elastin and Aortic-Aneurysm--Thoracic

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

Acute aortic dissection of the thoracic aorta represents a medical emergency that, despite its rare occurrence, is characterized by severe morbidity and mortality. Prompt diagnosis is the key to a desired outcome. According to current clinical data, diagnosis is mostly based on a high index of suspicion and diagnostic imaging and less on clinical manifestations. On the other hand, a biochemical approach to the entity is still falling short in terms of diagnostic practice, although optimistic efforts are being made towards the development of such methods. Myocin heavy-chain concentrations, D-dimer levels, and soluble elastin fragment measurement are some of the new promising tools emerging in the battle of acute diagnosis. Despite their potentials, all three still need to be reevaluated. More prospective clinical trials should be performed so as to improve and ensure a biochemical diagnostic method for acute aortic dissection of high sensitivity and specificity and thus of great clinical value. Search of the Literature: Two reviewers performed a literature search, identified the relevant studies to be included in this review, and extracted the data. Relevant studies for inclusion in this review were identified through PubMed as well as from references of the initially found articles. The search terms used were "myocin-heavy chains", "D-dimers", "soluble elastin fragments", "biochemical diagnosis", "aortic dissection", "sensitivity", "specificity", and "performance characteristics".

Topics: Acute Disease; Aorta; Aortic Aneurysm, Thoracic; Elastin; Fibrin Fibrinogen Degradation Products; Humans; Myosin Heavy Chains; Sensitivity and Specificity; Treatment Outcome

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

Fiber structures and pathological features, e.g., inflammation and glycosaminoglycan (GAG) deposition, are the primary determinants of aortic mechanical properties which are associated with the development of an aneurysm. This study is designed to quantify the association of tissue ultimate strength and extensibility with the structural percentage of different components, in particular, GAG, and local fiber orientation. Thoracic aortic aneurysm (TAA) tissues from eight patients were collected. Ninety-six tissue strips of thickened intima, media, and adventitia were prepared for uni-extension tests and histopathological examination. Area ratios of collagen, elastin, macrophage and GAG, and collagen fiber dispersion were quantified. Collagen, elastin, and GAG were layer-dependent and the inflammatory burden in all layers was low. The local GAG ratio was negatively associated with the collagen ratio (r2 = 0.173, p < 0.05), but positively with elastin (r2 = 0.037, p < 0.05). Higher GAG deposition resulted in larger local collagen fiber dispersion in the media and adventitia, but not in the intima. The ultimate stretch in both axial and circumferential directions was exclusively associated with elastin ratio (axial: r2 = 0.186, p = 0.04; circumferential: r2 = 0.175, p = 0.04). Multivariate analysis showed that collagen and GAG contents were both associated with ultimate strength in the circumferential direction, but not with the axial direction (collagen: slope = 27.3, GAG: slope = -18.4, r2 = 0.438, p = 0.002). GAG may play important roles in TAA material strength. Their deposition was found to be associated positively with the local collagen fiber dispersion and negatively with ultimate strength in the circumferential direction.

Topics: Aortic Aneurysm, Thoracic; Biomechanical Phenomena; Collagen; Elastin; Glycosaminoglycans; Humans; Macrophages

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

This study aims to identify the clinical utility of targeted-genetic sequencing in a cohort of patients with TAA and establish a new method for regional histological characterisation of TAA disease.. Fifty-four patients undergoing surgery for proximal TAA were recruited.. connective tissue disease, bicuspid aortic valves, redo surgery. All patients underwent next generation sequencing (NGS) using a custom gene panel containing 63 genes previously associated with TAA on Illumina MiSeqor NextSeq550 platforms. Explanted TAA tissue was obtained en-bloc from 34/54 patients, and complete circumferential strips of TAA tissue processed into whole slides which were subsequently digitalised. Computational pathology methods were employed to quantify elastin, cellularity and collagen in six equally divided regions across the whole aneurysm circumference.. Of 54 patients, clearly pathogenic or potentially pathogenic variants were found in 7.4%: namely LOX, PRKG1, TGFBR1 and SMAD3 genes. 55% had at least one variant of unknown significance (VUS) and seven of the VUSs were in genes with a strong disease association (category A) genes, whilst 15 were from moderate risk (category B) genes. Elastin and collagen abundance displayed high regional variation throughout the aneurysm circumference. In patients with <60% total elastin, the loss of elastin was more significant on the outer curve (38.0% vs 47.4%, p = 0.0094). The presence of VUS, higher pulse wave velocity and advancing age were predictors of elastin loss (regression analysis: p < 0.05).. These findings demonstrate the heterogeneity of TAA disease microstructure and the potential link between histological appearance and clinical factors, including genetic variation.

Topics: Aortic Aneurysm, Thoracic; Bicuspid Aortic Valve Disease; Collagen; Elastin; Humans; Pulse Wave Analysis

Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene. It is associated with formation of thoracic aortic aneurysms that can potentially be a life-threatening condition due to aortic rupture or dissection. Excessive non-canonical transforming growth factor beta signalling, mediated by activation of extracellular signal-regulated kinases 1/2 (ERK1/2), as well as inducible nitric oxide synthase (NOS2)-dependent nitric oxide production, have been identified to drive aortic pathology in MFS through induction of elastin fragmentation and smooth muscle cell apoptosis. Despite promising results in animal studies, specific pharmacological interventions approved for clinical use in patients with MFS-related aortic disease are rare. Nitro-oleic acid (NO2-OA) is an endogenously generated signalling modulator, which is available as an oral compound and has been shown to inhibit ERK1/2 activation and NOS2 expression in different disease models, thereby exerting promising therapeutic effects. In this study, we investigated whether NO2-OA decreases aortic dilation in MFS.. Eight-week-old MFS (Fbn1C1041G/+) mice were treated with NO2-OA or vehicle for 4 weeks via subcutaneously implanted osmotic minipumps. Echocardiography indicated progressive ascending aortic dilation and wall stiffening in MFS mice, which was significantly attenuated by NO2-OA treatment. This protective effect was mediated by inhibition of aortic ERK1/2, Smad2 as well as nuclear factor kappa B overactivation and consequent attenuation of elastin fragmentation by matrix metalloproteinase 2, apoptosis, and collagen deposition. Critically, the therapeutic efficacy of NO2-OA in MFS was further emphasized by demonstrating its capability to reduce lethal aortic complications in Fbn1C1041G/+ mice challenged with Angiotensin II.. NO2-OA distinctly attenuates progression of aortic dilation in MFS via modulation of well-established disease-mediating pathways, thereby meriting further investigation into its application as a therapeutic agent for the treatment of this condition.

Topics: Animals; Aortic Aneurysm; Aortic Aneurysm, Thoracic; Aortic Diseases; Disease Models, Animal; Elastin; Fibrillin-1; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Nitro Compounds; Oleic Acids

Although aortic root and ascending aortic aneurysms are treated the same, they differ in embryological development and pathological processes. This study examines the microscopic structural differences between aortic root and ascending aortic aneurysms, correlating these features to the macroscopic pathophysiological processes.. We obtained surgical samples from ascending aortic aneurysms (n = 11), aortic root aneurysms (n = 3), and non-aneurysmal patients (n = 7), Aortic collagen and elastin content were examined via histological analysis, and immunohistochemistry techniques used to determine collagen I, III, and IV subtypes. Analysis was via observational features, and colour deconvolution quantification techniques.. Elastin fiber disruption and fragmentation was the most extensive in the proximal aneurysmal regions. Medial fibrosis and collagen density increased in proximal aneurysmal regions and aortic root aneurysms (p < 0.005). Collagen I was seen in highest quantity in aortic root aneurysms. Collagen I content was greatest in the sinus tissue regions compared to the valvular and ostial regions (p < 0.005) Collagen III and IV quantification did not vary greatly. The most susceptible regions to ultrastructural changes in disease are the proximal ascending aorta and aortic root.. The aortic root differs histologically from the ascending aorta confirming its unique composition in aneurysm pathology. These findings should prompt further evaluation on the influence of this altered structure on function which could potentially guide clinical management.

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

Thoracic aortic aneurysm (TAA) is a serious disease usually happening in elder people and with high death rate. Accumulating studies have reported that long non-coding RNAs (lncRNAs) are implicated in the progression of various human diseases, including TAA.. In our study, we intended to explore the function of elastin (Eln) and its upstream mechanism in TAA.. RT-qPCR determined gene expressions and western blot tested changes in protein levels. Ang Ⅱ treatment was implemented to induce cell apoptosis. Flow cytometry analysis, TUNEL assay and JC-1 assay were exploited to measure cell apoptosis. Meanwhile, mechanistic assays such as RIP, RNA pull down and luciferase reporter assays were employed to identify the interplay between RNAs.. Eln inhibition was identified to protect rat arterial smooth muscle cells from apoptosis. Also, miR-29b-3p was identified to bind to Eln, and X inactive specific transcript (Xist) could boost Eln expression through absorbing miR-29b-3p. Meanwhile, Eln overexpression counteracted the suppression of silenced Xist on the apoptosis of rat arterial smooth muscle cells. More importantly, such ceRNA network was proved to aggravate the apoptosis of human aortic smooth muscle cells.. LncRNA Xist contributes to arterial smooth muscle cell apoptosis through miR-29b-3p/Eln pathway, providing new potential roads for treating TAA.

Topics: Angiotensin II; Animals; Aortic Aneurysm, Thoracic; Apoptosis; Apoptosis Regulatory Proteins; Caspase 3; Cell Line; Elastin; Humans; Mice; MicroRNAs; Muscle, Smooth, Vascular; Rats; RNA, Long Noncoding; Signal Transduction

Topics: Actins; Angiography; Animals; Aortic Aneurysm, Thoracic; Elastin; Hydrogels; Magnetic Resonance Imaging; Mesenchymal Stem Cell Transplantation; Organ Sparing Treatments; Stents; Swine; Vascular Patency

Medial degeneration is a common histopathological finding in aortopathy and is considered a mechanism for dilatation. We investigated if medial degeneration is specific for sporadic thoracic aortic aneurysms versus nondilated aortas. Specimens were graded by pathologists, blinded to the clinical diagnosis, according to consensus histopathological criteria. The extent of medial degeneration by qualitative (semi-quantitative) assessment was not specific for aneurysmal compared to nondilated aortas. In contrast, blinded quantitative assessment of elastin amount and medial cell number distinguished aortic aneurysms and referent specimens, albeit with marked overlap in results. Specifically, the medial fraction of elastin decreased from dilution rather than loss of protein as cross-sectional amount was maintained while the cross-sectional number, though not density, of smooth muscle cells increased in proportion to expansion of the media. Furthermore, elastic lamellae did not thin and interlamellar distance did not diminish as expected for lumen dilatation, implying a net gain of lamellar elastin and intralamellar cells or extracellular matrix during aneurysmal wall remodeling. These findings support the concepts that: (1) medial degeneration need not induce aortic aneurysms, (2) adaptive responses to altered mechanical stresses increase medial tissue, and (3) greater turnover, not loss, of mural cells and extracellular matrix associates with aortic dilatation.

Topics: Adaptation, Physiological; Adult; Aged; Aorta; Aortic Aneurysm, Thoracic; Bicuspid Aortic Valve Disease; Cell Count; Comorbidity; Elastin; Extracellular Matrix; Female; Humans; Male; Middle Aged; Myocytes, Smooth Muscle; Single-Blind Method; Staining and Labeling; Tunica Media; Vascular Remodeling

To explore the micromechanical, biochemical, and microstructural differences between bicuspid aortic valve aneurysm (BAV-A) and tricuspid aortic valve idiopathic degenerative aneurysm (DA), compared with normal aorta.. Aortic tissue was obtained from patients undergoing aneurysmal repair surgery (BAV-A; n = 15 and DA; n = 15). Control tissue was obtained from aortic punch biopsies during coronary artery bypass graft surgery (n = 9). Nanoindentation was used to determine the elastic modulus on the medial layer. Glycosaminoglycan, collagen, and elastin levels were measured using biochemical assays. Verhoeff Van Gieson-stained cross-sections were imaged for elastin microstructural quantification.. The elastic modulus was more than 20% greater for BAV-A relative to control and DA (signifying a loss of compliance). No significance difference between control and DA were observed. Collagen levels for BAV-A (36.9 ± 7.4 μg/mg) and DA (49.9 ± 10.9 μg/mg) were greater compared with the control (30.2 ± 13.1 μg/mg). Glycosaminoglycan and elastin levels were not significant between the groups. Elastin segments were uniform throughout the control. Aneurysmal tissues had less elastin segments close to the intima and adventitia layers. Both BAV-A and DA had elastin segments compacted in the media; however, elastin segments were highly fragmented in DA.. BAV-A has a greater loss of aortic wall compliance relative to DA and the control. Although elastin levels were equal for all groups, spatial distribution of elastin provided a unique profile of matrix degradation for BAV-A. Elastin compaction within the media of BAV-A may have resulted from the altered hemodynamic pressure against the wall, which could explain for the stiffness of the tissue.

Topics: Aged; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Bicuspid Aortic Valve Disease; Biopsy; Collagen; Disease Progression; Echocardiography; Elastin; Female; Glycosaminoglycans; Humans; Male; Middle Aged

SMAD3 pathogenic variants are associated with the development of thoracic aortic aneurysms. We sought to determine the role of SMAD3 in lineage-specific vascular smooth muscle cells (VSMCs) differentiation and function. Approach and Results:. SMAD3-dependent TGF-β signaling was essential for the differentiation of cardiovascular progenitor cell-VSMCs but not for the differentiation of neural crest stem cell-VSMCs. The lineage-specific TGF-β responses in human VSMCs may potentially contribute to the development of aortic root aneurysms in patients with

Topics: Aortic Aneurysm, Thoracic; Cell Differentiation; Cell Lineage; Cells, Cultured; Elastin; Extracellular Matrix; Frameshift Mutation; Gene Expression Regulation; Humans; Induced Pluripotent Stem Cells; MicroRNAs; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phosphorylation; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Vascular Remodeling; Vasoconstriction

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

In its permanent quest of mechanobiological homeostasis, our vasculature significantly adapts across multiple length and timescales in various physiological and pathological conditions. Computational modeling of vascular growth and remodeling (G&R) has significantly improved our insights into the mechanobiological processes of diseases such as hypertension or aneurysms. However, patient-specific computational modeling of ascending thoracic aortic aneurysm (ATAA) evolution, based on finite element models (FEM), remains a challenging scientific problem with rare contributions, despite the major significance of this topic of research. Challenges are related to complex boundary conditions and geometries combined with layer-specific G&R responses. To address these challenges, in the current paper, we employed the constrained mixture model (CMM) to model the arterial wall as a mixture of different constituents such as elastin, collagen fiber families and smooth muscle cells. Implemented in Abaqus as a UMAT, this first patient-specific CMM-based FEM of G&R in human ATAA was first validated for canonical problems such as single-layer thick-wall cylindrical and bilayer thick-wall toric arterial geometries. Then it was used to predict ATAA evolution for a patient-specific aortic geometry, showing that the typical shape of an ATAA can be simply produced by elastin proteolysis localized in regions of deranged hemodymanics. The results indicate a transfer of stress to the adventitia by elastin loss and continuous adaptation of the stress distribution due to change in ATAA shape. Moreover, stress redistribution leads to collagen deposition where the maximum elastin mass is lost, which in turn leads to stiffening of the arterial wall. As future work, the predictions of this G&R framework will be validated on datasets of patient-specific ATAA geometries followed up over a significant number of years.

Topics: Aorta, Thoracic; Aortic Aneurysm, Thoracic; Biomechanical Phenomena; Collagen; Elastin; Finite Element Analysis; Humans; Models, Cardiovascular; Stress, Mechanical

Topics: Aged; Antigens, Surface; Aorta; Aortic Aneurysm, Thoracic; Biomarkers; Biomechanical Phenomena; Cohort Studies; Collagen; Elastin; Female; Gene Expression; Glycosaminoglycans; Humans; Male; Matrix Metalloproteinase 2; Middle Aged; Milk Proteins; Mitral Valve; Phenotype; Shear Strength; Tricuspid Valve

Ascending aorta aneurysms (AsAA) are associated with a degeneration of the aortic wall tissue, which leads to changes in tissue mechanical properties. Risk factors for the development of the AsAA disease are recognized in patient age and gender, valve type, hypertension, diabetes mellitus, smoking history, and a prior diagnosis of Marfan syndrome. The present study aims to assess how such clinico-pathological factors can affect the mechanical properties of human dilated ascending aorta. Specimens of AsAA are excised from 68 patients who underwent elective AsAA surgical repair and stretched until rupture during the execution of uniaxial tensile tests. Experimental stress-stretch curves are used to determine tissue mechanical properties (stress and stretch at failure point and at transition point, low and high elastic modulus). Data are divided into groups according to region (anterior vs posterior), direction (circumferential vs longitudinal), and then according to age (young vs old), gender (male vs female), valve type (tricuspid aortic valve, TAV, vs bicuspid aortic valve, BAV), and presence of hypertension, diabetes mellitus, and/or Marfan syndrome (yes/no). Moreover, data are grouped according to the critical value of body mass index (BMI), maximum AsAA diameter, and aortic stiffness index (ASI), respectively. Finally, a non-parametric statistical analysis is performed to find possible significant differences and correlations between mechanical properties and clinico-pathological data. Our results confirm the anisotropy and heterogeneity of the AsAA tissue and highlight that ageing and hypertension make the AsAA tissue weaker and less extensible, whereas the valve type affects the tissue strength with higher values in BAV than in TAV patients. No effects of gender, critical BMI, critical maximum AsAA diameter, critical ASI, smoking status, and presence of diabetes mellitus, and Marfan syndrome are evidenced.

Topics: Aged; Anisotropy; Aorta; Aortic Aneurysm, Thoracic; Aortic Valve; Bicuspid Aortic Valve Disease; Biomechanical Phenomena; Body Mass Index; Body Weight; Collagen; Diabetes Mellitus; Elastin; Female; Heart Valve Diseases; Humans; Hypertension; Male; Marfan Syndrome; Middle Aged; Models, Statistical; Risk Factors; Stress, Mechanical; Tensile Strength; Vascular Stiffness

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

Abnormal mechanosensing of smooth muscle cells (SMCs) resulting from the defective elastin-contractile units has been suggested to drive the formation of thoracic aortic aneurysms; however, the precise molecular mechanism has not been elucidated.. The aim of this study was to identify the crucial mediator(s) involved in abnormal mechanosensing and propagation of biochemical signals during the aneurysm formation and to establish a basis for a novel therapeutic strategy.. We used a mouse model of postnatal ascending aortic aneurysms ( Fbln4. Thbs1 is a critical component of mechanotransduction, as well as a modulator of elastic fiber organization. Maladaptive upregulation of Thbs1 results in disruption of elastin-contractile units and dysregulation of actin cytoskeletal remodeling, contributing to the development of ascending aortic aneurysms in vivo. Thbs1 may serve as a potential therapeutic target for treating thoracic aortic aneurysms.

Topics: Actin Cytoskeleton; Aged; Aged, 80 and over; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Cells, Cultured; Cofilin 2; Dilatation, Pathologic; Disease Models, Animal; Early Growth Response Protein 1; Elastic Tissue; Elastin; Extracellular Matrix Proteins; Female; Humans; Male; Mechanotransduction, Cellular; Mice, Knockout; Middle Aged; Muscle, Smooth, Vascular; Phosphoprotein Phosphatases; Phosphorylation; Pressoreceptors; Rats; Stress, Mechanical; Thrombospondin 1; Vascular Remodeling

Regular low-impact physical activity is generally allowed in patients with Marfan syndrome, a connective tissue disorder caused by heterozygous mutations in the fibrillin-1 gene. However, being above average in height encourages young adults with this syndrome to engage in high-intensity contact sports, which unfortunately increases the risk for aortic aneurysm and rupture, the leading cause of death in Marfan syndrome. In this study, we investigated the effects of voluntary (cage-wheel) or forced (treadmill) aerobic exercise at different intensities on aortic function and structure in a mouse model of Marfan syndrome. Four-week-old Marfan and wild-type mice were subjected to voluntary and forced exercise regimens or sedentary lifestyle for 5 mo. Thoracic aortic tissue was isolated and subjected to structural and functional studies. Our data showed that exercise improved aortic wall structure and function in Marfan mice and that the beneficial effect was biphasic, with an optimum at low intensity exercise (55-65% V̇o

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Dilatation, Pathologic; Disease Models, Animal; Elasticity; Elastin; Male; Marfan Syndrome; Matrix Metalloproteinase 2; Mice; Mice, Inbred C57BL; Mice, Transgenic; Physical Conditioning, Animal

Mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysm and dissection (TAAD). Mice that do not express

Topics: Animals; Animals, Newborn; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Arterial Pressure; Biomechanical Phenomena; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Extracellular Matrix Proteins; Gene Expression Profiling; Gene Expression Regulation; Genetic Predisposition to Disease; Mechanotransduction, Cellular; Mice, Knockout; Phenotype; Protein-Lysine 6-Oxidase; Stress, Mechanical; Vascular Stiffness

Marfan syndrome (MFS) is a multi-system connective tissue disorder that results from mutations to the gene that codes the elastin-associated glycoprotein fibrillin-1. Although elastic fibers are compromised throughout the arterial tree, the most severe phenotype manifests in the ascending aorta. By comparing biaxial mechanics of the ascending and descending thoracic aorta in a mouse model of MFS, we show that aneurysmal propensity correlates well with both a marked increase in circumferential material stiffness and an increase in intramural shear stress despite a near maintenance of circumferential stress. This finding is corroborated via a comparison of the present results with previously reported findings for both the carotid artery from the same mouse model of MFS and for the thoracic aorta from another model of elastin-associated glycoprotein deficiency that does not predispose to thoracic aortic aneurysms. We submit that the unique biaxial loading of the ascending thoracic aorta conspires with fibrillin-1 deficiency to render this aortic segment vulnerable to aneurysm and rupture.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Disease Models, Animal; Elastic Tissue; Elastin; Fibrillin-1; Humans; Male; Marfan Syndrome; Mechanical Phenomena; Mice; Stress, Mechanical; Weight-Bearing

Ascending thoracic aortic aneurysms (ATAAs) can lead to a dissection or rupture of the aorta, causing death or disability of the patients. Surgical interventions used to treat this disease are associated with risks of mortality and morbidity. Several studies have investigated the rupture mechanisms of ATAAs; however, underlying reasons behind aortic rupture (failure) have not been fully elucidated and further investigations are necessary. The rupture of pathological aortic tissue is a local phenomenon resulting from defects or tears in the vessel wall. In this work, the toughness-based rupture properties of ATAAs have been examined. The toughness, biaxial tensile properties, and histological properties of aneurysmal and control human ascending thoracic aortas (ATAs) were characterized from four quadrants of surgically excised aortic rings. The aneurysmal tissue population included aortas from patients with bicuspid aortic valves (BAV) and tricuspid aortic valves (TAV). The toughness, incremental modulus, and thickness properties of the aortas were determined and compared regionally. Additionally, to further explore the rupture propensity of ATAAs, the inter-correlation of the toughness properties with histological characteristics have been explored. We found no correlation between toughness and incremental modulus. However, toughness decreased significantly with the amount of collagen. In the outer curvature, there was an increase in incremental modulus with collagen+elastin content, but a decrease in toughness. These results suggest tissue remodeling could affect toughness and stiffness differently in ascending aortic aneurysms.

Topics: Aortic Aneurysm, Thoracic; Aortic Valve; Biomechanical Phenomena; Collagen; Elastic Modulus; Elastin; Humans

Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM). Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm.. Male 10-week-old MMP2-deficient (MMP2(-/-)) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2(-/-) mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II-induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2(-/-) thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2(-/-)-Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2(-/-)-Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-β and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2(-/-) mice were protected against CaCl2-induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis.. This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development.

Topics: Angiotensin II; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Calcium Chloride; Cells, Cultured; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Genotype; Male; Matrix Metalloproteinase 2; Mice, Inbred C57BL; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Phenotype; RNA, Messenger; Signal Transduction; Smad2 Protein; Smad3 Protein; Transforming Growth Factor beta; Ultrasonography; Vascular Remodeling

Development of thoracic aortic aneurysms is the most significant clinical phenotype in patients with Marfan syndrome. An inflammatory response has been described in advanced stages of the disease. Because the hallmark of vascular inflammation is local interleukin-6 (IL-6) secretion, we explored the role of this proinflammatory cytokine in the formation of aortic aneurysms and rupture in hypomorphic fibrillin-deficient mice (mgR/mgR).. MgR/mgR mice developed ascending aortic aneurysms with significant dilation of the ascending aorta by 12 weeks (2.7 ± 0.1 and 1.3 ± 0.1 for mgR/mgR versus wild-type mice, respectively; P<0.001). IL-6 signaling was increased in mgR/mgR aortas measured by increases in IL-6 and SOCS3 mRNA transcripts (P<0.05) and in cytokine secretion of IL-6, MCP-1, and GM-CSF (P<0.05). To investigate the role of IL-6 signaling, we generated mgR homozygous mice with IL-6 deficiency (DKO). The extracellular matrix of mgR/mgR mice showed significant disruption of elastin and the presence of dysregulated collagen deposition in the medial-adventitial border by second harmonic generation multiphoton autofluorescence microscopy. DKO mice exhibited less elastin and collagen degeneration than mgR/mgR mice, which was associated with decreased activity of matrix metalloproteinase-9 and had significantly reduced aortic dilation (1.0 ± 0.1 versus 1.6 ± 0.2 mm change from baseline, DKO versus mgR/mgR, P<0.05) that did not affect rupture and survival.. Activation of IL-6-STAT3 signaling contributes to aneurysmal dilation in mgR/mgR mice through increased MMP-9 activity, aggravating extracellular matrix degradation.

Topics: Animals; Aorta; Aortic Aneurysm, Thoracic; Aortic Rupture; Chemokine CCL2; Collagen; Dilatation, Pathologic; Disease Models, Animal; Elastin; Extracellular Matrix; Fibrillin-1; Fibrillins; Granulocyte-Macrophage Colony-Stimulating Factor; Interleukin-6; Marfan Syndrome; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Microfilament Proteins; RNA, Messenger; Severity of Illness Index; Signal Transduction; STAT3 Transcription Factor; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Time Factors; Up-Regulation

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

We hypothesized that female gender may have a specific negative impact on the mechanical characteristics, composition, and expression of matrix metalloproteinases/tissue inhibitors (MMPs/TIMPs) in the wall of ascending thoracic aortic aneurysms (ATAAs). Degenerative ATAAs were resected from 35 patients (age: 67±2 years, male: 20, ATAA diameter: 5.5±0.1cm) undergoing elective surgery. Tissue specimens were grouped by gender, region, and direction and submitted to immunohistochemistry for semi-quantitative assessment of MMP-2, MMP-9, TIMP-1, and TIMP-2 expressions, i.e. of staining intensity in extracellular matrix and immunoreactivity in vascular cells, as well as to histology for quantitation of elastin/collagen contents. Biomechanical characterization by the Fung-type model and examination of failure properties was performed. Gender differences in patient age, ATAA diameter, and ATAA diameter/body-surface area were non-significant. Increased MMP-2 and MMP-9, and decreased TIMP-1 and TIMP-2 expressions were observed in females. Elastin/collagen contents were higher in males than females, as was failure stress in circumferential but not longitudinal specimens. In both directions, failure stretch was invariant, while the Fung-type model parameters and elastic moduli calculated at physiologic stress levels were higher in females, suggestive of increased wall stiffness compared to males. MMP and TIMP expressions did not differ with region, unlike failure stress longitudinally that was greater posteriorly than anteriorly. The female gender is associated with impaired ATAA strength and increased stiffness, relating to the more extensive extracellular matrix breakdown and significantly higher ratio of MMP/TIMP expression witnessed in females. The present data may aid to identify the underlying pathophysiology accountable for the higher rupture risk, documented by epidemiologic studies in females.

Topics: Aged; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Biomechanical Phenomena; Collagen; Elastin; Female; Gene Expression Regulation, Enzymologic; Humans; Male; Matrix Metalloproteinases; Mechanical Phenomena; Sex Characteristics; Tissue Inhibitor of Metalloproteinases

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

An aortic aneurysm is characterized by widening of the aortic lumen diameter with adverse remodelling of the vascular extracellular matrix. A thoracic aortic aneurysm (TAA) is highly prevalent in patients with a bicuspid aortic valve (BAV). We investigated the structural remodelling in the aneurysmal ascending aorta in correlation to molecular alterations in male versus female BAV-TAA patients. Aneurysmal aortic samples (diameter >4.4 cm) from male and female patients were compared to non-aneurysmal non-BAV samples. The diameter of the aneurysmal aorta was smaller in females but comparable to that of male patients when normalized to body mass index. Disorganized elastin fibres and reduced elastin protein were found in samples from males and females with BAV-TAA. However, disarrayed collagen fibres and reduced protein were detected only in aortas from males with BAV-TAA. Elastin and collagen I messenger RNA (mRNA) levels were comparable in the BAV-TAA and control groups of both genders, suggesting post-translation degradation. Total elastase activity was elevated similarly in both genders. The activity of MT1-MMP, a potent collagenase, was increased more in aortic samples from males than females with BAV-TAA samples. MMP8 and MMP13 were lower whereas MMP2 was higher in female compared to samples from male BAV-TAA group. TIMP3 and TIMP4 decreased similarly in both genders, while TIMP2 increased in the female BAV-TAA group. Lower smooth muscle cell density in the medial layer of aortas from males with BAV-TAA samples corresponded to the increased caspase-3 cleavage compared to that of females.. We report a gender-dependent MMP/TIMP axis, collagen remodelling and smooth muscle cell (SMC) survival in the BAV-TAA aorta. The elevated TIMP2 could protect against the collagenolytic activity of MT1-MMP, leading to reduced collagen disarray and degradation in female BAV.. More collagen degradation/disarray and smooth muscle cell loss in male BAV-TAA patients. Similar elastin degradation/disarray in the aneurysmal aorta of both genders. Reduced collagen and elastin in BAV-TAA due to enhanced degradation, not reduced synthesis. Elevated TIMP2 in female BAV-TAA aortas protects against collagen degradation by MT1-MMP.

Topics: Aorta; Aortic Aneurysm, Thoracic; Aortic Valve; Bicuspid Aortic Valve Disease; Caspase 3; Collagen; Elastin; Extracellular Matrix; Female; Heart Valve Diseases; Humans; Male; Matrix Metalloproteinase 14; Middle Aged; Proteolysis; Sex Factors; Tissue Inhibitor of Metalloproteinase-2

Elevated plasma aldosterone concentrations in patients have been linked to a spectrum of cardiovascular diseases. Mineralocorticoid receptor antagonists provide additional benefits in patients with heart failure. However, whether aldosterone and the mineralocorticoid receptor are involved in aortic aneurysm is unknown.. We report that administration of deoxycorticosterone acetate (DOCA) and salt or aldosterone and salt, but not DOCA or salt alone, to C57BL/6 male mice induced abdominal and thoracic aortic aneurysm formation and rupture in an age-dependent manner. DOCA and salt- or aldosterone and salt-induced aortic aneurysm mimicked human aortic aneurysm with respect to elastin degradation, inflammatory cell infiltration, smooth muscle cell degeneration and apoptosis, and oxidative stress. Aortic aneurysm formation did not correlate with the increase in blood pressure induced by DOCA and salt. Systemic administration of the angiotensin-converting enzyme inhibitor, enalapril, or angiotensin type 1 receptor antagonist, losartan, did not affect DOCA and salt-induced aortic aneurysm. In contrast, the mineralocorticoid receptor antagonists, spironolactone or eplerenone, significantly attenuated DOCA and salt- or aldosterone and salt-induced aortic aneurysm.. The current study describes a novel aortic aneurysm animal model induced by mineralocorticoid receptor agonist and high salt, and reveals a previously unrecognized but potentially significant role of aldosterone in the pathogenesis of aortic aneurysm. These findings imply that mineralocorticoid receptor antagonists may be effective in the treatment of some aortic aneurysms.

Topics: Aldosterone; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Aortic Rupture; Apoptosis; Blood Pressure; Desoxycorticosterone; Disease Models, Animal; Elastin; Enalapril; Eplerenone; Losartan; Male; Mice; Mice, Inbred C57BL; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Oxidative Stress; Receptors, Mineralocorticoid; Sodium Chloride, Dietary; Spironolactone; Time Factors

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

Thoracic aortic aneurism (TAA) develops as a result of complex series of events that dynamically alter the structure and composition of the aortic vascular extracellular matrix (ECM). The main elements that alter the composition of aortic wall are smooth muscle cells (SMC). The purpose of the present work was to study alteration of smooth muscle cell functions derived from the patients with TAA and from healthy donors. As it is supposed that TAA associated with bicuspid aortic valve (BAV) and with tricuspid aortic valve (TAV) differ in their pathogenesis, we compared the SMC and tissues samples from BAV-, TAV-patients and healthy donors. We compared TAA patients' derived tissues and SMC to healthy donors' ones in several parameters: SMC growth, migration and apoptotic dynamics; metalloproteinase MMP2 and MMP9 activity (zymography) and elastin, collagen and fibrillin content (Western blot) in both tissue samples and cultured SMC. Proliferation ability of both BAV and TAV SMC was decreased comparing to donors cells; migration ability in scratch tests was increased in TAV-derived SMC comparing to donor cells. BAV-cells migration ability was not changed comparing to donor-SMC. Elastin content was decreased in TAA SMC comparing to donor cells whereas the content of fibrillin and collagen was not altered. At the same time elastin and collagen protein level was significantly higher in tissue samples of TAA patients comparing to donor-derived samples. SMS proliferation and migration ability is differently affected in TAV and BAV-associated TAA that supports the idea of different nature of these two groups of TAA. Also our data show that SMC functional properties are altered in TAA patients and these alterations could play a significant role in the disease pathogenesis.

Topics: Aorta; Aortic Aneurysm, Thoracic; Aortic Valve; Apoptosis; Bicuspid Aortic Valve Disease; Biomarkers; Case-Control Studies; Cell Movement; Cell Proliferation; Collagen; Elastin; Fibrillins; Heart Valve Diseases; Humans; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Microfilament Proteins; Myocytes, Smooth Muscle; Tricuspid Atresia

Elastase incubation was performed in the LCCA in 13 New Zealand white rabbits. Three weeks after incubation, DSA demonstrated that 10 (10/13, 77%) bifurcation-type aneurysms at the origin of the LCCA were present; mean aneurysm neck, width, and height values were 3.7 ± 1.1, 3.8 ± 0.9, and 8.7 ± 2.3 mm, respectively. The LCCA can be used to create bifurcation aneurysms in rabbits.

Topics: Aneurysm; Angiography, Digital Subtraction; Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Carotid Artery Diseases; Carotid Artery, Common; Disease Models, Animal; Elastin; Ligation; Rabbits

Marfan syndrome (MFS) is an inherited disorder of connective tissue caused by mutations in the gene for fibrillin-1 (FBN1). The complex pathogenesis of MFS involves changes in transforming growth factor beta (TGF-β) signaling and increased matrix metalloproteinase (MMP) expression. Fibrillin-1 and elastin have repeated Gly-x-x- Pro-Gly (GxxPG) motifs that can induce a number of effects including macrophage chemotaxis and increased MMP activity by induction of signaling through the elastin-binding protein (EBP). In this work, we test the hypothesis that antagonism of GxxPG fragments can suppress disease progression in the Marfan aorta. Fibrillin-1 underexpressing mgR/mgR Marfan mice were treated with weekly intraperitoneal (i.p.) injections of an antibody directed against GxxPG fragments. The treatment was started at 3 weeks of age and continued for 8 weeks. The treatment significantly reduced MMP-2, MMP-9 and pSmad2 activity, as well as fragmentation and macrophage infiltration in the aorta of the mgR/mgR mice. Additionally, airspace enlargement and increased pSmad2 activity in the lungs of mgR/mgR animals were prevented by the treatment. Our findings demonstrate the important role of secondary cellular events caused by GxxPG-containing fragments and matrix-induced inflammatory activity in the pathogenesis of thoracic aortic aneurysm (TAA) in mgR/mgR mice. Moreover, the results of the current study suggest that antagonism of the effects of GxxPG fragments may be a fruitful therapeutic strategy in MFS.

Topics: Amino Acid Motifs; Animals; Antibodies, Monoclonal; Aortic Aneurysm, Thoracic; Aortic Diseases; Blotting, Western; Disease Models, Animal; Elastin; Enzyme-Linked Immunosorbent Assay; Fibrillin-1; Fibrillins; Immunohistochemistry; Latent TGF-beta Binding Proteins; Macrophages; Marfan Syndrome; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Microfilament Proteins; Mutation; Peptides; Signal Transduction; Smad2 Protein; Transforming Growth Factor beta; Up-Regulation

Marfan syndrome is an autosomal dominantly inherited disorder of connective tissue with prominent skeletal, ocular, and cardiovascular manifestations. Aortic aneurysm and dissection are the major determinants of premature death in untreated patients. In previous work, we showed that extracts of aortic tissues from the mgR mouse model of Marfan syndrome showed increased chemotactic stimulatory activity related to the elastin-binding protein. Aortic samples were collected from 6 patients with Marfan syndrome and 8 with isolated aneurysms of the ascending aorta. Control samples were obtained from 11 organ donors without known vascular or connective tissue diseases. Soluble proteins extracted from the aortic samples of the two patient groups were compared against buffer controls and against the aortic samples from controls with respect to the ability to induce macrophage chemotaxis as measured using a modified Boyden chamber, as well as the reactivity to a monoclonal antibody BA4 against bioactive elastin peptides using ELISA. Samples from Marfan patients displayed a statistically significant increase in chemotactic inductive activity compared to control samples. Additionally, reactivity to BA4 was significantly increased. Similar statistically significant increases were identified for the samples from patients with idiopathic thoracic aortic aneurysm. There was a significant correlation between the chemotactic index and BA4 reactivity, and the increases in chemotactic activity of extracts from Marfan patients could be inhibited by pretreatment with lactose, VGVAPG peptides, or BA4, which indicates the involvement of EBP in mediating the effects. Our results demonstrate that aortic extracts of patients with Marfan syndrome can elicit macrophage chemotaxis, similar to our previous study on aortic extracts of the mgR mouse model of Marfan syndrome (Guo et al., Circulation 2006; 114:1855-62).

Topics: Adult; Aged; Animals; Antibodies, Monoclonal; Aorta; Aortic Aneurysm, Thoracic; Cattle; Chemotaxis; Elastin; Enzyme-Linked Immunosorbent Assay; Female; Humans; Macrophages; Male; Marfan Syndrome; Mice; Middle Aged; Tissue Extracts; Young Adult

We imaged the protease activity of matrix metalloproteinases (MMPs) upregulated during aneurysm formation, using protease-activatable near-infrared fluorescence probes. We tested whether these protease-activatable sensors can directly report the in vivo activity of the key biomarkers in aneurysm, using our genetically modified fibulin-4 mouse models for aneurysm formation. Mice homozygous for the fibulin-4 reduced-expression allele (fibulin-4(R/R)) show dilatation of the ascending aorta and a tortuous, stiffened aorta resulting from disorganized elastic fiber networks. Strikingly, even a moderate reduction in expression of fibulin-4 in the heterozygous fibulin-4(+/R) mice occasionally results in modest aneurysm formation.. Aorta transcriptome and protein expression analysis of fibulin-4(+/R) and fibulin-4(R/R) animals identified excessive transforming growth factor-β signaling as the critical event in the pathogenesis of aneurysm formation. To determine whether a perturbed elastin lamellar structure arose from induction of transforming growth factor-β-regulated MMPs, we performed gelatin zymography and used a protease-activatable near-infrared fluorescence probe to monitor and quantify MMP upregulation in animals, using various in vivo optical imaging modules and coregistration of the fluorescence signal with CT images of the same animals. Gelatin zymography demonstrated a significant increase in the presence of the active form of MMP-9 in the aortic arch of fibulin-4(R/R) mice. In vivo analysis of MMP upregulation using the near-infrared fluorescence probe and subsequent isosurface concentration mapping from reconstructed tomographic images from fibulin-4(+/R) and fibulin-4(R/R) mice revealed a graded increase in activation of MMPs within the aneurysmal lesions.. We aimed to develop molecular imaging procedures for faster, earlier, and easier recognition of aortic aneurysms. We show that in vivo coregistration of MMP activity by noninvasive tomographic imaging methods allows the detection of increased MMP activity, even before the aneurysm has actually formed.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortography; Biomarkers; Biosensing Techniques; Disease Models, Animal; Disease Progression; Early Diagnosis; Elastin; Enzyme Activation; Extracellular Matrix Proteins; Fluorescence; Magnetic Resonance Angiography; Matrix Metalloproteinase 9; Matrix Metalloproteinases; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Imaging; Predictive Value of Tests; Signal Transduction; Spectroscopy, Near-Infrared; Tomography, X-Ray Computed; Transforming Growth Factor beta; Up-Regulation

The present study tested the hypothesis that changes in the resident endogenous cellular population accompany alterations in aortic collagen and elastin content during thoracic aortic aneurysm (TAA) development in a murine model. Descending thoracic aortas were analyzed at various time points (2, 4, 8, and 16 weeks) post-TAA induction (0.5 M CaCl2, 15 minutes). Aortic tissue sections were subjected to histological staining and morphometric analysis for collagen and elastin, as well as immunostaining for cell-type-specific markers to quantify fibroblasts, myofibroblasts, and smooth-muscle cells. Results were compared with reference control mice processed in the same fashion. Aortic dilatation was accompanied by changes in the elastic architecture that included: a decreased number of elastic lamellae (from 6 to 4); altered area fraction of elastin (elevated at 4 weeks and decreased at 16 weeks); and a decreased area between elastic lamellae (minimum reached at 4 weeks). Total collagen content did not change over time. Increased immunoreactivity for fibroblast and myofibroblast markers was observed at 8- and 16-week post-TAA-induction, whereas immunoreactivity for smooth-muscle cell markers peaked at 4 weeks and returned to baseline by 16 weeks. Therefore, this study demonstrated that changes in aortic elastin content were accompanied by the emergence of a subset of fibroblast-derived myofibroblasts whose altered phenotype may play a significant role in TAA development through the enhancement of extracellular matrix proteolysis.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Apoptosis; Collagen; Elastin; Female; Fibroblasts; Immunohistochemistry; Male; Mice; Mice, Inbred C57BL; Organ Specificity

Persistent endoleak and endotension, complications after endovascular aortic repair, may be caused by an unorganized thrombus inside the aneurysm. The experimental study was designed to evaluate the effectiveness of stent grafts (S/Gs) with slow release of basic fibroblast growth factor (bFGF) for the organization.. The S/Gs were constructed of self-expanding Z stent covered with expanded polytetra fluoroethylene graft, and coated with elastin to be able to bind and slowly release bFGF. Five elastin-coated S/Gs with bFGF (bFGF-S/Gs) and without bFGF (C-S/Gs) were placed in the normal canine aorta respectively. The thoracic aortic aneurysm models were surgically created with a jugular vein patch in 12 beagles. S/Gs with six holes, for creating endoleaks, were used in the experiment of aneurysmal repair. The bFGF-S/Gs (n = 6) and C-S/Gs (n = 6) were implanted. The beagles were sacrificed at two weeks after the endovascular procedure and examined histologically.. The bFGF-S/Gs induced six times the intimal proliferation of the C-S/Gs in normal aorta. Twelve animals had successfully created aneurysms, and had endoleaks just after the endovascular procedure. At two weeks after the endovascular procedure, the percentage of fibrous area in the aneurysmal cavity treated with bFGF-S/G (35.7 +/- 4.3%) was significantly greater than C-S/G (13.6 +/- 2.2%) (P < .01).. bFGF-S/Gs are effective for accelerating organization of the aneurysm cavity and developing neointima. Further research on bFGF-S/Gs would clarify the association of endoleaks.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Blood Vessel Prosthesis Implantation; Cardiovascular Agents; Cell Proliferation; Delayed-Action Preparations; Disease Models, Animal; Dogs; Drug-Eluting Stents; Elastin; Feasibility Studies; Fibroblast Growth Factor 2; Fibrosis; Humans; Polytetrafluoroethylene; Prosthesis Design; Recombinant Proteins; Tunica Intima

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

Endovascular aortic repair by stent grafts (S/Gs) has been developed as a less invasive treatment for aortic aneurysms. However, some aneurysmal cavities can remain without organization, causing re-expansion. We demonstrated previously that transplantation of a cell combination (myoblasts and fibroblasts) promoted thrombus organization in a rat model. We also developed basic fibroblast growth factor (bFGF) slow-delivery S/Gs coated with elastin and impregnated with bFGF. Here, we evaluated the effects of cell transplantation combined with bFGF slow release on canine thoracic aortic aneurysmal sacs after S/Gs repair.. Thoracic aortic aneurysms were surgically created with jugular vein patches in 15 beagles. Myoblasts and fibroblasts of autologous skeletal muscle were isolated and cultured for cell transplantation. The S/Gs had 6 holes and produced endoleaks in the excluded cavities. Collagen gel (gel group, n=5) or a mixture of skeletal myoblasts and fibroblasts with collagen gel (cell group, n=5) were injected into the aneurysmal sacs excluded by the S/Gs. We also studied the effects of combined therapy of bFGF slow-release S/Gs and cell transplantation (hybrid group, n=5). After 14 days, histological analyses revealed that the excluded aneurysmal cavities of the gel group were filled with fresh thrombus, whereas the excluded cavities in the cell-transplanted groups were occupied by organized tissue. The percentages of the organized areas relative to the excluded cavities, evaluated by Masson's trichrome staining, were 18.1+/-4.0%, 52.6+/-4.0%, and 77.1+/-6.9% in the gel, cell, and hybrid groups, respectively. Collagen fibers had already appeared, and increased numbers of alpha-smooth muscle actin-positive cells were observed in the hybrid group.. Cell transplantation accelerated thrombus organization. Moreover, slow release of bFGF enhanced the effects of cell transplantation. Cell transplantation into unorganized spaces may improve the outcomes of endovascular treatments of aortic aneurysms.

Topics: Animals; Aortic Aneurysm, Thoracic; Blood Coagulation; Catheterization; Cells, Cultured; Collagen; Combined Modality Therapy; Dogs; Drug Implants; Elastin; Equipment Design; Equipment Failure; Fibroblast Growth Factor 2; Fibroblasts; Fibrosis; Gels; Humans; Implants, Experimental; Muscle, Skeletal; Myoblasts; Polytetrafluoroethylene; Recombinant Proteins; Stainless Steel; Stents; Transplantation, Autologous

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

Lysyl oxidases (Lox), which are members of the amine oxidase family, are involved in the maturation of elastic lamellae and collagen fibers. Modifications of amine oxidases in idiopathic annulo-aortic ectasia disease (IAAED) have never been investigated. Our aim was to examine the expression of several proteins that might interfere with elastic fiber organization in control (n=10) and IAAED (n=18) aortic tissues obtained at surgery. Expression of amine oxidases and semicarbazide-sensitive amine oxidase (SSAO), and cellular phenotypic markers were examined by immunohistopathology and confocal microscopy. The expression of these proteins was assessed in relation to clinical and histomorphological features of the arterial wall. In control aorta, SSAO staining was expressed along elastic lamellae, whereas in aneurysmal areas of IAAED, SSAO was markedly decreased, in association with severe disorganization of elastic lamellae. Smooth muscle myosin heavy chain was also decreased in IAAED compared with controls, indicating smooth muscle cell dedifferentiation. Multiple regression analysis showed that elastic lamellar thickness (ELT) was correlated positively with the SSAO:elastin ratio and negatively with the Lox:elastin ratio, and that the clinical features of IAAED (aneurysm, thoracic aorta diameter, and aortic insufficiency) were positively correlated with ELT but not with SSAO. The relationship between SSAO expression and ELT suggests that this amine oxidase may be involved in elastic fiber organization. However, in advanced IAAED, the deficit in SSAO expression could be secondary to the decrease and fragmentation of elastic fibers and/or to vascular smooth muscle cell dedifferentiation.

Topics: Amine Oxidase (Copper-Containing); Aorta, Thoracic; Aortic Aneurysm, Thoracic; Aortic Valve Insufficiency; Cell Differentiation; Elastin; Extracellular Matrix; Female; Humans; Immunohistochemistry; Male; Microscopy, Confocal; Middle Aged; Muscle, Smooth, Vascular; Myosin Heavy Chains; Protein-Lysine 6-Oxidase; Regression Analysis

Elastic fiber is one of the major component of the extracellular matrix, which provides the resilience to many tissues. Elasticity is an important property of human aorta, and this elastic property decreases in various pathological conditions such as dissecting aneurysm (DA). Since the cross-linking structures in elastin are responsible for this elasticity, we studied the alteration of various cross-linking amino acids in human aorta associated with DA by a new method using high-performance liquid chromatography (HPLC). Materials were obtained from non-atherosclerotic areas of thoracic aorta of 27 autopsy cases which had no particular aortic disease and 19 cases of DA at replacement operation. After acid hydrolysis, SEP-PAK silica-gel column and Fe3+/activated charcoal column pretreatment were carried out for analysis of desmosine (DES), isodesmosine (ISDES), neodesmosine (NEO), oxodesmosine (OXO) and isooxodesmosine (ISOXO), and for analysis of aldosine (ALD), respectively. These prepared samples were applied to the reversed-phase HPLC column. We also analyzed pyridinoline (PYR), a major cross-linking amino acid of collagen as an index of fibrosis. All crosslinks of elastin were decreased in DA as compared to the age-matched control. The decrease of ISOXO was marked. The increase of PYR and PYR/(DES+ISDES) were not statistically significant. It is suggested oxidative degradation on elastin crosslinks occur in DA, and the ratio of collagen to elastin didn't contribute to the pathogenesis of DA.

Topics: Adult; Aged; Amino Acids; Aortic Aneurysm, Thoracic; Chromatography, High Pressure Liquid; Cross-Linking Reagents; Elasticity; Elastin; Humans; Middle Aged

Aortic valve disease and aneurysmal dilation of the ascending aorta are managed by prosthetic valve conduit replacement or homograft replacement. Requirement of anticoagulation, risk of thromboembolism or bleeding, and increased risk for homograft degeneration in young patients suggest that a Ross root replacement with replacement or reduction of the ascending aorta could be a preferred alternative. To assess efficacy, the present review was undertaken. Between April 19, 1995, and February 1999, 64 patients (age, 8 months to 59 years; median age, 37 years) had a Ross operation, with resection of the ascending aorta in 30 and reduction aortoplasty in 34. Annular fixation was performed in 57 patients, with aortic annulus reduction in 39. Clinical evaluation with echocardiogram was completed within 1 year of closure in 62 patients. There was one operative death and one non-valve-related late death. Autograft valve insufficiency (AI) was 0 to trace in the perioperative period in all patients. One patient developed progressive annular dilation with moderate AI at 2 months. Reoperation with annular reduction and fixation restored autograft valve function. Postoperative mean aortic annulus diameter was 22.5+/-0.4 mm (Z-value, -0.2+/-0.2) and 23.2+/-0.8 mm (Z-value, -0.02+/-0.5) at 1 year. Aortic sinus diameter was 33+/-6 postoperative and 36+/-5 at 1 year. The autograft root sinus diameter was greater than 39 mm in 11 patients at the most recent echocardiogram. Mean echocardiography measurements of the aortic root have been constant during the postoperative follow-up period. Two patients have required reoperation for homograft obstruction 1.3 and 2.1 years after operation. Ross root replacement of the aortic valve with resection or reduction aortoplasty can be performed with a low operative risk and limited morbidity. Its early durability appears to be similar to other Ross operations.

Topics: Adolescent; Adult; Aortic Aneurysm, Thoracic; Child; Child, Preschool; Elastin; Extracellular Matrix Proteins; Female; Fibrillins; Humans; Infant; Male; Microfilament Proteins; Middle Aged; Vascular Surgical Procedures

Abdominal aortic aneurysms are characterized by degradation of the extracellular matrix, with a reduction in the elastin concentration of the arterial media. These changes are mediated by increased levels of endogenous metalloproteinases (MMPs) within the aorta, which provide a potential therapeutic target for pharmacologic agents aimed at reducing the growth rate of small aneurysms. In this study, the ability of doxycycline--an MMP inhibitor--to reduce matrix degradation was assessed in a previously described model of aneurysmal disease that used a brief pulse of elastase to induce MMP production and elastin degradation in arterial organ cultures.. Porcine aortic segments (n = 8) were preincubated in exogenous pancreatic elastase for 24 hours before culture in standard conditions for 13 days with both 1 and 10 mg/L doxycycline. Control segments were cultured both without doxycycline and without elastase. At the termination of culture, MMPs were extracted from the tissue and quantified by a combination of substrate gel enzymography and immunoblotting. The volume fractions of elastin and collagen were determined by stereologic analysis of sections stained with Miller's elastin and van Gieson's stain.. Stereologic analysis demonstrated a significant preservation of elastin in aorta treated with doxycycline 10 mg/L (p < 0.001) and demonstrated that this preservation was accompanied by a significant reduction in MMP-9 activity (p < 0.02). Immunoblotting for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) showed no decreased production in the doxycycline-treated groups.. Therapeutic ranges of doxycycline significantly inhibited elastin degradation and MMP-9 production within aortic organ cultures. These data suggest that doxycycline may have a potential application in reducing the growth rates of small abdominal aortic aneurysms.

Topics: Animals; Aorta, Thoracic; Aortic Aneurysm, Thoracic; Doxycycline; Elastin; Enzyme Inhibitors; Matrix Metalloproteinase 9; Matrix Metalloproteinase Inhibitors; Metalloendopeptidases; Organ Culture Techniques; Swine

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

The molecular mechanisms predisposing to atherosclerotic aneurysm formation remain undefined. Nevertheless, rupture of aortic aneurysms is a major cause of death in Western societies, with few available treatments and poor long-term prognosis. Indirect evidence suggests that matrix metalloproteinases (MMPs) and plasminogen activators (PAs) are involved in its pathogenesis. MMPs are secreted as inactive zymogens (pro-MMPs), requiring activation in the extracellular compartment. Plasmin, generated from the zymogen plasminogen by tissue-type plasminogen activator (t-PA) or urokinase-type plasminogen activator (u-PA; refs 14,15), has been proposed as a possible activator in vitro, but evidence for such a role in vivo is lacking. Analysis of atherosclerotic aorta in mice with a deficiency of apoliprotein E (Apoe-/-; ref. 18), singly or combined with a deficiency of t-PA (Apoe-/-:Plat-/-) or of u-PA (Apoe-/-:Plau-/-; ref. 19), indicated that deficiency of u-PA protected against media destruction and aneurysm formation, probably by means of reduced plasmin-dependent activation of pro-MMPs. This genetic evidence suggests that plasmin is a pathophysiologically significant activator of pro-MMPs in vivo and may have implications for the design of therapeutic strategies to prevent aortic-wall destruction by controlling Plau gene function.

Topics: Animals; Aortic Aneurysm, Abdominal; Aortic Aneurysm, Thoracic; Arteriosclerosis; Collagen; Diet, Atherogenic; Elastin; Enzyme Activation; Female; Fibrinolysin; Macrophages; Male; Metalloendopeptidases; Mice; Mice, Knockout; Tunica Media; Urokinase-Type Plasminogen Activator

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