumed.
Assuntos
Anestesia , Artéria Carótida Externa/efeitos dos fármacos , Artéria Carótida Interna/efeitos dos fármacos , Hidrodinâmica , Modelos Cardiovasculares , Resistência ao Cisalhamento/efeitos dos fármacos , Estresse Mecânico , Animais , Artéria Carótida Externa/fisiologia , Artéria Carótida Interna/fisiologia , Simulação por Computador , Feminino , Hemodinâmica , CamundongosRESUMO
High-resolution Doppler is a popular tool for evaluating cardiovascular physiology in mutant mice, though its 1-D nature and spectral broadening processes complicate interpretation of the measurement. Hence, it is crucial for pre-clinical researchers to know how error sources in Doppler assessments reveal themselves in the murine arterial system. Therefore, we performed virtual Doppler experiments in a computer model of an aneurysmatic murine aorta with full control of the imaging and insonified fluid dynamics. We observed significant variability in Doppler performance and derived vascular indices depending on the interrogated flow, operator settings and signal processing. In particular, we found that (i) Doppler spectra in the upper aortic branches and celiac artery exhibited more broadening because of complex out-of-beam flow paths; (ii) mean frequency tracking outperforms tracking of the outer envelope, but is sensitive to errors in angle correction; and (iii) imaging depths deviating much from the elevation focus suffer from decreased spectral quality.
Assuntos
Aorta/fisiologia , Simulação por Computador , Ultrassonografia Doppler/métodos , Animais , Aorta/anatomia & histologia , Velocidade do Fluxo Sanguíneo/fisiologia , Masculino , Camundongos , Modelos Animais , Modelos BiológicosRESUMO
OBJECTIVE: To understand the anatomy and physiology of ascending aortic aneurysms in angiotensin II-infused ApoE(-/-) mice. APPROACH AND RESULTS: We combined an extensive in vivo imaging protocol (high-frequency ultrasound and contrast-enhanced microcomputed tomography at baseline and after 3, 10, 18, and 28 days of angiotensin II infusion) with synchrotron-based ultrahigh resolution ex vivo imaging (phase contrast X-ray tomographic microscopy) in n=47 angiotensin II-infused mice and 6 controls. Aortic regurgitation increased significantly over time, as did the luminal volume of the ascending aorta. In the samples that were scanned ex vivo, we observed one or several focal dissections, with the largest located in the outer convex aspect of the ascending aorta. The volume of the dissections moderately correlated to the volume of the aneurysm as measured in vivo (r(2)=0.46). After 3 days of angiotensin II infusion, we found an interlaminar hematoma in 7/12 animals, which could be linked to an intimal tear. There was also a significant increase in single laminar ruptures, which may have facilitated a progressive enlargement of the focal dissections over time. At later time points, the hematoma was resorbed and the medial and adventitial thickness increased. Fatal transmural dissection occurred in 8/47 mice at an early stage of the disease, before adventita remodeling. CONCLUSIONS: We visualized and quantified the dissections that lead to ascending aortic aneurysms in angiotensin II-infused mice and provided unique insight into the temporal evolution of these lesions.
Assuntos
Aorta/patologia , Aneurisma da Aorta Abdominal/patologia , Dissecção Aórtica/patologia , Ruptura Aórtica/patologia , Remodelação Vascular , Dissecção Aórtica/induzido quimicamente , Dissecção Aórtica/diagnóstico por imagem , Angiotensina II , Animais , Aorta/diagnóstico por imagem , Aorta/metabolismo , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/diagnóstico por imagem , Ruptura Aórtica/induzido quimicamente , Ruptura Aórtica/diagnóstico por imagem , Insuficiência da Valva Aórtica/etiologia , Aortografia/métodos , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Dilatação Patológica , Modelos Animais de Doenças , Progressão da Doença , Tecido Elástico/patologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fatores de Tempo , Ultrassonografia Doppler de Pulso , Microtomografia por Raio-XRESUMO
At a time of growing concern over the ethics of animal experimentation, mouse models are still an indispensable source of insight into the cardiovascular system and its most frequent pathologies. Nevertheless, reference data on the murine cardiovascular anatomy and physiology are lacking. In this work, we developed and validated an in silico, one dimensional model of the murine systemic arterial tree consisting of 85 arterial segments. Detailed aortic dimensions were obtained in vivo from contrast-enhanced micro-computed tomography in 3 male, C57BL/6J anesthetized mice and 3 male ApoE(-/-) mice, all 12-weeks old. Physiological input data were gathered from a wide range of literature data. The integrated form of the Navier-Stokes equations was solved numerically to yield pressures and flows throughout the arterial network. The resulting model predictions have been validated against invasive pressure waveforms and non-invasive velocity and diameter waveforms that were measured in vivo on an independent set of 47 mice. In conclusion, we present a validated one-dimensional model of the anesthetized murine cardiovascular system that can serve as a versatile tool in the field of preclinical cardiovascular research.
Assuntos
Alternativas aos Testes com Animais , Artérias/fisiologia , Simulação por Computador , Modelos Cardiovasculares , Algoritmos , Animais , Artérias/anatomia & histologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Ultrassonografia Doppler Dupla , Microtomografia por Raio-X/métodosRESUMO
The ApoE(-)(/)(-) mouse is a common small animal model to study atherosclerosis, an inflammatory disease of the large and medium sized arteries such as the carotid artery. It is generally accepted that the wall shear stress, induced by the blood flow, plays a key role in the onset of this disease. Wall shear stress, however, is difficult to derive from direct in vivo measurements, particularly in mice. In this study, we integrated in vivo imaging (micro-Computed Tomography-µCT and ultrasound) and fluid-structure interaction (FSI) modeling for the mouse-specific assessment of carotid hemodynamics and wall shear stress. Results were provided for 8 carotid bifurcations of 4 ApoE(-)(/)(-) mice. We demonstrated that accounting for the carotid elasticity leads to more realistic flow waveforms over the complete domain of the model due to volume buffering capacity in systole. The 8 simulated cases showed fairly consistent spatial distribution maps of time-averaged wall shear stress (TAWSS) and relative residence time (RRT). Zones with reduced TAWSS and elevated RRT, potential indicators of atherosclerosis-prone regions, were located mainly at the outer sinus of the external carotid artery. In contrast to human carotid hemodynamics, no flow recirculation could be observed in the carotid bifurcation region.
Assuntos
Modelos Cardiovasculares , Resistência ao Cisalhamento , Estresse Mecânico , Animais , Apolipoproteínas E/deficiência , Aterosclerose/fisiopatologia , Artéria Carótida Externa/diagnóstico por imagem , Artéria Carótida Externa/fisiologia , Artéria Carótida Interna/diagnóstico por imagem , Artéria Carótida Interna/fisiologia , Simulação por Computador , Elasticidade , Feminino , Hemodinâmica , Camundongos , Microtomografia por Raio-XRESUMO
It is generally accepted that low and oscillatory wall shear stress favors the initiation and development of atherosclerosis. However, a quantitative analysis of the association between shear stress metrics at baseline and lesion prevalence at a later stage is challenging to perform in vivo on a within-subject basis. In this study, we assessed carotid hemodynamics and derived hemodynamic wall parameters from subject-specific fluid-structure interaction simulations in the left and right carotid arteries of 4 ApoE(-/-) mice prior to disease development. We then applied a point-by-point quantitative association (surrogate sample data analysis) between various established and more recent shear related parameters and the extent of macrophage infiltration at a later stage. We conclude that, for the atherosclerotic murine carotid bifurcation, (i) there is an association between hemodynamics and macrophage infiltration; (ii) this correlation is most apparent when assessed at the level of the entire carotid bifurcation; (iii) the strongest spatial correlation between hemodynamics and atherosclerosis development was found for the time averaged wall shear stress (negative correlation) and the relative residence time (positive correlation); (iv) aggregating the data leads to an overestimation of the correlation.
Assuntos
Aterosclerose/fisiopatologia , Artérias Carótidas/fisiopatologia , Hemodinâmica , Modelos Cardiovasculares , Resistência ao Cisalhamento , Estresse Mecânico , Animais , Apolipoproteínas E/deficiência , Aterosclerose/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Artérias Carótidas/metabolismo , Artérias Carótidas/patologia , Modelos Animais de Doenças , Macrófagos/metabolismo , Macrófagos/patologia , Camundongos , Camundongos KnockoutRESUMO
Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1ß inhibition, anti-angiogenic agents and urocortins.
RESUMO
INTRODUCTION: Since the initial publication in 2000, Angiotensin II-infused mice have become one of the most popular models to study abdominal aortic aneurysm in a pre-clinical setting. We recently used phase contrast X-ray based computed tomography to demonstrate that these animals develop an apparent luminal dilatation and an intramural hematoma, both related to mural ruptures in the tunica media in the vicinity of suprarenal side branches. AIMS: The aim of this narrative review was to provide an extensive overview of small animal applicable techniques that have provided relevant insight into the pathogenesis and morphology of dissecting AAA in mice, and to relate findings from these techniques to each other and to our recent PCXTM-based results. Combining insights from recent and consolidated publications we aimed to enhance our understanding of dissecting AAA morphology and anatomy. RESULTS AND CONCLUSION: We analyzed in vivo and ex vivo images of aortas obtained from macroscopic anatomy, histology, high-frequency ultrasound, contrast-enhanced micro-CT, micro-MRI and PCXTM. We demonstrate how in almost all publications the aorta has been subdivided into a part in which an intact lumen lies adjacent to a remodeled wall/hematoma, and a part in which elastic lamellae are ruptured and the lumen appears to be dilated. We show how the novel paradigm fits within the existing one, and how 3D images can explain and connect previously published 2D structures. We conclude that PCXTM-based findings are in line with previous results, and all evidence points towards the fact that dissecting AAAs in Angiotensin II-infused mice are actually caused by ruptures of the tunica media in the immediate vicinity of small side branches.