Search Results (9)

Aortic aneurysm is a vascular disease with a complex pathogenesis which is usually asymptomatic but can lead to high mortality with sudden rupture. This review comprehensively examines the molecular mechanisms of aortic aneurysms in the context of extracellular matrix destruction, smooth muscle cell apoptosis, chronic inflammation, oxidative stress, genetic mutations, and epigenetic regulations. In addition, the potential of molecular biomarkers in diagnosis and prognosis and targeted treatment strategies are evaluated. Animal models and translational findings form the basis for establishing a bridge between preclinical and clinical applications. This study aims to provide insight into the integration of molecular findings into clinical practice in light of the current literature and to guide future research. Full article

Background/Objectives: Pectus excavatum (PEx) is considered, at least partially, a familial disorder. A variety of inheritance patterns, associations with genetic syndromes, and pathogenic variants have been reported. However, the etiology of this condition is still not completely understood, and no known genes have been identified as definitive contributors. Methods: Family members with a confirmed PEx diagnosis (one proband and two first-degree relatives) and non-affected members were recruited into this study. Exome sequencing was performed on all affected familial PEx cases to systematically screen for candidate genes that are likely to be causative for PEx, and on non-affected family members for variant segregation analysis. Results: Ten families, with three affected members each, participated, providing thirty familial PEx cases. Different inheritance patterns were represented across the ten pedigrees, with possible incomplete penetrance. Genetic variants in REST (essential for neuronal development and associated with pectus deformities in prior studies), SMAD4 (variants can predispose individuals to thoracic aortic diseases), and COL5A (associated with Ehlers–Danlos syndrome and Fibromuscular dysplasia) were initially identified as potentially linked to the development of pectus deformities and segregated with the phenotype. No variants were shared across families in the studied population. Conclusions: Germline exome sequencing of families with multiple individuals affected by PEx in our study identified potential gene candidates linked to PEx. These candidates are private to individual families and no strong candidates shared across multiple families were identified. These findings suggest that the inheritance of PEx may not be strongly related to a shared single genetic variant in known genes. Given the accumulating evidence for the genetic basis of familial PEx, further studies, including polygenic analyses, as well as assessment of the non-coding genome and possible epigenetic markers are warranted. Full article

The extracellular matrix is a complex network of proteins and other molecules that are essential for the support, integrity, and structure of cells and tissues within the human body. The genes ZNF469 and PRDM5 each produce extracellular-matrix-related proteins that, when mutated, have been shown to result in the development of brittle cornea syndrome. This dysfunction results from aberrant protein function resulting in extracellular matrix disruption. Our group recently identified and published the first known associations between variants in these genes and aortic/arterial aneurysms and dissection diseases. This paper delineates the proposed effects of mutated ZNF469 and PRDM5 on various essential extracellular matrix components, including various collagens, TGF-B, clusterin, thrombospondin, and HAPLN-1, and reviews our recent reports associating single-nucleotide variants to these genes’ development of aneurysmal and dissection diseases. Full article

Syndromic aortic diseases (SADs) encompass various pathological manifestations affecting the aorta caused by known genetic factors, such as aneurysms, dissections, and ruptures. However, the genetic mutation underlying aortic pathology also gives rise to clinical manifestations affecting other vessels and systems. As a consequence, the main syndromes currently identified as Marfan, Loeys–Dietz, and vascular Ehlers–Danlos are characterized by a complex clinical picture. In this contribution, we provide an overview of the genetic mutations currently identified in order to have a better understanding of the pathogenic mechanisms. Moreover, an update is presented on the basis of the most recent diagnostic criteria, which enable an early diagnosis. Finally, therapeutic strategies are proposed with the goal of improving the rates of patient survival and the quality of life of those affected by these SADs. Full article

Thoracic aortic aneurysms are clinical conditions that are associated with severe clinical endpoints including dissection and rupture, potentially leading to sudden death. Contrary to their abdominal counterparts, thoracic aortic aneurysms are well-recognized to have a genetic basis underlying their development. Among all patients with aneurysmal disease who underwent clinical genetic screening in our program (N = 145), two patients were found to have variants of uncertain significance (VUS) in the PRDM5 gene. This gene is responsible for multiple regulatory functions in extracellular matrix development, and this is the first report, to our knowledge, to associate this gene with aortopathy. Full article

As yet, there is no agreed definition for the so-called “hypoplastic left heart syndrome”. Even its origin remains contentious. Noonan and Nadas, who as far as we can establish first grouped together patients as belonging to a “syndrome” in 1958, suggested that Lev had named the entity. Lev, however, when writing in 1952, had described “hypoplasia of the aortic outflow tract complex”. In his initial description, as with Noonan and Nadas, he included cases with ventricular septal defects. In a subsequent account, he suggested that only those with an intact ventricular septum be included within the syndrome. There is much to commend this later approach. When assessed on the basis of the integrity of the ventricular septum, the hearts to be included can be interpreted as showing an acquired disease of fetal life. Recognition of this fact is important to those seeking to establish the genetic background of left ventricular hypoplasia. Flow is also of importance, with septal integrity then influencing its effect on the structure of the hypoplastic ventricle. In our review, we summarise the evidence supporting the notion that an intact ventricular septum should now be part of the definition of the hypoplastic left heart syndrome. Full article

Thoracic aortic aneurysms and dissections often have inter-related pathologies that are increasingly recognized to have a genetic basis. A patient with a vascular history consisting of a spontaneous aorto-iliac dissection and thoracic aortic aneurysm belonged to a family with a significant self-reported history of aneurysmal disease. Suspecting a genetic component, genetic investigation was undertaken. Three variants of unknown significance were found in the ZNF469 gene, which is responsible for the production of a collagen-related zinc finger protein involved in multiple aspects of the development and regulation of major extracellular matrix components. This is the first report to associate this gene with vasculopathy, and further investigation by our group is underway to understand the role it plays in the development of aneurysmal diseases. Full article

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. Full article

The present paper briefly reviews the literature supporting the pathogenetic importance of hemodynamics in the development of bicuspid aortic valve-associated aortopathy. The hypothesis of a genetic basis for this disease, whether it is a common defect for bicuspid malformation and predisposition to aortic aneurysm or not, should not be discarded. However, a more complex, multifactorial pathogenesis model is here proposed, based on the hypotheses raised by recent studies both on clinical and pre-clinical aspects of bicuspid aortopathy, whereby in at least some forms of the disease the biomechanical factors capable to induce aortic wall maladaptive remodeling may be necessary to the development of the aortopathy. The main scope of this review is to underscore the importance of trying to advance the scientific knowledge not only on the genetic bases but also on the peculiar aspects of hemodynamics of bicuspid aortic valve and flow-induced vascular remodeling. Full article