elastin and Aortic-Dissection

The importance of maintaining contractile function in aortic smooth muscle cells (SMCs) is evident by the fact that heterozygous mutations in the major structural proteins or kinases controlling contraction lead to the formation of aneurysms of the ascending thoracic aorta that predispose to life-threatening aortic dissections. Force generation by SMC requires ATP-dependent cyclic interactions between filaments composed of SMC-specific isoforms of α-actin (encoded by ACTA2) and myosin heavy chain (MYH11). ACTA2 and MYH11 mutations are predicted or have been shown to disrupt this cyclic interaction predispose to thoracic aortic disease. Movement of the myosin motor domain is controlled by phosphorylation of the regulatory light chain on the myosin filament, and loss-of-function mutations in the dedicated kinase for this phosphorylation, myosin light chain kinase (MYLK) also predispose to thoracic aortic disease. Finally, a mutation in the cGMP-activated protein kinase (PRKG1) results in constitutive activation of the kinase in the absence of cGMP, thus driving SMC relaxation in part through increased dephosphorylation of the regulatory light chain and predisposes to thoracic aortic disease. Furthermore, SMCs cannot generate force without connections to the extracellular matrix through focal adhesions, and mutations in the major protein in the extracellular matrix, fibrillin-1, linking SMCs to the matrix also cause thoracic aortic disease in individuals with Marfan syndrome. Thus, disruption of the ability of the aortic SMC to generate force through the elastin-contractile units in response to pulsatile blood flow may be a primary driver for thoracic aortic aneurysms and dissections.

Topics: Actins; Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Calcium-Binding Proteins; Cyclic GMP-Dependent Protein Kinase Type I; Dilatation, Pathologic; Elastin; Genetic Markers; Genetic Testing; Heredity; Humans; Mechanotransduction, Cellular; Muscle, Smooth, Vascular; Mutation; Myocytes, Smooth Muscle; Myosin Heavy Chains; Myosin-Light-Chain Kinase; Phenotype; Pulsatile Flow; Vasoconstriction

The medial layer of the aorta confers elasticity and strength to the aortic wall and is composed of alternating layers of smooth muscle cells (SMCs) and elastic fibres. The SMC elastin-contractile unit is a structural unit that links the elastin fibres to the SMCs and is characterized by the following: (1) layers of elastin fibres that are surrounded by microfibrils; (2) microfibrils that bind to the integrin receptors in focal adhesions on the cell surface of the SMCs; and (3) SMC contractile filaments that are linked to the focal adhesions on the inner side of the membrane. The genes that are altered to cause thoracic aortic aneurysms and aortic dissections encode proteins involved in the structure or function of the SMC elastin-contractile unit. Included in this gene list are the genes encoding protein that are structural components of elastin fibres and microfibrils, FBN1, MFAP5, ELN, and FBLN4. Also included are genes that encode structural proteins in the SMC contractile unit, including ACTA2, which encodes SMC-specific α-actin and MYH11, which encodes SMC-specific myosin heavy chain, along with MYLK and PRKG1, which encode kinases that control SMC contraction. Finally, mutations in the gene encoding the protein linking integrin receptors to the contractile filaments, FLNA, also predispose to thoracic aortic disease. Thus, these data suggest that functional SMC elastin-contractile units are important for maintaining the structural integrity of the aorta.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; DNA; Elastin; Genotype; Humans; Muscle, Smooth, Vascular; Phenotype; Vasoconstriction

This review discusses the role of biomarkers for both diagnoses and disease monitoring before, during, and after treatment of aortic dissection.

Topics: Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Calcium-Binding Proteins; Calponins; Elastin; Endothelin-1; Fibrin Fibrinogen Degradation Products; Humans; Microfilament Proteins; Natriuretic Peptide, Brain; Peptide Fragments; Peptidyl-Dipeptidase A; Receptors, Notch; Smooth Muscle Myosins; Transforming Growth Factor beta

Acute aortic dissection is a disease that is often a challenge to diagnose. Early and immediate diagnosis is important for initiation of treatment and improved survival. Despite recent advances in imaging methods to diagnose the disease, biochemical methods are not available.. Biomarkers that might be useful for the biochemical detection of acute aortic dissection have been recently described, such as assays for the circulating proteins, smooth muscle myosin heavy chain, creatine kinase BB-isozyme, calponin (smooth muscle troponin) and elastin. C-reactive protein and D-dimer have also been shown to be useful.. Biomarker-assisted diagnosis of acute aortic dissection would be helpful in detecting this acute catastrophic aortic disease, which still remains a challenge to diagnose. Although recent progress in development of biomarkers has been made, there is no widely accepted strategy. Available biomarkers such as D-dimer may play an assistive role in the meantime.

Topics: Algorithms; Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Calcium-Binding Proteins; Calponins; Elastin; Fibrin Fibrinogen Degradation Products; Humans; Isoenzymes; Microfilament Proteins; Practice Guidelines as Topic; Transforming Growth Factor beta1

Acute aortic syndromes have an incidence of >30 per million per annum and a high mortality without definitive treatment. Survival may relate to the speed of diagnosis. Although pain is the most common symptom, there is a large fraction of patients in whom the diagnosis may be mistaken or overlooked. Currently, a high index of clinical suspicion is the chief prompt that diverts a patient into a definitive algorithm of imaging investigations. Although there is no point-of-care biochemical test that can be reliably used to positively identify dissection, biomarkers are available that could accelerate the diagnostic pathway and thereby expedite treatment.

Topics: Acute Disease; Animals; Aortic Aneurysm; Aortic Dissection; Biomarkers; C-Reactive Protein; Elastin; Humans; Myosin Heavy Chains

We aimed to establish an enzyme-linked immunosorbent assay for measuring soluble elastin fragments (sELAF) in serum and to reveal its usefulness in diagnosing acute aortic dissection (AAD).. An enzyme-linked immunosorbent assay to measure sELAF in serum was developed by using the newly created double monoclonal antibodies, which recognize the different epitopes of human aortic elastin. Twenty-five AAD patients, 50 patients with acute myocardial infarction (AMI), and 474 healthy individuals were enrolled in the study. The sELAF levels from healthy subjects gradually increased with aging. When the cutoff point for positivity was set at the mean+3 SD (ie, 3 SD above the mean in healthy subjects at each age), 16 AAD patients (64.0%) were found be positive, whereas only 1 AMI patient was found to be positive (2.0%). AAD patients with either an open or a partially open pseudolumen were found be 88.9% positive for sELAF, whereas those with its early closure were 0% positive. The difference in the sELAF levels between AAD patients with and without a thrombotic closure of false lumen was significant (60.3+/-15.6 versus 135.4+/-53.2 ng/mL, respectively; P<0.005).. The sELAF level in serum may be a useful marker for helping in the diagnosis and screening of AAD and may also help to distinguish AAD from AMI.

Topics: Acute Disease; Adult; Aged; Aortic Aneurysm; Aortic Dissection; Biomarkers; Case-Control Studies; Diagnosis, Differential; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged; Myocardial Infarction; Reference Values; Risk Factors

Abdominal aortic aneurysm disease is the local enlargement of the aorta, typically in the infrarenal section, causing up to 200,000 deaths/year. In vivo information to characterize the individual elastic properties of the aneurysm wall in terms of rupture risk is lacking. We used a method that combines 4D ultrasound and direct deformation estimation to compute in vivo 3D Green-Lagrange strain in murine angiotensin II-induced dissecting aortic aneurysms, a commonly used mouse model. After euthanasia, histological staining of cross-sectional sections along the aorta was performed in areas where in vivo strains had previously been measured. The histological sections were segmented into intact and fragmented elastin, thrombus with and without red blood cells, and outer vessel wall including the adventitia. Meshes were then created from the individual contours based on the histological segmentations. The isolated contours of the outer wall and lumen from both imaging modalities were registered individually using a coherent point drift algorithm. 2D finite element models were generated from the meshes, and the displacements from the registration were used as displacement boundaries of the lumen and wall contours. Based on the resulting deformed contours, the strains recorded were grouped according to segmented tissue regions. Strains were highest in areas containing intact elastin without thrombus attachment. Strains in areas with intact elastin and thrombus attachment, as well as areas with disrupted elastin, were significantly lower. Strains in thrombus regions with red blood cells were significantly higher compared to thrombus regions without. We then compared this analysis to statistical distribution indices and found that the results of each aligned, elucidating the relationship between vessel strain and structural changes. This work demonstrates the possibility of advancing in vivo assessments to a microstructural level ultimately improving patient outcomes.

Topics: Animals; Aorta; Aortic Dissection; Cross-Sectional Studies; Elastin; Humans; Mice; Ultrasonography

The transition of aortic dissection from acute to chronic is poorly understood. We examined time-dependent mechanical behaviour and biochemical properties of chronic dissection tissues.. Aorta samples were obtained from 14 patients with mixed aetiology who were undergoing elective surgery for chronic dissected aneurysms, ranging from 3 months to 15 years post-dissection. The tissue elastic modulus and tissue deformation following application of loading for 5 h were measured for the false lumen (FL), true lumen (TL) and flap (FP) tissues with a custom-indentation technique. Collagen, elastin and glycosaminoglycan levels were determined with established biochemical assays. Elastin fragmentation was graded from histological sections. The number of tissues characterized was as follows: FP (n = 10), TL (n = 5 for biomechanical testing, n = 8 for biochemical analysis, n = 8 for histological assessment) and FL (n = 4).. Tissues stiffness was highest in FP [59.8 (14.8) kPa] as compared with TL [50.7 (6.2) kPa] and FL [40.5 (4.7) kPa] (P = 0.023 and P = 0.006, respectively). FP [0.5 (0.08) mm] also exhibited reduced deformation relative to TL [0.7 (0.02) mm] and FL [0.9 (0.08) mm] (P = 0.003 and P = 0.006, respectively), lowest collagen concentration [FP: 40.1 (19.6) µg/mg, TL: 59.9 (19.5) µg/mg, P = 0.008; FL: 79.1 (32.0) µg/mg, P = 0.006] and the lowest collagen: elastin ratio [0.4 (0.1)] relative to the other tissues [TL; 0.6 (0.3), P = 0.006, FL; 1.5 (0.4); P = 0.003]. Significant elastin loss was evident in the FL-stained tissue sections whereas highly aligned, long fibres were visible in the FP and TL. A linear relationship was found between the stiffness, deformation and the time from the dissection event to surgical intervention for the FP. All data are presented as median (interquartile range).. FP exhibited reduced time-dependent deformation and distinct biochemical properties relative to TL and FL irrespective of connective tissue disorder or the anatomical region of the dissection.

Topics: Aorta; Aortic Aneurysm, Thoracic; Aortic Dissection; Elastin; Humans

This study investigated the association between the macroscopic mechanical response of aortic dissection (AoD) flap, its fibre features, and patient physiological features and clinical presentations.. Uniaxial test was performed with tissue strips in both circumferential and longitudinal directions from 35 patients with (AoD:CC) and without (AoD:w/oCC) cerebral/coronary complications, and 19 patients with rheumatic or valve-related heart diseases (RH). A Bayesian inference framework was used to estimate the expectation of material constants (C. The elastin area percentage was negatively associated with age (p = 0.008), while collagen increased about 6% from age 40 to 70 (p = 0.03). Elastin fibre was less dispersed and wavier in old patients and no significant association was found between patient age and collagen fibre dispersion or waviness. Features of fibrous microstructures, either elastin or collagen, were comparable between AoD:CC and AoD:w/oCC group. Elastin and collagen area percentages were positively correlated with C. Fibre dispersion and waviness in the aortic dissection flap changed with patient age and clinical presentations, and these can be captured by the material constants in the strain energy density function.. Aortic dissection (AoD) is a severe cardiovascular disease. Understanding the mechanical property of intimal flap is essential for its risk evaluation. In this study, mechanical testing and histology examination were combined to quantify the relationship between mechanical presentations and microstructure features. A Bayesian inference framework was employed to estimate the expectation of the material constants in the modified Mooney-Rivlin constitutive equation. It was found that fibre dispersion and waviness in the AoD flap changed with patient age and clinical presentations, and these could be captured by the material constants. This study firstly demonstrated that the expectation of material constants can be used to characterise tissue microstructures and differentiate patients with different clinical presentations.

Topics: Adult; Aged; Aortic Dissection; Bayes Theorem; Biomechanical Phenomena; Collagen; Elastin; Humans; Middle Aged; Stress, Mechanical

Background The biological mechanism of action for osteoprotegerin, a soluble decoy receptor for the receptor activator of nuclear factor-kappa B ligand in the vascular structure, has not been elucidated. The study aim was to determine if osteoprotegerin affects aortic structural integrity in angiotensin II (Ang II)-induced hypertension. Methods and Results Mortality was higher (

Topics: Angiotensin II; Animals; Aortic Dissection; Aortic Rupture; Disease Models, Animal; Elastin; Hypertension; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Osteoprotegerin; RANK Ligand

Thoracic aortic aneurysm/dissection (TAAD) is a life-threatening disease with diverse clinical manifestations. Although the association between methamphetamine (METH) and TAAD is frequently observed, the causal relationship between METH abuse and aortic aneurysm/dissection has not been established. This study was designed to determine if METH causes aortic aneurysm/dissection and delineate the underlying mechanism.. A new TAAD model was developed by exposing METH to SD rats pre-treated with lysyl oxidase inhibitor β-aminopropionitrile (BAPN). Combination of METH and BAPN caused thoracic aortic aneurysm/dissection in 60% of rats. BAPN+METH significantly increased the expression and activities of both matrix metalloproteinase MMP2 and MMP9, consistent with the severe elastin breakage and dissection. Mechanistically, METH increased CCAAT-enhancer binding protein β (C/EBPβ) expression by enhancing mothers against decapentaplegic homolog 3 (Smad3) and extracellular regulated protein kinase (ERK1/2) signaling. METH also promoted C/EBPβ binding to MMP2 and MMP9 promoters. Blocking C/EBPβ significantly attenuated METH+BAPN-induced TAAD and MMP2/MMP9 expression. Moreover, BAPN+METH promoted aortic medial smooth muscle cell (SMC) apoptosis through C/EBPβ-mediated IGFBP5/p53/PUMA signaling pathways. More importantly, the expression of C/EBPβ, MMP2/MMP9, and apoptosis-promoting proteins was increased in the aorta of human patients with thoracic aortic dissection, suggesting that the mechanisms identified in animal study could be relevant to human disease.. Our study demonstrated that METH exposure has a casual effect on TAAD. C/EBPβ mediates METH-introduced TAAD formation by causing elastin breakage, medial cell loss and degeneration. Therefore, C/EBPβ may be a potential factor for TAAD clinical diagnosis or treatment.

Topics: Aminopropionitrile; Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; CCAAT-Enhancer-Binding Protein-beta; Elastin; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Methamphetamine; Rats; Rats, Sprague-Dawley

Fluoroquinolones are one of the most frequently prescribed antibiotics. However, their use increases the risk of Aortic aneurysm and dissection (AAD). The mechanism underlying this effect remains unclear. AAD are caused by weakening of the aortic wall and loss of vascular smooth muscle cells. Osteopontin is involved in the occurrence and development of AAD. The aim of the present study was to examine the role of moxifloxacin, a fluoroquinolone, in the occurrence of AAD using a moderate-severity AAD mouse model. Four-week-old male C57BL/6J mice were fed a high-fat diet. At 8 weeks of age, the mice were infused with saline or angiotensin II (1000 ng kg

Topics: Angiotensin II; Animals; Anti-Bacterial Agents; Aortic Aneurysm; Aortic Dissection; Disease Models, Animal; Elastin; Eosine Yellowish-(YS); Hematoxylin; Male; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Moxifloxacin; Muscle Proteins; Myocytes, Smooth Muscle; Osteopontin; Rubber; Water

Aortic dissection (AD) is a lethal aortic pathology without effective medical treatments since the underlying pathological mechanisms responsible for AD remain elusive. Matrix metalloproteinase-8 (MMP8) has been previously identified as a key player in atherosclerosis and arterial remodeling. However, the functional role of MMP8 in AD remains largely unknown. Here, we report that an increased level of MMP8 was observed in 3-aminopropionitrile fumarate (BAPN)-induced murine AD. AD incidence and aortic elastin fragmentation were markedly reduced in MMP8-knockout mice. Importantly, pharmacologic inhibition of MMP8 significantly reduced the AD incidence and aortic elastin fragmentation. We observed less inflammatory cell accumulation, a lower level of aortic inflammation, and decreased smooth muscle cell (SMC) apoptosis in MMP8-knockout mice. In line with our previous observation that MMP8 cleaves Ang I to generate Ang II, BAPN-treated MMP8-knockout mice had increased levels of Ang I, but decreased levels of Ang II and lower blood pressure. Additionally, we observed a decreased expression level of vascular cell adhesion molecule-1 (VCAM1) and a reduced level of reactive oxygen species (ROS) in MMP8-knockout aortas. Mechanistically, our data show that the Ang II/VCAM1 signal axis is responsible for MMP8-mediated inflammatory cell invasion and transendothelial migration, while MMP8-mediated SMC inflammation and apoptosis are attributed to Ang II/ROS signaling. Finally, we observed higher levels of aortic and serum MMP8 in patients with AD. We therefore provide new insights into the molecular mechanisms underlying AD and identify MMP8 as a potential therapeutic target for this life-threatening aortic disease.

Topics: Aminopropionitrile; Angiotensin II; Animals; Aortic Dissection; Disease Models, Animal; Elastin; Humans; Inflammation; Matrix Metalloproteinase 8; Mice; Mice, Knockout; Reactive Oxygen Species; Vascular Cell Adhesion Molecule-1

Perlecan (HSPG2), a basement membrane-type heparan sulfate proteoglycan, has been implicated in the development of aortic tissue. However, its role in the development and maintenance of the aortic wall remains unknown. Perlecan-deficient mice (

Topics: Animals; Aorta; Aortic Dissection; Biomarkers; Elasticity; Elastin; Extracellular Matrix Proteins; Fibrillin-1; Heparan Sulfate Proteoglycans; Matrix Metalloproteinases; Mice, Transgenic; Myocardial Contraction; Myocytes, Smooth Muscle; Protein Biosynthesis; Risk Factors; RNA, Messenger

Aortic dissections progress, in part, by delamination of the wall. Previous experiments on cut-open segments of aorta demonstrated that fluid injected within the wall delaminates the aorta in two distinct modes: stepwise progressive tearing in the abdominal aorta and a more prevalent sudden mode of tearing in the thoracic aorta that can also manifest in other regions. A microstructural understanding that delineates these two modes of tearing has remained wanting. We implemented a phase-field finite-element model of the aortic wall, motivated in part by two-photon imaging, and found correlative relations for the maximum pressure prior to tearing as a function of local geometry and material properties. Specifically, the square of the pressure of tearing relates directly to both tissue stiffness and the critical energy of tearing and inversely to the square root of the torn area; this correlation explains the sudden mode of tearing and, with the microscopy, suggests a mechanism for progressive tearing. Microscopy also confirmed that thick interlamellar radial struts are more abundant in the abdominal region of the aorta, where progressive tearing was observed previously. The computational results suggest that structurally significant radial struts increase tearing pressure by two mechanisms: confining the fluid by acting as barriers to flow and increasing tissue stiffness by holding the adjacent lamellae together. Collectively, these two phase-field models provide new insights into the mechanical factors that can influence intramural delaminations that promote aortic dissection.

Topics: Animals; Aorta, Abdominal; Aortic Dissection; Elastin; Female; Finite Element Analysis; Humans; Mice, Inbred C57BL; Microscopy, Fluorescence, Multiphoton; Models, Cardiovascular; Pressure

Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1β). However, the exact mechanism remains unknown. This study aimed to investigate the role of IL-1β, matrix metalloproteinase (MMP)-2, MMP-9, smooth muscle cell apoptosis, and elastic fibre fracture in the development of TAD in a rat model.. The TAD rat model was induced by β-aminopropionitrile (BAPN). TAD was investigated in 112 male Sprague-Dawley rats, which were equally divided into four groups of 28 rats (Control, BAPN, BAPN + IL-1β, and BAPN + IL-1β antibody). Systolic blood pressure, survival, and the development of TAD were measured after six weeks. Expression of IL-1β, MMP-2, and MMP-9 was measured by Western blot. Apoptosis, aortic elastin concentration, and biomechanical characteristics were measured by the TdT mediated dUTP nick end labelling assay, Victoria blue staining, and in vitro testing.. During six weeks, the mortality was 0% (0/28) in the control group, 53.6% (15/28) in the BAPN group (p < .001 compared with the control group), 75.0% (21/28) in the BAPN + IL-1β group (p = .007 compared with the BAPN group), and 35.7% (10/28) in the BAPN + IL-1β antibody group (p = .023 compared with BAPN group and p < .001 compared with the BAPN + IL-1β group). IL-1β treatment deteriorates BAPN induced mortality and aneurysm expansion, which were attenuated by anti-IL-1β treatment. In BAPN + IL-1β group, stress and strain parameters were decreased by 13.5%-53.5% and elastin content was decreased by 14%, and IL-1β, MMP-2, and MMP-9 were expressed higher by 117%, 108%, and 75% when compared with the rats in the BAPN group. Contrarily, in the BAPN + IL-1β antibody group, the above changes could be completely (strain, elastin content, and expression of MMP-2) or partly (elasticity modulus, stress, and expression of MMP-9) blocked by anti-IL-1β treatment.. IL-1β plays a critical role in TAD formation by altering the expression of MMP-2 and MMP-9, degrading the aortic wall matrix, causing elastic fibre rupture, and changing the stress or strain of the aortic wall. Anti-IL-1β reduces the later effects and could be one of the molecular targets for prognosis and drug treatment of TAD in the future.

Topics: Aminopropionitrile; Animals; Antibodies; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Apoptosis; Disease Models, Animal; Elastin; Interleukin-1beta; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Rats; Rats, Sprague-Dawley; Survival Rate

Mechanical characteristics of both the healthy ascending aorta and acute type A aortic dissection were investigated using in vitro biaxial tensile tests, in vivo measurements via transoesophageal echocardiography and histological characterisations. This combination of analysis at tissular, structural and microstructural levels highlighted the following: (i) a linear mechanical response for the dissected intimomedial flap and, conversely, nonlinear behaviour for both healthy and dissected ascending aorta; all showed anisotropy; (ii) a stiffer mechanical response in the longitudinal than in the circumferential direction for the healthy ascending aorta, consistent with the histological quantification of collagen and elastin fibre density; (iii) a link between dissection and ascending aorta stiffening, as revealed by biaxial tensile tests. This result was corroborated by in vivo measurements with stiffness index, β, and Peterson modulus, E

Topics: Aged; Anisotropy; Aorta; Aortic Aneurysm; Aortic Dissection; Biomechanical Phenomena; Collagen; Echocardiography, Transesophageal; Elastin; Female; Humans; Male; Middle Aged; Stress, Mechanical; Tensile Strength

Arterial wall dissection, which results from various pathophysiological processes, can lead to the occurrence of large area delamination in the aortic wall that can potentially block blood flow and lead to deleterious clinical conditions. Despite its critical clinical relevance, few studies have focused on investigating the failure mode of delamination in the arterial wall. In this study, we quantify the energy release rate of the medial layer of a porcine abdominal aorta via two delamination experiments: the mixed-mode delamination experiment and the "T"-shaped delamination experiment. A cohesive zone model (CZM) is applied to simulate the arterial wall delamination and Holzapfel-Gasser-Ogden (HGO) material model is used to capture the bulk arterial material behavior. A set of parameter values for the HGO and CZM models are identified through matching simulation predictions of the load vs. load-point displacement curve with experimental measurements. Then the parameter values and critical energy release rates obtained from experiments are used as input data for simulation predictions for two arterial wall delamination experiments. The simulation predictions show that the delamination front matches well with experimental measurements. Moreover, the mixed-mode delamination experiment reveals a shear mode-dominated failure event, whereas the "T"-shaped delamination experiment is an opening failure process. The integration of experimental data and numerical predictions of arterial delamination events provides a comprehensive description of distinct failure modes and aids in the prediction of aortic dissection.

Topics: Animals; Aorta, Abdominal; Aortic Dissection; Arteries; Cell Adhesion; Computer Simulation; Elastin; Finite Element Analysis; Humans; Materials Testing; Models, Cardiovascular; Shear Strength; Stress, Mechanical; Swine

Topics: Aminopropionitrile; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Cells, Cultured; Cytokine Receptor Common beta Subunit; Dilatation, Pathologic; Disease Models, Animal; Elastin; Extracellular Signal-Regulated MAP Kinases; Interleukin-3; JNK Mitogen-Activated Protein Kinases; Macrophages; Matrix Metalloproteinase 12; Mice, Inbred C57BL; Mice, Knockout; Signal Transduction; Transcription Factor AP-1; Up-Regulation

To explore the role of microRNA (miR)-30a in the development of aortic dissection.. Human aortic specimens of aortic dissections and aneurysms were harvested. Aortic specimens from donors for heart transplantation served as controls. Rat aortic vascular smooth muscle cells (VSMCs) were transfected with agomiR-30a or antagomiR-30a, and control cells were incubated with empty vectors. Rats were pretreated with agomiR-30a or antagomiR-30a (5 × 10. Gene expression of miR-30a was much higher, and protein abundance of LOX and elastin was significantly lower, in the aortic dissection specimens (P < .05 vs controls). Transfection of agomiR-30a markedly decreased the luciferase activity of LOX in VSMCs of wild type, but not of LOX 3'-UTR mutant (P = .002). In cultured VSMCs, transfection of agomiR-30a dramatically enhanced the gene expression of miR-30a and down-regulated the protein abundance of LOX and elastin (P < .05 vs controls). Pretreatment with agomiR-30a in vivo enhanced miR-30a expression and down-regulated the protein abundance of LOX and elastin in rat aortas (P < .05 vs controls). The rate of dissection was significantly higher in rats pretreated with agomiR-30a (P = .003 vs controls).. Overexpression of miR-30a contributes to the development of aortic dissection, possibly by targeting LOX.

Topics: Animals; Aorta; Aortic Aneurysm; Aortic Dissection; Case-Control Studies; Cells, Cultured; Disease Models, Animal; Elastin; Gene Expression Regulation, Enzymologic; Humans; Male; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Protein-Lysine 6-Oxidase; Rats, Sprague-Dawley; Up-Regulation

Previous reports have shown that serum elastin fragments (SEFs) may be a useful biomarker for the diagnosis of an acute aortic dissection (AAD). However, because the reference interval of SEFs has not been established, it has not been determined whether SEFs are really useful for the diagnosis of AAD. The purpose of this study was to determine the usefulness of measuring SEFs for the diagnosis of AAD. A total of 42 consecutive patients aged 68 ± 18 years who were diagnosed with an AAD were studied. Patient background and SEF levels were examined on admission. SEF levels were also measured in patients undergoing a medical examination (n = 531, age 54 ± 17 years) to compare with those with an AAD. In the control group, SEF levels increased with age (R = 0.725, p <0.001). Then, we defined the upper limit of the reference interval of SEF levels as the 97.5th percentile of control SEF grouped by decade of life from the sixth to ninth decade. The overall risk of AAD exceeding the upper limit of the reference interval at each decade was 10% (4 of 42). For patients in their 60s and 70s, median SEF levels in the AAD group (89 [77 to 104], 93 [60 to 123] ng/ml, respectively) were not significantly higher than those in the control group (79 [68 to 92], 90 [79 to 106] ng/ml, respectively; p = 0.081 and 0.990, respectively). Our data suggest that measuring SEF levels may not be useful in the diagnosis of an AAD as the upper limit of the reference interval of the SEF level was unexpectedly higher.

Topics: Acute Disease; Aged; Aortic Aneurysm; Aortic Dissection; Biomarkers; Diagnosis, Differential; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Male; Middle Aged

Degradation and fragmentation of elastic fibers in the media dilate the aortic wall excessively in patients with acute Stanford type A aortic dissection (AD). Such dilatation occurs not via aortic stiffening, which is diagnosed using imaging under physiological loading, but due to the abovementioned intrinsic changes in elastic fibers, which can be detected at the low-stress region of the stress-strain relationship. Our objective is to determine an age-related correlation between distensibility and histology. We conducted uniaxial stretching tests and a histological evaluation of the ascending aorta (AA) using AD samples obtained at surgery from 9 elderly patients (aged 52-85 yr), with no heritable connective tissue disorders, and control (CN) samples from 10 subjects at autopsy (aged 56-86 yr). We compared the distensibility, or an increase in strain for the uniaxial tensile stress of 0-50 kPa, between the AD and CN groups, and correlated it with age and histology. Distensibility was significantly greater in the AD than that in the CN group (p=0.030), but elastin content was significantly lower (p=0.0025). The positive correlation between distensibility and elastin content in CN samples suggests that the distensibility increases with elastic fiber histological abnormalities. The age-matched collagen content decreased with the age of the patients, and did not differ between the AD and CN groups. The age-matched distensibility in the AD and CN groups decreased and became closer with aging. Such intrinsic properties should be considered during imaging to assess distensibility in patients with AD.

Topics: Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Dissection; Biomechanical Phenomena; Case-Control Studies; Collagen; Elasticity; Elastin; Female; Humans; Male; Middle Aged

Sirtuin-1 (SirT1), a nicotinamide adenine dinucleotide(+)-dependent deacetylase, is a key enzyme in the cellular response to metabolic, inflammatory, and oxidative stresses; however, the role of endogenous SirT1 in the vasculature has not been fully elucidated. Our goal was to evaluate the role of vascular smooth muscle SirT1 in the physiological response of the aortic wall to angiotensin II, a potent hypertrophic, oxidant, and inflammatory stimulus.. Mice lacking SirT1 in vascular smooth muscle (ie, smooth muscle SirT1 knockout) had drastically high mortality (70%) caused by aortic dissection after angiotensin II infusion (1 mg/kg per day) but not after an equipotent dose of norepinephrine, despite comparable blood pressure increases. Smooth muscle SirT1 knockout mice did not show any abnormal aortic morphology or blood pressure compared with wild-type littermates. Nonetheless, in response to angiotensin II, aortas from smooth muscle SirT1 knockout mice had severely disorganized elastic lamellae with frequent elastin breaks, increased oxidant production, and aortic stiffness compared with angiotensin II-treated wild-type mice. Matrix metalloproteinase expression and activity were increased in the aortas of angiotensin II-treated smooth muscle SirT1 knockout mice and were prevented in mice overexpressing SirT1 in vascular smooth muscle or with use of the oxidant scavenger tempol.. Endogenous SirT1 in aortic smooth muscle is required to maintain the structural integrity of the aortic wall in response to oxidant and inflammatory stimuli, at least in part, by suppressing oxidant-induced matrix metalloproteinase activity. SirT1 activators could potentially be a novel therapeutic approach to prevent aortic dissection and rupture in patients at risk, such as those with hypertension or genetic disorders, such as Marfan's syndrome.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm; Aortic Dissection; Cells, Cultured; Cyclic N-Oxides; Disease Models, Animal; Elastic Tissue; Elastin; Free Radical Scavengers; Hypertension; Matrix Metalloproteinases; Mice, Inbred C57BL; Mice, Knockout; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Sirtuin 1; Spin Labels; Time Factors

Thrombus ages, defined as four relative age phases, are related to different compositions of the intraluminal thrombus (ILT) in the abdominal aortic aneurysm (AAA) (Tong et al., 2011b). Experimental studies indicate a correlation between the relative thrombus age and the strength of the thrombus-covered wall.. On 32 AAA samples we performed peeling tests with the aim to dissect the material (i) through the ILT thickness, (ii) within the individual ILT layers and (iii) within the aneurysm wall underneath the thrombus by using two extension rates (1mm/min, 1mm/s). Histological investigations and mass fraction analysis were performed to characterize the dissected morphology, to determine the relative thrombus age, and to quantify dry weight percentages of elastin and collagen in the AAA wall.. A remarkably lower dissection energy was needed to dissect within the individual ILT layers and through the thicknesses of old thrombi. With increasing ILT age the dissection energy of the underlying intima-media composite continuously decreased and the anisotropic dissection properties for that composite vanished. The quantified dissection properties were rate dependent for both tissue types (ILT and wall). Histology showed that single fibrin fibers or smaller protein clots within the ILT generate smooth dissected surfaces during the peeling. There was a notable decrease in mass fraction of elastin within the thrombus-covered intima-media composite with ILT age, whereas no significant change was found for that of collagen.. These findings suggest that intraluminal thrombus aging leads to a higher propensity of dissection for the ILT and the intima-media composite of the aneurysmal wall.

Topics: Aged; Aged, 80 and over; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Dissection; Collagen; Elastin; Endothelium, Vascular; Fibrin; Humans; Middle Aged; Pressure; Thrombosis

Aortic dissection (AoD) is a common condition that often leads to life-threatening cardiovascular emergency. From a biomechanics viewpoint, AoD involves failure of load-bearing microstructural components of the aortic wall, mainly elastin and collagen fibers. Delamination strength of the aortic wall depends on the load-bearing capacity and local micro-architecture of these fibers, which may vary with age, disease and aortic location. Therefore, quantifying the role of fiber micro-architecture on the delamination strength of the aortic wall may lead to improved understanding of AoD. We present an experimentally-driven modeling paradigm towards this goal. Specifically, we utilize collagen fiber micro-architecture, obtained in a parallel study from multi-photon microscopy, in a predictive mechanistic framework to characterize the delamination strength. We then validate our model against peel test experiments on human aortic strips and utilize the model to predict the delamination strength of separate aortic strips and compare with experimental findings. We observe that the number density and failure energy of the radially-running collagen fibers control the peel strength. Furthermore, our model suggests that the lower delamination strength previously found for the circumferential direction in human aorta is related to a lower number density of radially-running collagen fibers in that direction. Our model sets the stage for an expanded future study that could predict AoD propagation in patient-specific aortic geometries and better understand factors that may influence propensity for occurrence.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Biomechanical Phenomena; Elastin; Extracellular Matrix; Female; Fibrillar Collagens; Humans; Models, Cardiovascular; Weight-Bearing

Ascending aortic dissection and rupture remain a life-threatening complication in patients with Marfan syndrome. The extracellular matrix provides strength and elastic recoil to the aortic wall, thereby preventing radial expansion. We have previously shown that ascending aortic aneurysm formation in Marfan mice (Fbn1(C1039G/+)) is associated with decreased aortic wall elastogenesis and increased elastin breakdown. In this study, we test the feasibility of quantifying aortic wall elastin content using MRI with a gadolinium-based elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) mice.. Ascending aorta elastin content was measured in 32-week-old Fbn1(C1039G/+) mice and wild-type (n=9 and n=10, respectively) using 7-T MRI with a T1 mapping sequence. Significantly lower enhancement (ie, lower R1 values, where R1=1/T1) was detected post-elastin-specific magnetic resonance contrast agent in Fbn1(C1039G/+) compared with wild-type ascending aortas (1.15±0.07 versus 1.36±0.05; P<0.05). Post-elastin-specific magnetic resonance contrast agent R1 values correlated with ascending aortic wall gadolinium content directly measured by inductively coupled mass spectroscopy (P=0.006).. Herein, we demonstrate that MRI with elastin-specific magnetic resonance contrast agent accurately measures elastin bound gadolinium within the aortic wall and detects a decrease in aortic wall elastin in Marfan mice compared with wild-type controls. This approach has translational potential for noninvasively assessing aneurysm tissue changes and risk, as well as monitoring elastin content in response to therapeutic interventions.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Chelating Agents; Contrast Media; Disease Models, Animal; Elastin; Feasibility Studies; Heterocyclic Compounds, 1-Ring; Magnetic Resonance Imaging; Male; Marfan Syndrome; Mice; Mice, Inbred C57BL; Reproducibility of Results

It was recently demonstrated by our group that the delamination strength of ascending thoracic aortic aneurysms (ATAA) was lower than that of control (CTRL, non-aneurysmal) ascending thoracic aorta (ATA), and the reduced strength was more pronounced among bicuspid (BAV) vs. tricuspid aortic valve (TAV) patients, suggesting a different risk of aortic dissection for BAV patients. We hypothesized that aortic valve morphologic phenotype predicts fiber micro-architectural anomalies in ATA. To test the hypothesis, we characterized the micro-architecture in the longitudinal-radial (Z-RAD) and circumferential-radial (Θ-RAD) planes of human ATA tissue that was artificially dissected medially. The outer and inner-media of CTRL-ATA, BAV-ATAA and TAV-ATAA were imaged using multi-photon microscopy in the Z-RAD and Θ-RAD planes to observe collagen and elastin. Micrographs were processed using an image-based tool to quantify several micro-architectural characteristics. In the outer-media of BAV-ATAA, elastin was more undulated and less aligned about the Θ-axis when compared with CTRL-ATA, which is consistent with increased tensile stretch at inflection point of Θ-strips of adventitial-medial half of BAV-ATAA (1.28) when compared with CTRL-ATA (1.13). With increasing age, collagen became more undulated about the Z-axis within the outer-media of TAV-ATAA, and elastin became more oriented in the Z-axis and collagen less radially-oriented within the inner-media of TAV-ATAA. This discrepancy in the micro-architecture with fibers in the inner layers being more stretched and with disrupted radially-oriented components than fibers in the outer layers may be associated with the development, progression and vascular remodeling in aneurysms arising in TAV patients.

Topics: Analysis of Variance; Aortic Aneurysm, Thoracic; Aortic Dissection; Aortic Rupture; Aortic Valve; Biomechanical Phenomena; Collagen; Elastin; Female; Humans; Male; Microscopy, Fluorescence, Multiphoton; Middle Aged; Phenol; Tunica Intima; Tunica Media

The main purpose of the present study is the investigation of gender differences in the biomechanical properties, thrombus age, mass fraction and key clinical factors of abdominal aortic aneurysms (AAAs).. A total of 90 AAA samples (78 males and 12 females) were harvested from open surgical aneurysm repairs. Biaxial extension and peeling tests were performed to characterise the biaxial mechanical responses and to determine dissection properties of both the intraluminal thrombi (ILTs) and the thrombus-covered walls. Relative thrombus age was determined by characterising the ILT histological microstructure. Mass fraction analyses quantified dry weight percentages of elastin and collagen within the AAA walls. Moreover, we statistically compared clinical factors between male and female.. The luminal layers of the female thrombi and the female AAA walls showed a significantly lower tissue stiffness (modulus) in the longitudinal direction when compared to males. Gender differences were also shown in the dissection properties of the intima-media composite within the AAA walls, in which a statistically significantly lower energy to propagate a dissection was quantified for females than for males. Moreover, 82% of female thrombi were relatively older (ILT age phases III and IV), twice that of male thrombi (43%). A pronounced lower elastin content was identified for the intima-media composites of male AAA walls, whereas female AAA walls had significantly lower dry weight percentages of collagen. Regarding clinical factors, nicotine pack years, serum creatinine and AAA expansion rate were found to be much higher for male patients.. These findings may help to explain higher risks for AAA growth in males and the ruptures of smaller-sized AAAs in females.

Topics: Aged; Aged, 80 and over; Aorta, Abdominal; Aortic Aneurysm, Abdominal; Aortic Dissection; Aortic Rupture; Biomechanical Phenomena; Chi-Square Distribution; Collagen; Disease Progression; Elastic Modulus; Elastin; Female; Humans; Male; Middle Aged; Risk Factors; Sex Factors; Thrombosis; Time Factors; Vascular Stiffness

Acute aortic dissection is a life-threatening disease with a high rate of mortality. At the Institute of Legal Medicine of the Hanover Medical School, 30 cases with aortic dissections were found during autopsy and examined histologically between 2006 and 2009. The grade of medial alterations in the form of cystic medial necrosis, elastin fragmentation, fibrosis and medionecrosis were estimated semi-quantitatively. In order to assess the normal aging process, samples of the aortic wall of 25 decedents without dissecting aneurysms were analyzed histologically. This study demonstrates that there are partly quantitative differences, particularly with a statistically significant increase in cystic medial necrosis (p<0.001) and elastin fragmentation (p<0.001), between aortas from dissecting aneurysms and the normal aging aorta, which may help to identify genetically predisposed relatives of patients with a dissection of the aorta.

Topics: Adult; Aged; Aged, 80 and over; Aging; Aorta; Aortic Aneurysm; Aortic Dissection; Arteriosclerosis; Case-Control Studies; Elastin; Female; Fibrosis; Forensic Pathology; Humans; Male; Middle Aged; Necrosis; Tunica Media

Pathologic studies have demonstrated that aortic dissection is initiated by an intimal tear, followed by the rapid growth of an intramural hematoma that dissects the media and is characterized by elastin degradation. Genetic extracellular matrix abnormalities and proteinases may be the predisposing factors in aortic dissection, but little is known about the role of elastic fiber assembly. Fibulin-1 is an extracellular protein that is expressed in the vascular basement membrane. It regulates elastic fiber assembly and hence provides integrity in aortic structure. This study investigates the expression profiles of genes responsible for the elastolysis in the dissected human aorta, especially those coding fibulin-1, matrix metalloproteinase-9 (MMP-9), and elastin.. Intraoperative aortic samples were obtained from Chinese patients with Stanford Type A aortic dissection. Both the ascending dissected aortas (primary tear) and the adjacent intact aortas were collected for comparison. Control aortic tissues were obtained from healthy organ donors. The gene profile study was determined by the Affymetrix HG-U133A GeneChip (Affymetrix, Santa Clara, Calif) and analyzed by GeneSpring GX11.0 (Agilent Technologies Inc, Palo Alto, Calif). Only the genes displaying a net signal intensity two-fold higher than the mean background were used for analysis. To evaluate elastin expression, aortic sections were stained with Movat pentachrome stain. Fibulin-1, MMP-9, and elastin mRNA and protein expression were further confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunoblotting, respectively.. Eight male Chinese aortic dissection patients (mean age, 45.8 years) and eight gender- and age-matched organ donors were recruited for the study. On the Affymetrix platform, 2,250 of 22,283 genes (10.1%) were detectable. The dissected and adjacent macroscopically intact aorta displayed similar gene expression patterns. In contrast, 11.2% (252) of the detectable genes were differentially expressed in the dissected and control aortas. Of these, 102 genes were upregulated, and 150 genes were downregulated. Based on the gene ontology, genes that code for extracellular matrix protein components and regulating elastic fiber assembly, like fibulin-1 and elastin, were downregulated, while enzymes like MMP-9 and MMP-11 that degrade matrix proteins were upregulated in dissected aortas. RT-PCR and Western blot results further validated the results.. Our gender- and age-matched study demonstrated that the alternated genes in the elastin assembly of dissected aortas may predispose structural failure in the aorta leading to dissection. However, no significant gene alterations in the adjacent intact and dissected aortas of the same patient can be found. Therefore, the genetic changes found in the dissected aortas most likely developed before the dissection starts. The inhibition of the aberrant expression of the fibulin-1 gene and that of the related matrix proteinase may open a new avenue for preventing aortic dissection.

Topics: Adult; Aortic Aneurysm; Aortic Dissection; Blotting, Western; Calcium-Binding Proteins; Case-Control Studies; Elastin; Gene Expression Profiling; Humans; Male; Matrix Metalloproteinase 9; Middle Aged; Oligonucleotide Array Sequence Analysis; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Staining and Labeling

Should every patient with suspected aortic dissection undergo imaging? Of course. In a medical world with unlimited resources, that does not exist. A serum test for suspected aortic dissection would prove highly useful for low- and intermediate-risk populations and together with troponin and d-dimer may become part of a "Chest-Pain Panel" in the emergency department. Last decade has seen a myriad of serum markers being tested for this indication. It seems that quantitative d-dimer has an excellent negative predictive value for ruling out aortic dissection under appropriate context. Other blood tests focus on myosin heavy chain and metalloproteinase release for the aortic media during dissection. The future seems promising.

Topics: Algorithms; Aortic Diseases; Aortic Dissection; Biomarkers; C-Reactive Protein; Diagnosis, Differential; Elastin; Electrocardiography; Enzyme-Linked Immunosorbent Assay; Fatty Acid-Binding Proteins; Fibrin Fibrinogen Degradation Products; Humans; Metalloproteases; Myosin Heavy Chains; Sensitivity and Specificity

A chemical-induced, nonlethal, dissecting aortic aneurysm (DAA) is described following in utero exposure to semicarbazide, an inhibitor of the vascular enzyme semicarbazide sensitive amine oxidase (SSAO).. Sprague-Dawley rat dams were given semicarbazide (0.096-49.000 mg/kg/day) by IP injection on gestation days (GDs) 14-20, a period of rapid aortic development. Newborn rats (day 1) were killed and their thoracic organs were removed en bloc for near-serial cross sections and routine histopathology, Movat stain for elastin, and immunohistochemistry to differentiate cells involved in the evolution of the DAA. In subsequent experiments, pups from treated dams (0.096-6.125 mg/kg/day) were allowed to survive for 7 or 28 days.. DAA occurred in nearly 100% of the rats at all doses except the lowest tested (1.530, 0.096 mg/kg/day). Dissections frequently extended to the carotids and, less frequently, to the abdominal aorta. Remodeling of vascular lesions proceeded by organization of collections of blood in vascular media (the "false lumen"), proliferation of vascular smooth muscle cells, fibrosis, and formation of irregular frayed elastic lamellae in healed vascular media. Biochemical quantitation and Western blot analysis of main extracellular matrix proteins on GD 20 showed no overt difference in expression of collagen type I, fibrillin-1, or elastin.. This developmental model provides investigators an opportunity to explore the pathologic mechanisms of DAA and to examine the potential long-term effects of vascular remodeling of DAA.

Topics: Amine Oxidase (Copper-Containing); Analysis of Variance; Animals; Animals, Newborn; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Collagen; Dose-Response Relationship, Drug; Elastin; Female; Gestational Age; Immunohistochemistry; Injections, Intraperitoneal; Models, Biological; Pregnancy; Rats; Rats, Sprague-Dawley; Semicarbazides

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.

Topics: Aged; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Elastin; Extracellular Matrix Proteins; Female; Gene Expression; Humans; Male; Middle Aged; Recombinant Proteins; RNA, Messenger

This report describes 2 cases of spontaneous aortic dissecting hematoma in young Border Collie and Border Collie crossbred dogs. Histology was performed in one of the cases involving an unusual splitting of the elastin present within the wall of the aorta, consistent with elastin dysplasia as described in Marfan syndrome in humans. The first case involved a young purebred Border Collie that died suddenly and the second case involved a Border Collie crossbred dog that died after a 1-month history of seizures. Gross lesions included pericardial tamponade with dissection of the ascending aorta in the former case and thoracic cavity hemorrhage, mediastinal hematoma, and aortic dissection in the latter. Histologic lesions in the case of the Border Collie crossbred dog included a dissecting hematoma of the ascending aorta with elastin dysplasia and right axillary arterial intimal proliferation.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm; Aortic Dissection; Aortic Rupture; Dog Diseases; Dogs; Elastin; Fatal Outcome; Hematoma; Male; Seizures

We aimed to establish an enzyme-linked immunosorbent assay (ELISA) for measuring soluble elastin fragments (sELAF) in serum and to reveal its usefulness in diagnosing acute aortic dissection.. Acute aortic dissection is a life-threatening disease of the aorta. However, the diagnosis is still frequently missed, especially at onset. The establishment and clinical availability of simplified laboratory test(s) to help diagnose and screen acute aortic dissection patients is therefore urgently needed.. An ELISA to measure sELAF in serum was developed using the newly created double monoclonal antibodies which recognize the different epitopes of human aortic elastin. Twenty-five acute aortic dissection patients, 50 patients with acute myocardial infarction, and 474 healthy individuals were enrolled in the study. The sELAF levels from healthy subjects gradually increased with aging. When the cutoff point for positivity was set at the mean + 3SD above the mean of those in healthy subjects at each age, 16 acute aortic dissection patients (64.0%) were found to be positive, while only one acute myocardial infarction patient was positive (2.0%). Acute aortic dissection patients with either an open or a partially open pseudolumen were found to be 88.9% positive for sELAF, while those with its early closure was 0% positive. The difference in the sELAF levels between acute aortic dissection patients with and without a thrombotic closure of false lumen was significant (60.3 +/- 15.6 vs 135.4 +/- 53.2 ng/ml, p < 0.005).. The sELAF level in serum may be a useful marker for helping both diagnose and screen acute aortic dissection, while also helping distinguish acute aortic dissection from acute myocardial infarction.

Topics: Acute Disease; Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Aortic Aneurysm; Aortic Dissection; Biomarkers; Elastin; Enzyme-Linked Immunosorbent Assay; Humans; Middle Aged; Solubility

Topics: Acute Disease; Aortic Aneurysm; Aortic Dissection; Aortography; Biomarkers; Echocardiography, Transesophageal; Elastin; Humans; Magnetic Resonance Imaging; Sensitivity and Specificity; Tomography, X-Ray Computed

An in vitro model was used to determine the influence of tear depth on the propagation pressure of aortic dissections. Saline was injected into the media of segments of 20 porcine thoracic aortas to create blebs. A circumferential slit was made on the intimal side of each bleb, connecting the true lumen to the false lumen. Each aorta was then pressurized under no-flow conditions until propagation in either the anterograde or retrograde direction occurred. Histological sections of each principal propagating edge were used to determine depth of tear, measured as the ratio of elastin layers in the intimal flap to the elastin layers in the intact wall. Propagation occurred for tear depths ranging from 0.44 to 0.89, with dissections closest to the adventitia (with tear depths near 1) requiring the lowest pressures. Propagation pressure (P) depends on the number of elastin layers (L) in the outer wall of a dissection, P = 0.44 L + 25(kPa), r2 = 0.465, p = 0.003 and also on tear depth (d): P = -58 d + 81(kPa), r2 = 0.547, p < 0.001. Various in vivo factors are discussed which may affect these experimentally determined relationships.

Topics: Algorithms; Aneurysm, Ruptured; Animals; Aortic Aneurysm, Thoracic; Aortic Dissection; Blood Pressure; Elastic Tissue; Elastin; Models, Cardiovascular; Pressure; Stress, Mechanical; Swine; Tunica Intima

Topics: Aged; Aortic Dissection; Elastin; Facial Neoplasms; Fatal Outcome; Female; Hemangioma, Cavernous; Histocytochemistry; Humans; Pulmonary Artery

Although directional atherectomy (DA) reduces the plaque burden, successful revascularization is not associated with a reduced restenosis rate when compared with percutaneous transluminal coronary angioplasty (PTCA). The purpose of this study was to compare and contrast the vascular response to DA-induced and PTCA-induced injury. Six to 8 weeks after induction of atherosclerosis, PTCA (n = 34) was performed in one iliac artery and DA in the other (n = 30). Arteries were obtained at 6 time points: 1, 3, 5, 7, 14, and 28 days. Eleven arteries that did not undergo an intervention acted as controls. Radiograms obtained before and after intervention and at euthanization were compared. Morphometric, histologic, and immunohistochemical analyses were performed. Both PTCA and DA resulted in an immediate increase in luminal diameter that subsequently decreased over the ensuing month. PTCA caused deep dissection (7 of 8 arteries), often extending to the adventitia, whereas stand alone DA resulted in deep cleft formation (4 of 5). Of the 30 arteries that underwent DA, 4 exhibited an increase in luminal diameter in the absence of tissue retrieval. Thrombus was observed in both the dissection planes and the clefts within the first 7 days, and cellular ingrowth was appreciated at 5 to 7 days. By 7 days the artery was repaired, and the histologic appearance of the arteries that had undergone PTCA could not be differentiated from the arteries that had undergone DA. Increased intimal and medial collagen and elastin was noted at 14 and 28 days. An increase in the area bordered by the external elastic lamina was observed in both groups. Although successful DA results in tissue removal and the production of a deep tissue cleft and PTCA causes a dissection, both produce a condition in which the arterial injury exposes the arterial media to blood, causing thrombus formation and inflammation with subsequent cellular accumulation into the thrombotic framework.

Topics: Angioplasty, Balloon; Angioplasty, Balloon, Coronary; Animals; Aortic Dissection; Arteriosclerosis; Arteritis; Atherectomy; Atherectomy, Coronary; Collagen; Elastic Tissue; Elastin; Iliac Aneurysm; Iliac Artery; Immunohistochemistry; Rabbits; Radiography; Recurrence; Thrombosis; Tunica Intima; Tunica Media; Wound Healing

Aneurysmal dilation of the aorta with subsequent rupture or dissection occurs frequently in patients with Marfan syndrome and is the primary cause of morbidity. These complications are related to the altered composition and disorganized structure of the aortic media. Our goal was to use high-frequency ultrasonic tissue characterization to identify these structural changes in abnormal aorta from patients with Marfan syndrome. We measured integrated backscatter and anisotropy of backscatter of ultrasound from specimens of aorta from patients with Marfan syndrome undergoing aortic root replacement and compared these values with those from aortic specimens of patients without clinical aortic pathology.. Aortic tissue was obtained at the time of surgery from 11 patients with Marfan syndrome undergoing repair of an aortic aneurysm or dissection. Normal tissue was obtained at the time of autopsy from 8 patients without evidence of aortic disease. Acoustic microscopy at 50 MHz was performed to measure integrated backscatter from each specimen. The magnitude of ultrasonic anisotropy of backscatter for each tissue type was determined as an index of the three-dimensional (3D) organization of the vessel matrix. The collagen content of each specimen was determined with a hydroxyproline assay. Marfan aortas exhibited less backscatter than did normal aortas (-40.9 +/- 2.9 versus -32.6 +/- 2.2 dB for patients with Marfan syndrome and healthy subjects, respectively, P < .0001). No significant difference in collagen concentrations was observed between normal and Marfan aorta (262.7 +/- 52.7 versus 282.4 +/- 41.8 mg/g tissue for normal and Marfan aortas, respectively, P = .42), despite the large difference in backscatter. Histological analysis revealed striking differences in both the amount and organization of the elastin in the aortic aneurysm segments from patients with Marfan syndrome compared with normal aorta. Normal aorta was characterized by well-formed elastin fibers arranged in a lamellar pattern. The media from aneurysms in Marfan aorta exhibited a profound decrease in elastin content that was associated with loss of the highly aligned and ordered lamellar arrangement. The directional dependence of scattering, or ultrasonic anisotropy, also differed dramatically between the two tissue types. Backscatter from normal aorta decreased substantially when the media was insonified parallel compared with perpendicular to the principal axis of the elastin fibers. Marfan aorta exhibited a much smaller directional dependence of scattering. Normal aortas manifested a 14-fold greater ultrasonic anisotropy than did Marfan aortas (24.1 +/- 3.7 versus 12.4 +/- 3.3 dB for normal and Marfan aortas, P < .0001), which is indicative of the profound extent of matrix disorganization in Marfan syndrome.. These data show that high-frequency ultrasonic tissue characterization sensitively detects changes in vessel wall composition and organization that occur in the aorta of patients with Marfan syndrome. Aortic segments from these patients manifested a significant decrease in integrated backscatter compared with normal aorta (approximately 8 dB, or greater than a 6-fold decrease in scattering). A 15-fold reduction in the ultrasonic anisotropy of Marfan tissue was observed, which suggests a marked disorganization of the 3D architecture of these aortas. These data support the hypothesis that high-frequency ultrasonic tissue characterization may be useful for identifying abnormalities of vessel wall composition, architecture, and material properties.

Topics: Adult; Anisotropy; Aorta; Aortic Aneurysm; Aortic Dissection; Collagen; Elastin; Female; Humans; Male; Marfan Syndrome; Tunica Media; Ultrasonography

Topics: Aorta; Aortic Aneurysm; Aortic Dissection; Collagen; Elastin; Extracellular Matrix Proteins; Fibrillins; Humans; Marfan Syndrome; Microfilament Proteins; Ultrasonography

An antibody to elastin-derived chemotactic peptide Val-Gly-Val-Ala-Pro-Gly was used to study human artery samples from 18 patients with various vascular lesions, such as aneurysms or occlusive arteriopathy. The antibody recognised epitopes in two artery specimens, one occlusive arteriopathy and one aneurysm, and both specimens were also characterised by a segmental destruction of media. The positive staining for the peptide was located in the elastic membranes and endothelial cells that were also stained with antibodies to IgG. This study suggests that elastin-derived chemotactic peptides may have a role in vascular lesions characterised by a destruction of media and a formation of aneurysm. Since elastin-derived chemotactic peptides are more chemotactic to monocytes than to neutrophils, it is possible that mononuclear phagocytes are involved in the segmental destruction of elastin.

Topics: Adult; Aged; Aortic Aneurysm, Abdominal; Aortic Dissection; Arterial Occlusive Diseases; Arteries; Arteriosclerosis; Arteritis; Chemotactic Factors; Elastic Tissue; Elastin; Endothelium, Vascular; Female; Humans; Immunoenzyme Techniques; Male; Middle Aged; Peptides; Tunica Media; Vascular Diseases

Topics: Adrenergic beta-Antagonists; Aortic Aneurysm; Aortic Dissection; Aortic Valve Insufficiency; Elastin; Fibrillins; Genetic Counseling; Humans; Marfan Syndrome; Microfilament Proteins; Mitral Valve Insufficiency; Myofibrils; Patient Care Team; Phenotype

The aim was to investigate whether changes in elastin distribution in the thoracic aorta are associated with occurrence of dissecting aneurysms.. Ten thoracic aortas were obtained at necropsy from dissections (mean patient age 74.3 years, SD 7.3) and from 10 age matched controls (mean age 73.1 years, SD 6.9). Full wall thickness samples (1 cm diameter) were taken at 12 sites between heart and diaphragm from aortas of dissections and controls. Elastin content (total elastin per sample), concentration (mg.mg-1 tissue dry weight), degree of cross linking, and amino acid composition were determined.. Comparison of areas of dissected aortas involved in dissection with corresponding areas of controls showed significant increases in content of elastin (p < 0.05), content and concentration of proteins other than elastin and collagen (p < 0.01), and a decrease in elastin concentration (p < 0.01). Comparison of areas remote from dissection with corresponding areas in controls showed no significant differences except for decreased elastin concentration (p < 0.05). There were no differences in elastin cross linking. Elastin from dissected aortas had a higher content of aspartate, threonine, serine, glutamate, and lysine and a lower content of glycine, alanine, and valine than elastin from controls (p < 0.05).. Biochemical changes in dissections are localised to the dissected area, with increased deposition of elastin, collagen, and other proteins. The altered matrix composition is likely to change the mechanical properties, possibly increasing the tendency to rupture.

Topics: Aged; Aged, 80 and over; Amino Acids; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Dissection; Collagen; Elastin; Female; Humans; Male; Middle Aged

Weanling Sprague-Dawley rats received beta-aminopropionitrile (BAPN) and/or hypertensive treatment, namely, heminephrectomy and administration of deoxycorticosterone acetate-NaCl. The BAPN-treated rats (lathyritic rats) died of dissecting aneurysm, and the victims with hypertensive treatment was greater in number and died earlier than those without the treatment, indicating that the rise of blood pressure promoted the onset of dissecting aneurysm. The elastic architecture of the ascending aortic media was examined not only by transmission electron microscopy with tannic acid stain and/or toluidine blue O stain, but also by scanning electron microscopy after hot formic acid treatment, and the area of interlaminar elastic fibers were morphometrically analyzed by a point counting method using transmission electron microscopic photographs. In the lathyritic rats, interlaminar elastic fibers showed a significant reduction compared with the control rats, and elastic fibers tended to become round-shaped and were frequently spotted with glycosaminoglycan, which suggest a disturbance of elastogenesis. On the other hand, elastic laminae were not disrupted and smooth muscle cells were well preserved. These results suggest that the alteration of the elastic architecture causes an unstable connection between each elastic lamina, and is related to the initiation and the progression of dissecting aneurysm.

Topics: Aminopropionitrile; Animals; Aorta; Aortic Aneurysm; Aortic Dissection; Blood Pressure; Body Weight; Elastic Tissue; Elastin; Glycosaminoglycans; Hypertension; Lathyrism; Male; Rats; Rats, Inbred Strains

Elastin of the ascending aortic media of 10 cases with type A dissecting aneurysm, 14 hypertensive cases, and 30 control cases were prepared by the treatment of aortas with hot formic acid, and three-dimensional architecture was observed by scanning electron microscopy. In the control cases, elastin showed framework-like continuous structure consisting of elastic laminae, and interlaminar fibers that interconnected the laminae. In 6 of 10 cases of dissecting aneurysm, the interlaminar fibers were apparently irregular in arrangement and shape, and decreased in number, especially in the outer media. This architectural alteration resulted in a rarefaction of interconnection between the elastic laminae in the media, and possibly resulted in the local weakness against the dissecting force of the laminae. This medial weakness may be related to the mechanism of initiation and progression of dissecting aneurysm. The cystic medial necrosis (CMN) was found in 3 cases, but only 1 of them was accompanied by a mild decrease of the interlaminar fibers in the area outside of CMN, suggesting that the initiation of CMN did not directly relate to the decrease of the interlaminar fibers. The aortic media of hypertensives generally showed an increase of interlaminar fibers, but their focal decrease was encountered in the outer media of 3 cases. These findings suggest that the decrease of the interlaminar fibers of medial elastin seen in dissecting aneurysms were related to hypertension.

Topics: Adult; Aged; Aged, 80 and over; Aorta; Aortic Aneurysm; Aortic Dissection; Elastin; Female; Humans; Hypertension; Male; Marfan Syndrome; Microscopy, Electron, Scanning; Middle Aged

We studied the histologic and histometric features of the aortic media in cases of dissecting aneurysm in order to clarify the pathologic background of this condition. The results were then compared with cases of true aneurysm and control specimens of "normal" aging aorta. Most cases of dissecting aneurysm and true aneurysm, as well as a number of control specimens, showed severe cystic medial necrosis, and therefore this feature does not appear to be specific to dissecting aneurysm. Fibrosis was noted in the process of repair of medionecrosis in dissecting aneurysm, true aneurysm, and controls. The main pathologic features of the aortic media in dissecting aneurysm included a higher grade of elastin fragmentation (offensive factor) and less fibrosis (defensive factor). Our findings indicate that the pathologic balance between these offensive and defensive factors is an important consideration when evaluating the pathogenesis of dissecting aneurysm.

Topics: Aged; Aging; Aortic Aneurysm; Aortic Dissection; Elastin; Female; Fibrosis; Humans; Male; Necrosis; Reference Values; Retrospective Studies

An intrinsic defect in the aortic media in six patients with Marfan's syndrome, who died of cardiovascular complications of the disease at an average age of 32 years, has been delineated by correlated morphologic, biochemical, and mechanical studies. The findings in the Marfan aortas have been compared with those in age- and sex-matched controls, who died of unrelated diseases without significant aortic lesions, and in three patients with dissecting aneurysms of non-Marfan origin. The results showed that there was a significant reduction in the tensile strength of the aorta in Marfan's syndrome. This finding was correlated by scanning electron microscopy with structural alterations of the medial elastic fibers, including enlarged interlaminar spaces and loss of interlaminar elastic fibrils. No structural alterations were identified in collagen fibers. Biochemical analyses of the aortic media revealed a substantial reduction in aortic elastin content. Furthermore, the desmosine content of the isolated elastin was reduced by approximately 50%. No changes were detected in the composition or solubility of the medial collagen. In contrast to Marfan aortas, the elastin and collagen contents of the dissecting aneurysms of non-Marfan origin were similar to those of the controls. These findings suggest that the vascular complications in Marfan's syndrome may be based on a genetic abnormality affecting elastin fibrillogenesis.

Topics: Adult; Aorta; Aortic Aneurysm; Aortic Dissection; Collagen; Elastin; Glycosaminoglycans; Humans; Hydroxyproline; Marfan Syndrome; Microscopy, Electron, Scanning; Tensile Strength

Insoluble elastins were isolated from control and aneurytic aortas by a sequential extraction procedure involving the use of purified collagenase. Marked differences in amino acid analyses and susceptibilities to pancreatic elastase were observed between normal and pathological samples. The incorporation of either 14C-lysine or 14C-glucosamine into proteins of the vessel wall was also studied. In addition, high amounts of elastase-type activity was extractable from pathological aorta specimens which may contribute significantly to the loss of elastic tissue evidenced by ultra-structural studies and confirmed by the biochemical technics. We propose therefore that increased elastase-type protease activity in these pathological aortas does significantly contribute to the weakening of the aortic wall and also may well be the main cause of the rupture of aneurysms observed occasionally.

Topics: Adult; Aged; Aorta; Aortic Aneurysm; Aortic Dissection; Elastic Tissue; Elastin; Female; Humans; Hydrolysis; Male; Marfan Syndrome; Middle Aged; Muscle, Smooth, Vascular; Organ Culture Techniques; Pancreatic Elastase