Academic literature on the topic 'Non-syndromic thoracic aneurysm'

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.

Thoracic aortic aneurysm and dissection (TAAD) affects many patients globally and has high mortality rates if undetected. Once thought to be solely a degenerative disease that afflicted the aorta due to high pressure and biomechanical stress, extensive investigation of the heritability and natural history of TAAD has shown a clear genetic basis for the disease. Here, we review both the cellular mechanisms and clinical manifestations of syndromic and non-syndromic TAAD. We particularly focus on genes that have been linked to dissection at diameters <5.0 cm, the current lower bound for surgical intervention. Genetic screening tests to identify patients with TAAD associated mutations that place them at high risk for dissection are also discussed.

Heritable thoracic aortic disease (HTAD) is a term used to define a large group of disorders characterized by the occurrence of aortic events, mainly represented by aneurysm or dissection. These events generally involve the ascending aorta, although the involvement of other districts of the aorta or peripheral vessels may occur. HTAD can be classified as non-syndromic if the disorder is limited to the aorta, and syndromic when associated with extra-aortic features. About 20–25% of patients with non-syndromic HTAD exhibit a family history of aortic disease. Thus, a careful clinical evaluation of the proband and the first-degree family members is required to differentiate familial and sporadic cases. Genetic testing is essential since it allows confirmation of the etiological diagnosis of HTAD (particularly in patients with a significant family history) and may guide family screening. In addition, genetic diagnosis significantly impacts patients’ management since the different conditions significantly differ with respect to natural history and treatment strategies. The prognosis in all HTADs is determined by the progressive dilation of the aorta, potentially leading to acute aortic events, such as dissection or rupture. Moreover, the prognosis varies according to the underlying genetic mutations. This review aims to describe the clinical characteristics and natural history of the most common HTADs, with particular emphasis on the role of genetic testing in risk stratification and management.

The main challenge in diagnosing and managing thoracic aortic aneurysm and dissection (TAA/D) is represented by the early detection of a disease that is both deadly and “elusive”, as it generally grows asymptomatically prior to rupture, leading to death in the majority of cases. Gender differences exist in aortic dissection in terms of incidence and treatment options. Efforts have been made to identify biomarkers that may help in early diagnosis and in detecting those patients at a higher risk of developing life-threatening complications. As soon as the hereditability of the TAA/D was demonstrated, several genetic factors were found to be associated with both the syndromic and non-syndromic forms of the disease, and they currently play a role in patient diagnosis/prognosis and management-guidance purposes. Likewise, circulating biomarker could represent a valuable resource in assisting the diagnosis, and several studies have attempted to identify specific molecules that may help with risk stratification outside the emergency department. Even if promising, those data lack specificity/sensitivity, and, in most cases, they need more testing before entering the “clinical arena”. This review summarizes the state of the art of the laboratory in TAA/D diagnostics, with particular reference to the current and future role of molecular-genetic testing.

MicroRNAs (miRNAs) are critical regulators of the functional pathways involved in the pathogenesis of cardiovascular diseases. Understanding of the disease-associated alterations in tissue and plasma will elucidate the roles of miRNA in modulation of gene expression throughout development of sporadic non-syndromic ascending thoracic aortic aneurysm (TAA). This will allow one to propose relevant biomarkers for diagnosis or new therapeutic targets for the treatment. The high-throughput sequencing revealed 20 and 17 TAA-specific miRNAs in tissue and plasma samples, respectively. qRT-PCR analysis in extended cohort revealed sex-related differences in miR-10a-5p, miR-126-3p, miR-155-5p and miR-148a-3p expression, which were the most significantly dysregulated in TAA tissues of male patients. Unexpectedly, the set of aneurysm-related miRNAs in TAA plasma did not resemble the tissue signature suggesting more complex organism response to the disease. Three of TAA-specific plasma miRNAs were found to be restored to normal level after aortic surgery, further signifying their relationship to the pathology. The panel of two plasma miRNAs, miR-122-3p, and miR-483-3p, could serve as a potential biomarker set (AUC = 0.84) for the ascending TAA. The miRNA-target enrichment analysis exposed TGF-β signaling pathway as sturdily affected by abnormally expressed miRNAs in the TAA tissue. Nearly half of TAA-specific miRNAs potentially regulate a key component in TGF-β signaling: TGF-β receptors, SMADs and KLF4. Indeed, using immunohistochemistry analysis we detected increased KLF4 expression in 27% of TAA cells compared to 10% of non-TAA cells. In addition, qRT-PCR demonstrated a significant upregulation of ALK1 mRNA expression in TAA tissues. Overall, these observations indicate that the alterations in miRNA expression are sex-dependent and play an essential role in TAA via TGF-β signaling.

ObjectiveThe aetiology of thoracic aortic aneurysm (TAA) is largely unknown, but inflammation is likely to play a central role in the pathogenesis. In this present study, we aim to investigate the complement receptors in TAA.MethodsAortic tissue and blood from 31 patients with non-syndromic TAA undergoing thoracic aortic repair surgery were collected. Aortic tissue and blood from 36 patients with atherosclerosis undergoing coronary artery bypass surgery or aortic valve replacement were collected and served as control material. The expression of the complement anaphylatoxin receptors C3aR1, C5aR1 and C5aR2 in aortic tissue were examined by quantitative RT-PCR and C5aR2 protein by immunohistochemistry. Colocalisation of C5aR2 to different cell types was analysed by immunofluorescence. Complement activation products C3bc and sC5b-9 were measured in plasma.ResultsCompared with controls, TAA patients had substantial (73%) downregulated gene expression of C5aR2 as seen both at the mRNA (p=0.005) level and protein (p=0.03) level. In contrast, there were no differences in the expression of C3aR1 and C5aR1 between the two groups. Immunofluorescence examination showed that C5aR2 was colocalised to macrophages and T cells in the aortic media. There were no differences in the degree of systemic complement activation between the two groups.ConclusionOur findings suggest downregulation of the C5aR2, regarded to act mainly anti-inflammatory, in electively operated TAA as compared with non-aneurysmatic aortas of patients with aortic stenosis and/or coronary artery disease. This may tip the balance towards a relative increase in the inflammatory responses induced by C5aR1 and thus enhance the inflammatory processes in TAA.

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.

Le patologie cardiovascolari rappresentano la principale causa di malattia e morte: solo negli Stati Uniti si stima che 62 milioni circa di persone siano affette da tali patologie e nel 2000, 946,000 decessi sono stati attribuiti a patologie cardiovascolari, un ammontare pari al 39% delle cause di morte a livello mondiale. Anche gli aneurismi dell’aorta toracica (TAA) rientrano tra le malattie cardiovascolari che sono cause di decesso. Tra le varie tipologie di TAA, i meno caratterizzati e definiti da un punto di vista eziopatologico sono gli aneurismi non sindromici, familiari e non. La mia tesi si colloca proprio in questo ambito e la ricerca da me svolta ha avuto lo scopo di approfondire le conoscenze degli aspetti morfologici e dei meccanismi molecolari sottostanti agli aneurismi non sindromici non familiari (NSTAA). In particolare, in collaborazione con la Sezione di Cardiochirurgia dell’Università di Verona ho selezionato nove campioni di tunica media provenienti da pazienti affetti da NSTAA e nove controlli di riferimento da analizzare mediante un approccio proteomico-bioinformatico, cui è seguita un’analisi mediante immunoblotting, istologia quantitativa (QH), e immunoistochimica (ICH)/immunofluorescenza (IF). La prima caratteristica che ho osservato nella tunica media degli NSTAA rispetto ai controlli è stata una profonda disorganizzazione a livello della matrice extracellulare (ECM). Ho infatti rilevato anomalie nelle reti di fibre elastiche accompagnate da un aumento della quantità delle fibre collagene. Inoltre, ho riscontrato una diminuzione del numero delle cellule muscolari lisce vascolari (VSMC) conseguente a un aumento dell’attività della proapoptotica Caspasi-3. Nei medesimi campioni è aumentata in modo significativo anche l’espressione delle due isoforme della cistationina gamma-liasi (CTH), la cui attività enzimatica potrebbe determinare un incremento della concentrazione di H2S nei tessuti oltre i livelli fisiologici, ed essere perciò almeno in parte responsabile sia dell’apoptosi che della diminuzione dell’attività proliferativa delle VSMC. Le analisi morfologiche da me condotte hanno permesso di evidenziare cambiamenti significativi del fenotipo delle VSMC che da contrattile è divenuto prevalentemente sintetico/secretorio. Esaminando le proteine solubili della ECM e le proteine coinvolte nei processi di adesione tra cellule ed ECM, ho riscontrato un aumento dell’espressione della Paxillina (PXN), nella sua forma intera e proteolizzata, e del proteoglicano Testican-2. Viceversa, l’espressione della microfibrillar-associated glycoprotein-1 (MAGP-1) era diminuita. Profonde alterazioni hanno interessato anche il citoscheletro, in cui l’espressione di una proteina caratteristica dei filamenti intermedi, la Vimentina (VIM) risulta diminuita in modo considerevole. Infine, ho riscontrato che rispetto ai controlli negli NSTAA, due importanti vie segnaletiche: Jagged1/Notch1 ed EDA/EDAR presentano modificazioni significative. La prima vede un aumento di espressione della forma intera di Jagged1 (JAG1) e del suo recettore Notch1. Tuttavia, tale signaling è contrastato dall’accumulo del frammento extracellulare solubile di JAG1. Nella seconda via, si verifica un incremento dell’espressione dell’ ectodisplasina (EDA), cui però si accompagna una diminuita espressione del recettore corrispondente (EDAR). In conclusione, la mia ricerca, basata sull’utilizzo di un approccio proteomico ed istologico funzionale, mi ha permesso di evidenziare diverse cause dell’indebolimento della parete aortica nei NSTAA, come uno squilibrio tra la componente elastica e quella fibrosa, una perturbazione dell’equilibrio tra la frazione proliferativa e la morte cellulare delle VSMC, profonde alterazioni di componenti della ECM, citoscheletro e di più vie cellulari segnaletiche. Tutte queste modificazioni concorrono alla progressione della patologia aneurismatica.
Cardiovascular disease is the leading cause of illness and death in the whole world. In the United States, for example, there are an estimated 62 million people with cardiovascular disease. In 2000, approximately 946,000 deaths were attributed to cardiovascular disease, accounting for 39% of all deaths in the USA. Among these causes of death thoracic aorta aneurysms (TAAs) can be found. Both familial and nonfamilial nonsyndromic thoracic aortic aneurysms (NSTAAs) are less well characterized than syndromic ones. This is the aim of my thesis: increasing our knowledge about the specific morphological and molecular characteristics that underlie NSTAAs. Tunica media samples taken from nine selected nonfamilial NSTAAs and nine reference patients were investigated via proteomics-bioinformatics, immunoblotting, quantitative histology (QH), and immunohistochemistry (IHC)/immunofluorescence (IF). The first characteristic I observed is a deep disorganization at extracellular matrix (ECM) level. I found a distorted elastic fiber network partnered with an increase in collagen fibers. The vascular smooth cells (VSMCs) decreased in number due to a proapoptotic increase in Caspase-3 activity. In the same media samples cystathionine gamma-lyase (CTH) was diffusely upregulated, and by producing H2S might be responsible for both the apoptosis and a hindered cell proliferation. VSMCs presented even a change in their phenotype, switching from a contractile to synthetic/secretory one. At the ECM level I found an increase in Paxillin (PXN) holoprotein, and in its cleaved form. Expression of the Testican-2 proteoglycan was also boosted. Conversely, the microfibrillar-associated glycoprotein-1 (MAGP-1) was found decreased. Alterations at the cytoskeletal level were also present; in fact there was a significant down-regulation in Vimentin (VIM) expression. Moreover, I found deeply altered even two important cell signaling systems in NSTAAs. On the one hand, an upregulation of Jagged1 (JAG1) holoprotein and its receptor, Notch1, whose signal was hindered by an accumulation of extracellular soluble JAG1 fragments. On the other hand, I observed an upregulated ectodysplasin (EDA) protein combined with a downregulation of its receptor (EDAR). In conclusion, I found a weakening of the aortic wall caused by an imbalance between elastic and fibrosis components in NSTAAs. This imbalance is coupled with a perturbed ratio between dying and proliferating cell fractions. In NSTAAs I found even deep alterations in ECM, cytoskeleton, and cell signaling. All together these changes concur to aneurysm progression.