Littérature scientifique sur le sujet « Non-syndromic ascending aortic aneurysms »

AbstractAneurysm–osteoarthritis syndrome is a recently discovered inherited autosomal dominant connective tissue disease caused by SMAD3 mutations. Aneurysm–osteoarthritis syndrome is responsible for 2% of familial thoracic aortic aneurysms and dissections and is characterised by aneurysms, dissections, and tortuosity throughout the arterial tree in combination with osteoarthritis. Early-onset osteoarthritis is present in almost all patients. We present the case of a non-syndromic young boy with SMAD3 mutation isolated from the dilated aortic root and ascending aorta without osteoarthritis.

ABSTRACT The development of thoracic aortic aneurysms (TAAs) involves a multifactorial process resulting in alterations of the structure and composition of the extracellular matrix (ECM). Recently, modifications in microRNA (miRNA) expression were implicated in the pathogenesis of TAA. This study presents a preliminary miRNA microarray analysis conducted on pooled ascending aorta RNAs obtained from non familial non syndromic TAA patients (five males and five females) compared to matched control pools. Ninety-nine differentially expressed miRNAs with >1.5-foldup- or down-regulation in TAAs compared to controls were identified, 16.0% of which were similarly regulated in the two sexes. Genes putatively targeted by differentially expressed miRNAs belonged preferentially to focal adhesion and adherens junction pathways. The results indicate an altered regulation of miRNA-mediated gene expression in the cellular interactions of aneurysmal aortic wall.

Aneurysms-osteoarthritis syndrome (AOS) caused by haploinsufficiency ofSMAD3is a recently described cause of syndromic familial thoracic aortic aneurysm and dissection (TAAD). We identified a novelSMAD3mutation in a patient with hypoplastic left heart syndrome (HLHS) who developed progressive aortic aneurysm requiring surgical replacement of the neoaortic root, ascending aorta, and proximal aortic arch. Family screening for the mutation revealed that his father, who has vascular and skeletal features of AOS, and his brother, who is asymptomatic, also have the pathogenic mutation. This is the first case report of aSMAD3mutation in a patient with hypoplastic left heart syndrome. This case highlights the importance of genetic testing for known causes of aneurysm in patients with congenital heart disease who develop aneurysmal disease as it may significantly impact the management of those patients and their family members.

Introduction. According to recent data, thoracic aortic surgery have reduced morbidity and mortality, however, women are at increased postoperative risk of adverse outcomes. Our aim was to evaluate and compare early outcomes in male and female patients undergoing ascending aortic replacement.Methods. A total of 88 patients, consisting of 54 men (61.4%) and 34 women (38.6%) underwent ascending aortic surgery for non-syndromic aneurysms from January 2013 to December 2021. We analyzed clinical outcomes between males and females.Results. According to computed tomographic angiography, preoperative normalized aortic diameters were significantly larger in females (2.9 [2.7; 3.2] cm/m2) vs. (2.5 [2.3; 2.6] cm/m2, p < 0.001) in males, without differences in absolute values (51 [49; 53] mm vs. 52 [50; 53] mm, p = 0.356). There were no significant differences in neurological, cardiac, pulmonary, and renal complications in both groups in the early postoperative period. In-hospital mortality was 1.9% and 5.9% (p = 0.307) in male and female patients, respectively.Conclusions. Ascending aortic surgery for aneurysms below 5.5 cm threshold has tolerable early outcomes both in men and women.

Abstract OBJECTIVES The unicuspid aortic valve (UAV) is a rare cardiac malformation and is associated with the formation of ascending aortic aneurysms. To characterize its associated aortic wall changes, normal and aneurysmatic ascending aortic wall specimens were analysed, focusing on the potential mechanisms of aneurysm formation. Patients with tricuspid aortic valve (TAV) served as controls. METHODS In a retrospective observational study, 74 specimens (dilated and non-dilated aortas; individuals with UAV and TAV) obtained intraoperatively were studied. Standard stains and immunohistochemical labelling of cleaved caspase-3, cluster of differentiation 31 and endothelial nitric oxide synthase (eNOS) were performed to assess the degree of apoptosis, distribution of eNOS within the aortic wall, smooth muscle cell (SMC) nuclei loss and mucoid extracellular matrix accumulation (MEMA). RESULTS Deeper ingrowth of vasa vasorum was found in dilated aortas. Interestingly, eNOS was expressed mostly in vasa vasorum. More apoptosis was seen in UAV aortas compared to TAV aortas (P &lt; 0.001). Both UAV and TAV aortas were comparable regarding SMC nuclei loss (P = 0.419). In dilated compared to non-dilated aortas regardless valve morphology SMC nuclei loss was increased (P = 0.005) and more pronounced translamellar MEMA was present (P = 0.011). The highest grade of distribution (P = 0.043) and the highest severity (P = 0.005) regarding MEMA were seen in TAV dilated specimens compared to UAV dilated specimens. CONCLUSIONS Aneurysms with UAV show increased apoptosis, the role of which is unclear. Strikingly, more severe MEMA was found in TAV aneurysms compared to UAV aneurysms. Thus, UAV-associated aortic wall changes and resulting aneurysm may be less aggressive than aneurysms with TAV.

OBJECTIVES/SPECIFIC AIMS: Pre-clinical and clinical observations have noted that increased aortic dilation is associated with male sex. Using an experimental model of severe, syndromic thoracic aortic aneurysms, we quantify aortic dilation and elastin stability in male Versus female mice. METHODS/STUDY POPULATION: Ascending aortas from male and female FBN1mgR/mgR mice and their wild type littermates were assessed every 4 weeks from 6 to 18 weeks of age by ultrasound. Measurements were taken luminal edge to luminal edge in diastole. At termination, aortas were harvested for RT-PCR analysis of extracellular matrix genes. Aortas were serially sectioned and elastin fragmentation was imaged by auto-fluorescence. RESULTS/ANTICIPATED RESULTS: At 12 weeks of age, differences of aortic diameters between male and female FBN1mgR/mgR mice were significantly different (2.24±0.43 vs. 1.57±0.22 mm; p=0.002), while there were no significant differences between sexes of wild type littermates (1.29±0.13 vs. 1.23±0.08 mm; p=0.71). Male sex was associated with increased elastin but not fibrillin-1 mRNA expression. Ascending aortas from male and female FBN1mgR/mgR mice significantly differed in the degree of elastin fragmentation (2.76 vs. 1.85 breaks/ 100 µm aorta; p=0.03). DISCUSSION/SIGNIFICANCE OF IMPACT: Sexual dimorphism of thoracic aortic dilation observed in human TAA patients was recapitulated in the fibirllin-1 hypomorphic mouse model of syndromic thoracic aortic aneurysms. Differences in this mouse model could be explained by the differential expression of extracellular matrix genes.

Objective. The aim of this study was to identify predictors of adverse events after ascending aortic replacement for the aortic aneurysms in the early postoperative period.Material and Methods. The analysis included 151 patients with ascending aortic aneurysm who underwent non-hemiarch or hemiarch repair. The following adverse outcomes were selected: postoperative delirium, respiratory failure, bleeding, multiple organ dysfunction syndrome, and in-hospital mortality. Predictors of adverse clinical events were identified by constructing uni- and multivariate logistic regression.Results. Significant predictors of early outcomes and mortality after ascending aortic replacement were as follows: female gender, atrial fibrillation, low glomerular filtration rate, chronic obstructive pulmonary disease, aortic root repair, multiple organ dysfunction, duration of cardiac arrest, operation time, and reoperation for bleeding.Conclusions. The risk factors of adverse outcomes after ascending aortic replacement were decreased kidney function, atrial fibrillation, female gender, aortic root repair, and increased duration of cardiac arrest and operation time.

Objective. The aim of this study was to identify predictors of adverse events after ascending aortic replacement for the aortic aneurysms in the early postoperative period.Material and Methods. The analysis included 151 patients with ascending aortic aneurysm who underwent non-hemiarch or hemiarch repair. The following adverse outcomes were selected: postoperative delirium, respiratory failure, bleeding, multiple organ dysfunction syndrome, and in-hospital mortality. Predictors of adverse clinical events were identified by constructing uni- and multivariate logistic regression.Results. Significant predictors of early outcomes and mortality after ascending aortic replacement were as follows: female gender, atrial fibrillation, low glomerular filtration rate, chronic obstructive pulmonary disease, aortic root repair, multiple organ dysfunction, duration of cardiac arrest, operation time, and reoperation for bleeding.Conclusions. The risk factors of adverse outcomes after ascending aortic replacement were decreased kidney function, atrial fibrillation, female gender, aortic root repair, and increased duration of cardiac arrest and operation time.

Aim. To compare the shortand medium-term outcomes of hemiarch and nonhemiarch replacement for ascending aortic aneurysm (AAA).Material and methods. The study included 151 patients with non-syndromic AAA who underwent an elective replacement. Patients were divided into two groups: group 1 (non-hemiarch, n=40) — standard ascending aortic replacement; group 2 (hemiarch, n=111) — ascending aortic replacement with the hemiarch anastomosis in conditions of moderate hypothermia and circulatory arrest with unilateral antegrade cerebral perfusion. To eliminate systematic differences between the compared groups, the propensity score matching (PSM) method was used.Results. Before PSM, there were no significant intergroup differences in the incidence of neurological complications, myocardial infarction, prolonged ventilation, or acute kidney injury. Bleeding-related reoperation rates and hospital mortality significantly differed between groups. After pseudo-randomization between the non-hemiarch and hemiarch groups, there were no significant differences in the incidence of neurological events, myocardial infarction, prolonged ventilation, reoperations for bleeding, acute renal injury, and hospital mortality. Median-term survival and freedom from aortic reoperations also did not show significant intergroup differences.Conclusion. Hemiarch replacement for AAA does not lead to an increase in the incidence of postoperative complications, as well as the risk of shortand mediumterm mortality compared with non-hemiarch.

<p><strong>Background: </strong>Bicuspid aortic valves predispose to ascending aortic aneurysms, but the mechanisms underlying this aortopathy remain incompletely characterized. We sought to identify epigenetic pathways predisposing to aneurysm formation in bicuspid patients.</p><p><strong>Methods: </strong>Ascending aortic aneurysm tissue samples were collected at the time of aortic replacement in subjects with bicuspid and trileaflet aortic valves. Genome-wide DNA methylation status was determined on DNA from tissue using the Illumina 450K methylation chip, and gene expression was profiled on the same samples using Illumina Whole-Genome DASL arrays. Gene methylation and expression were compared between bicuspid and trileaflet individuals using an unadjusted Wilcoxon rank sum test. </p><p><strong>Results: </strong>Twenty-seven probes in 9 genes showed significant differential methylation and expression (P&lt;5.5x10^-4). The top gene was protein tyrosine phosphatase, non-receptor type 22 (<em>PTPN22</em>), which was hypermethylated (delta beta range: +15.4 to +16.0%) and underexpressed (log 2 gene expression intensity: bicuspid 5.1 vs. trileaflet 7.9, P=2x10^-5) in bicuspid patients, as compared to tricuspid patients. Numerous genes involved in cardiovascular development were also differentially methylated, but not differentially expressed, including <em>ACTA2</em> (4 probes, delta beta range: -10.0 to -22.9%), which when mutated causes the syndrome of familial thoracic aortic aneurysms and dissections</p><p><strong>Conclusions: </strong>Using an integrated, unbiased genomic approach, we have identified novel genes associated with ascending aortic aneurysms in patients with bicuspid aortic valves, modulated through epigenetic mechanisms. The top gene was <em>PTPN22</em>, which is involved in T-cell receptor signaling and associated with various immune disorders. These differences highlight novel potential mechanisms of aneurysm development in the bicuspid population.</p>

L’aneurisma non sindromico dell’aorta ascendente è una malattia complessa e ancora poco si conosce dell’espressione genica e della sua regolazione in individui patologici. La tonaca principalmente coinvolta nella patologia è la media. Scopo di questo studio è l’identificazione di differenze di espressione genica tra tonaca media di individui aneurismatici e non. Sono stati raccolti 41 frammenti di aorta ascendente con aneurisma (casi) e 22 frammenti di aorta ascendente senza aneurisma (controlli). I casi provenivano da pazienti che sono stati sottoposti a intervento di aneurismectomia e i controlli da pazienti che hanno subito trapianto di cuore. Le analisi di espressione genica su RNA della tonaca media sono state condotte utilizzando la tecnica dei microarray, che prevedeva una piattaforma di 21.329 geni umani, Real Time PCR e piattaforme di microRNA. Dallo studio di microarray, confrontando 3 singoli casi verso un pool di 10 controlli sono risultati differenzialmente espressi 17 geni, tra i quali Period homolog 2 (PER2), coinvolto nei ritmi circadiani periferici, il quale risultò sovra-espresso, e Decorin (DCN), coinvolto nella riorganizzazione della matrice extracellulare, che risultò sotto-espresso. Dal confronto di microarray tra 4 pool di 3 casi ognuno verso un pool di 15 controlli confermava la sovra-espressione di PER2. Finora abbiamo validato mediante TaqMan Real Time PCR la sovra-espressione di PER2 e la sottoespressione di DCN negli individui aneurismatici. Da una parallela analisi proteomica su individui aneurismatici e non sono state identificate proteine differenzialmente espresse. Abbiamo condotto analisi tramite Sybr Green Real Time PCR sui geni codificanti tali proteine. Il differente livello di espressione si confermava nei due tipi di esperimenti per 6 geni su 15, tra i quali NOTCH1 coinvolto nello sviluppo vascolare. Sono stati indagati mediante Sybr Green Real Time PCR geni selezionati della cascata NK-kB ed è stato evidenziato uno stato pro-infiammatorio più marcato nei soggetti aneurismatici con valvola aortica bicuspide in confronto ai controlli e ai soggetti aneurismatici con valvola tricuspide. Gli esperimenti di microarray di microRNA hanno evidenziato, oltre a vari microRNA differenzialmente espressi, la sotto-espressione di mir-133 nella tonaca media degli individui aneurismatici, coinvolto nella via di segnalazione dell’ossido nitrico. In conclusione, questo studio a vari livelli ha evidenziato differente espressione genica di geni coinvolti principalmente nell’infiammazione e nel remodelling della parete. Future analisi saranno condotte per avere un quadro più chiaro sulle possibili vie di segnalazione implicate nella predisposizione e nello sviluppo dell’aneurisma non sindromico dell’aorta ascendente.
The non-syndromic ascending aortic aneurysm is a complex and common disease. Little is known on gene expression and its regulation in aneurysms. The media coat is principally involved in the disease. Aim of this study is to identify gene expression differences between aneurysmal and normal ascending aortic media coats. A total of 41 aneurysmal aortic samples (cases) and 22 aortic samples without aneurysm (controls), has been collected from patients undergoing aneurysmectomy and heart transplantation, respectively. Gene expression analyses on media coats RNA have been conducted by whole genome microarrays, which detect a total of 21,329 human genes, Real Time PCR, and microRNA microarrays. Results from whole genome microarrays performed on 3 cases and a pool of 10 controls indicated a total of 17 differentially expressed genes, among which Period homolog 2 (PER2), involved in circadian rhythm, was upexpressed, and Decorin (DCN), involved in remodeling, was downexpressed. The analysis of 4 pool of 3 cases versus a pool of 15 controls confirmed PER2 up-expression. Presently, we validated by Real Time PCR PER2 up-expression and DCN down-expression in aneurysms. Expression study of a comparison of transcriptomic analysis with proteomic data confirmed up-regulation of 6 genes out of 15 investigated, including NOTCH1 , involved in vascular development. Expression study of selected genes of NF-kB cascade evidenced a proinflammatory status of aneurysmal subjects with bicuspid aortic valve compared to the normal and to tricuspid aortic valve aneurysmal subjects. Initial microRNA microarray analysis indicates that mir-133, related to NO signaling, may be down-regulated in aneurysms. In conclusion, genes mainly involved in inflammation and remodeling have been identified with this study. Further expression analyses will better indicate pathways involved in thoracic aortic aneurysms development.

Aortic diseases encountered in young women are mainly associated with syndromic diseases, which are often heritable, or bicuspid aortic valve. The most frequent syndromic disease is Marfan syndrome. In Marfan syndrome, the risk of aortic dissection is low during pregnancy when the maximum diameter of the ascending aorta is less than 45 mm. Dissection may affect the thoracic ascending or descending aorta. The risk of aortic dissection is low in bicuspid aortic valve when the aortic diameter is less than 50 mm. Beta blockers are recommended throughout pregnancy in Marfan syndrome and are often used in other causes of aortic aneurysms. Close echocardiographic follow-up is needed during pregnancy and after delivery.

Aortic diseases encountered in young women are mainly associated with syndromic diseases, which are often heritable, or bicuspid aortic valve. The most frequent syndromic disease is Marfan syndrome. In Marfan syndrome, the risk of aortic dissection is low during pregnancy when the maximum diameter of the ascending aorta is less than 45 mm. Dissection may affect the thoracic ascending or descending aorta. The risk of aortic dissection is low in bicuspid aortic valve when the aortic diameter is less than 50 mm. Beta blockers are recommended throughout pregnancy in Marfan syndrome and are often used in other causes of aortic aneurysms. Close echocardiographic follow-up is needed during pregnancy and after delivery.

Thoracic aortic aneurysm (TAA) is defined as aneurysmal degeneration that occurs in the thoracic aorta. The incidence of TAA is increasing with improvements in screening, as well as advances in imaging. They are often asymptomatic but in some cases, they may compress the innominate vein or airway or they may stretch the left recurrent laryngeal nerve, causing hoarseness. TAA often results from cystic medial degeneration and when it occurs at younger ages, it is classically associated with connective tissue disorders, such as Marfan syndrome or, less commonly, Ehlers–Danlos syndrome and Loeys–Dietz syndrome. Mycotic aneurysms, once the predominant cause of ascending and arch aneurysms, are rare today. Diagnosis is often casual and can be suspected on the basis of chest X-ray or as for ascending aortic aneurysms, diagnosed by transthoracic echocardiogram. However, the computed tomography angiography scan represents the gold standard examination for diagnosis. The aortic arch operation consists of the replacement of the arch with reimplantation of the supra-aortic vessels. Effective methods of cerebral, myocardial, as well as visceral protection are necessary to obtain acceptable results in terms of hospital mortality and morbidity. The ‘elephant trunk’ procedure can be an alternative technique for total arch repair; however, a recent evolution of the ‘elephant trunk’ procedure is the ‘frozen elephant trunk’ technique. This technique consists of the implantation of the stented distal segment of the hybrid prosthesis into the descending aorta through the opened aortic arch, while the proximal, non-stented segment is used for conventional replacement of the aortic arch.

Non-invasive diagnosis of cardiovascular diseases is a valuable tool to reduce patient’s risk and discomfort. The main aim of this work is to investigate the possibilities of using computational fluid dynamics as a tool to investigate the biomechanical characteristics of the aorta under different medical conditions. These conditions include an aorta with healthy conditions, atherosclerosis and aneurysm. A three dimensional pulsatile flow model for an elastic aorta is developed and constructed in ANSYS® CFX 12. Abnormalities are simulated as diameter changes at the root of the ascending aorta. The computational model shows the reflection of these diseases on the blood flow and the artery wall at other locations downstream along the aorta. This 3D model has several advantages over previously published 1D and 2D models by giving more realistic results as compared with clinical trials.