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High-Resolution Morphological Approach to Analyse Elastic Laminae Injuries of the Ascending Aorta in a Murine Model of Marfan Syndrome.

ABSTRACT: In Marfan syndrome, the tunica media is disrupted, which leads to the formation of ascending aortic aneurysms. Marfan aortic samples are histologically characterized by the fragmentation of elastic laminae. However, conventional histological techniques using transverse sections provide limited information about the precise location, progression and 3D extension of the microstructural changes that occur in each lamina. We implemented a method using multiphoton excitation fluorescence microscopy and computational image processing, which provides high-resolution en-face images of segmented individual laminae from unstained whole aortic samples. We showed that internal elastic laminae and successive 2^nd laminae are injured to a different extent in murine Marfan aortae; in particular, the density and size of fenestrae changed. Moreover, microstructural injuries were concentrated in the aortic proximal and convex anatomical regions. Other parameters such as the waviness and thickness of each lamina remained unaltered. In conclusion, the method reported here is a useful, unique tool for en-face laminae microstructure assessment that can obtain quantitative three-dimensional information about vascular tissue. The application of this method to murine Marfan aortae clearly shows that the microstructural damage in elastic laminae is not equal throughout the thickness of the tunica media and in the different anatomical regions of the ascending aorta.

SUBMITTER: Lopez-Guimet J

PROVIDER: S-EPMC5431420 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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High-Resolution Morphological Approach to Analyse Elastic Laminae Injuries of the Ascending Aorta in a Murine Model of Marfan Syndrome.

López-Guimet Júlia J Andilla Jordi J Loza-Alvarez Pablo P Egea Gustavo G

Scientific reports 20170504 1

In Marfan syndrome, the tunica media is disrupted, which leads to the formation of ascending aortic aneurysms. Marfan aortic samples are histologically characterized by the fragmentation of elastic laminae. However, conventional histological techniques using transverse sections provide limited information about the precise location, progression and 3D extension of the microstructural changes that occur in each lamina. We implemented a method using multiphoton excitation fluorescence microscopy a ...[more]

PMID: 28473723

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Project description:Marfan syndrome (MFS) is a hereditary disorder of the connective tissue that causes life-threatening aortic aneurysm, which initiates at the aortic root and can progress into the ascending portion. However, analysis of ascending aorta reactivity in animal models of MFS has remained elusive. Epidemiologic evidence suggests that although MFS is equally prevalent in men and women, men are at a higher risk of aortic complications than non-pregnant women. Nevertheless, there is no experimental evidence to support this hypothesis. The aim of this study was to explore whether there are regional and sex differences in the thoracic aorta function of mice heterozygous for the fibrillin 1 (Fbn1) allele encoding a missense mutation (Fbn1C1039G/+), the most common class of mutation in MFS. Ascending and descending thoracic aorta reactivity was evaluated by wire myography. Ascending aorta mRNA and protein levels, and elastic fiber integrity were assessed by qRT-PCR, Western blotting, and Verhoeff-Van Gieson histological staining, respectively. MFS differently altered reactivity in the ascending and descending thoracic aorta by either increasing or decreasing phenylephrine contractions, respectively. When mice were separated by sex, contractions to phenylephrine increased progressively from 3 to 6 months of age in MFS ascending aortas of males, whereas contractions in females were unchanged. Endothelium-dependent relaxation was unaltered in the MFS ascending aorta of either sex; an effect related to augmented endothelium-dependent hyperpolarization-type dilations. In MFS males, the non-selective cyclooxygenase (COX) inhibitor indomethacin prevented the MFS-induced enhancement of phenylephrine contractions linked to increased COX-2 expression. In MFS mice of both sexes, the non-selective nitric oxide synthase inhibitor L-NAME revealed negative feedback of nitric oxide on phenylephrine contractions, which was associated with upregulation of eNOS in females. Finally, MFS ascending aortas showed a greater number of elastic fiber breaks than the wild-types, and males exhibited more breaks than females. These results show regional and sex differences in Fbn1C1039G/+ mice thoracic aorta contractility and aortic media injuries. The presence of more pronounced aortic alterations in male mice provides experimental evidence to support that male MFS patients are at increased risk of suffering aortic complications.

Project description:IntroductionAneurysms of the ascending aorta (AA) correspond to a dilatation of the ascending aorta that progressively evolves over several years. The main complication of aneurysms of the ascending aorta is type A aortic dissection, which is associated with very high rates of morbidity and mortality. Prophylactic ascending aorta replacement guidelines are currently based on maximal AA diameter. However, this criterion is imperfect. Stretching tests on the aorta carried out ex-vivo make it possible to determine the elastic properties of healthy and aneurysmal aortic fragments (tension test, resistance before rupture). For several years now, cardiac magnetic resonance imaging (MRI) has provided another means of evaluating the elastic properties of the aorta. This imaging technique has the advantage of being non-invasive and of establishing aortic compliance (local measurement of stiffness) without using contrast material by measuring the variation of the aortic surface area during the cardiac cycle, and pulse wave velocity (overall stiffness of the aorta).Materials and methodsProspective single-center study including 100 patients with ascending aortic aneurysm requiring surgery. We will perform preoperative cine-MRI and biomechanical laboratory stretching tests on aortic samples collected during the cardiac procedure. Images will be acquired with a 3T MRI with only four other acquisitions in addition to the conventional protocol. These additional sequences are a Fast Low Angle Shot (FLASH)-type sequence performed during a short breath-hold in the transverse plane at the level of the bifurcation of the pulmonary artery, and phase-contrast sequences that encodes velocity at the same localization, and also in planes perpendicular to the aorta at the levels of the sino-tubular junction and the diaphragm for the descending aorta. For ex-vivo tests, the experiments will be carried out by a biaxial tensile test machine (ElectroForce®). Each specimen will be stretched with 10 times of 10% preconditioning and at a rate of 10 mm/min until rupture. During the experiment, the tissue is treated under a 37°C saline bath. The maximum elastic modulus from each sample will be calculated.ResultsThe aim of this study is to obtain local patient-specific elastic modulus distribution of the ascending aorta from biaxial tensile tests and to assess elastic properties of the aorta using MRI, then to evaluate the correlation between biaxial tests and MRI measurements.DiscussionOur research hypothesis is that there is a correlation between the evaluation of the elastic properties of the aorta from cardiac MRI and from stretching tests performed ex-vivo on aorta samples collected during ascending aorta replacement.

Project description:Background Penetrating ulcers of aorta, aortic dissections and intramural hematomas all come under acute aortic syndromes and have important similarities and differences. Case report We report a 67?year old man with rupture of a large penetrating ulcer of the distal ascending aorta with hemopericardium and left hemothorax. He underwent interposition graft replacement of ascending aorta and hemi-arch with a 30?mm Gelweave Vascutek graft but represented 6?months later with development of a penetrating ulcer which ruptured into a huge 14?cm pseudoaneurysm. This was repaired with a 28?mm Vascutek Gelseal graft replacement of arch and interposition graft reconstruction of innominate and left common carotid arteries. 6?weeks later, however, he ruptured his proximal descending aorta and underwent TEVAR satisfactorily. Unfortunately, 2?days later, he developed a pathological fracture of left proximal tibia with metastasis from a primary renal cell carcinoma. He died 3?weeks later from respiratory failure. We shall briefly outline the similarities and differences in presentation and management of penetrating aortic ulcers, aortic dissections and intramural haematomas. We shall discuss, in greater detail, penetrating ulcers of thoracic aorta, their natural history, location, complications and management. Conclusion This case report is unique on account of initial successful surgical redressal following rupture of penetrating ulcer of distal ascending aorta into left pleural and pericardial cavities, normally associated with instant death. The haemodynamic effects of the rupture were staggered due to initial contained rupture into a smaller pseudoaneurysm, followed by a further rupture into a false aneurysmal sac followed eventually by generalised rupture into the pleural and pericardial cavities - a unique way of aortic rupture. Further development of another penetrating ulcer and a small pseudoaneurysm in the distal arch 6?months later which further ruptured into a larger 14?cm false aneurysmal sac, which again did not result in exsanguination, is again extraordinarily rare. Thereafter he underwent emergency thoracic endovascular aortic repair (TEVAR) for a further rupture of descending thoracic aorta. All three ruptures were managed successfully and would usually be associated with near-certain death, only for the patient to succumb eventually to the complications of metastatic renal cell carcinoma.

Project description:BackgroundAlthough a bicuspid aortic valve (BAV) is known to be associated with progressive ascending aortic dilatation, the fate of the residual aorta after aortic valve and ascending aorta surgery is unknown. We reviewed surgical outcomes and explored serial changes in the size of the sinus of Valsalva (SOV) and distal ascending aorta (DAAo) in 89 patients with a BAV undergoing aortic valve replacement (AVR) and graft replacement (GR) of the ascending aorta.MethodsWe retrospectively examined patients who underwent AVR and GR of the ascending aorta for BAV-and related disease and thoracic aortic dilatation at our institution between January 2009 and December 2018. Patients who underwent AVR alone or required intervention for the aortic root and aortic arch and patients with connective tissue diseases were excluded. Aortic diameters were examined using computed tomography (CT). Late CT more than 1 year after surgery was performed in 69 patients (78%) with a mean follow-up of 4.9±2.8 years.ResultsThe surgical indication for aortic valve etiology was stenosis in 61 patients (69%), regurgitation in 10 (11%), and mixed in 18 (20%). Preoperative maximum short diameters of the ascending aorta, SOV, and DAAo were 47.3±4.7, 36.0±5.2, and 37.2±3.6 mm, respectively. The diameter of the SOV increased non-significantly by 0.08±0.45 mm per year [95% confidence interval (CI): -0.12 to 0.11, P=0.150], while that of the DAAo increased significantly by 0.11±0.40 mm per year (95% CI: 0.02-0.21, P=0.005). One patient required reoperation 6 years postoperatively due to a pseudo-aneurysm at the proximal anastomotic site. No patient required reoperation due to progressive dilatation of the residual aorta. According to the Kaplan-Meier analysis, the long-term survival rates were 98.9%, 98.9%, and 92.7% at 1, 5, and 10 years postoperatively, respectively.ConclusionsRapid dilatation of the residual aorta rarely occurred in patients with a BAV who underwent AVR and GR of the ascending aorta in the mid-term follow-up. For selected patients with a surgical indication for ascending aortic dilatation, simple AVR and GR of the ascending aorta may be sufficient surgical options.

Dataset Information

High-Resolution Morphological Approach to Analyse Elastic Laminae Injuries of the Ascending Aorta in a Murine Model of Marfan Syndrome.

Publications

High-Resolution Morphological Approach to Analyse Elastic Laminae Injuries of the Ascending Aorta in a Murine Model of Marfan Syndrome.

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