Search Results (24)

Thoracic aortic aneurysm and dissection (TAAD) encompasses a clinically heterogeneous group of diseases characterized by high morbidity and mortality. Genetic studies over the past two decades have significantly expanded our understanding of the molecular landscape underlying heritable TAAD, revealing contributions from multiple interconnected biological pathways. This review systematically summarizes more than 75 genes implicated in TAAD pathogenesis, categorizing them according to major mechanistic roles including TGF-β signaling, extracellular matrix remodeling, smooth muscle cell contractility and cytoskeletal regulation, cell–matrix and cell–cell adhesion, metabolic processes, ion transport, and transcriptional regulation. Special emphasis is placed on emerging genes with variable or overlapping clinical phenotypes, dual-mechanism candidates, and their implications for personalized clinical management, including surveillance and surgical intervention thresholds. The integration of molecular insights into clinical practice, along with cautious consideration of genes of uncertain significance, promises to enhance diagnostic precision and risk stratification in individuals and families affected by heritable aortic disease. Full article

Pathogenic variants of MYH11, which encode smooth muscle myosin heavy chain 11, have been linked to familial thoracic aortic aneurysms and dissections (FTAAD). However, molecular pathways affected by these mutations have not been well understood. To explore downstream consequences of Myh11 disruption, we analyzed transcriptomic and proteomic profiles of aortas from male Myh11 mice with homozygous deletion of lysine 1256 (K1256) and of wild-type controls. Of 6499 proteins quantified, 1763 were differentially expressed (adjusted p < 0.05), including 942 that were downregulated and 821 that were upregulated in mutant aortas. Enrichment analysis of downregulated genes and proteins revealed a consistent reduction in extracellular matrix-related pathways. Among downregulated proteins, we identified tenascin Xb, transforming growth factor β (Tgfb) 2, and Tgfb receptor 1/2, malfunctions of which are linked to connective tissue diseases, such as Ehlers–Danlos and Loeys–Dietz syndromes. Nevertheless, unlike these syndromic diseases, mice with Myh11 pathogenic variants and patients with FTAAD do not exhibit syndromic features, likely reflecting expression of Myh11 restricted to smooth muscle. These results suggest that loss of Myh11 disrupts maintenance of extracellular matrix by SMCs, the loss of which contributes to aortic fragility without affecting other tissues. Full article

Thoracic aortic aneurysms are life-threatening vascular conditions linked to inherited disorders such as Marfan syndrome, Loeys–Dietz syndrome, vascular Ehlers–Danlos syndrome, and familial thoracic aortic aneurysms and dissections. While traditionally associated with the extracellular matrix and contractile defects in vascular smooth muscle cells, emerging evidence suggests the key role of mitochondrial dysfunction. Here, we show that the overexpression of ACTA2^R179H and TGFBR2^G357W in murine aortic VSMCs reduces Mitochondrial Transcription Factor A (Tfam) expression, decreases mitochondrial DNA (mtDNA) content, and impairs oxidative phosphorylation, shifting metabolism toward glycolysis. Notably, nicotinamide riboside, a NAD⁺ precursor, restores mitochondrial respiration, increases Tfam and mtDNA levels, and promotes a contractile phenotype by enhancing actin polymerization and reducing matrix metalloproteinase activity. These findings identify mitochondrial dysfunction as a shared feature in hereditary thoracic aortic aneurysm, not only in Marfan syndrome, but also in other genetic forms, and highlight mitochondrial boosters as a potential therapeutic strategy. Full article

The incidence of thoracic aortic aneurysms (TAAs) is approximately 10.4 cases per 100,000 person-years. Although most cases of TAA are caused by degenerative disease, associated aortic valve abnormalities have been heavily linked to this condition. These include unicuspid, bicuspid and quadricuspid aortic valves. These non-tricuspid aortic valves occur sporadically but can occur in familial clusters with variable penetrance. The presence of non-tricuspid aortic valves has significant implications for patients, as they become prone to valvular dysfunction and aortic dissection. Therefore, understanding of the pathophysiology and natural history of this condition is imperative for early diagnosis, regular surveillance and timely intervention. In this review article, we discuss the normal anatomy of the aortic valve, non-tricuspid aortic valves and their association with TAAs. We also highlight the role of various cardiac imaging modalities in the management of affected patients. Full article

Background/Objectives: Congenital bicuspid aortic valve (BAV) signifies the most frequent category of congenital cardiovascular anomaly globally, occurring in approximately 0.5–2% of the general population worldwide. BAV is a major cause of thoracic aortopathy, encompassing aortic stenosis, aortic root dilation with regurgitation, aortic dissection, and aortic aneurysms, consequently leading to substantial late-onset morbidity and mortality. Accumulating evidence convincingly demonstrates the strong genetic basis underpinning BAV, though the inheritable reasons responsible for BAV in most patients remain largely obscure. Methods: A genome-wide genotyping with 400 polymorphic genetic markers followed by linkage analysis, haplotype assay, and sequencing analysis of candidate genes was conducted in a 4-generation BAV kindred of 47 individuals. Biochemical assays were performed to evaluate the functional effect of the identified mutation on TBX20. Results: A novel BAV-causative locus was mapped to chromosome 7p14. A sequencing assay of the genes within the mapped chromosomal region (locus) unveiled that only the c.656T>G (p.Ile219Arg) variation of TBX20 was in co-segregation with BAV in the entire pedigree. The missense mutation was not uncovered in 322 healthy persons employed as control individuals. Functional deciphers revealed that the mutation significantly decreased the transcriptional activation of the representative target gene ANP and the binding ability to the ANP promoter and impaired the intranuclear distribution of TBX20. Conclusions: This investigation maps a new genetic locus (chromosome 7p14) linked to BAV and uncovers TBX20 as a novel causative gene for familial BAV, adding more insight into the mechanisms underlying BAV and providing a molecular target for the individualized management of BAV. Full article

Background/Objectives: Thoracic aortic aneurysms (TAAs) are potentially life-threatening medical conditions, and their etiology involves both genetic and multiple risk factors. Coxiella burnetii endocarditis is one of the most frequent causes of blood culture-negative infective endocarditis (BCNIE) in patients with previous cardiac surgery. Our review aims to emphasize the importance of genetic testing in patients with thoracic aortic aneurysms but also the importance of additional testing in patients with suspected endocarditis whose blood cultures remain negative. The reported case has a history of acute DeBakey type I aortic dissection that developed during her second pregnancy, for which the Bentall procedure was performed at that time. Ten years after the surgery, the patient started developing prolonged febrile syndrome with repeatedly negative blood cultures, the serological tests revealing the presence of an infection with Coxiella burnetii. Considering her family history and the onset of her aortic pathology at a young age, genetic tests were performed, disclosing a missense variant in the actin alpha-2 (ACTA2) gene in heterozygous status. Methods: For a better understanding of both conditions, our research was conducted in two directions: one reviewing the literature on patients with Coxiella burnetii BCNIE and the other focusing on patients who had a familial thoracic aortic aneurysm (FTAA) due to the ACTA2 variant. This review incorporates studies found on PubMed and ResearchGate up to August 2024. Conclusions: BCNIE represents a condition with several diagnostic challenges and may lead to severe complications if timely treatment is not initiated. Also, diagnosing an FTAA requires genetic testing, enabling better follow-up and management. Full article

Emerging evidence has indicated a possible link between attenuation of contractility in aortic smooth muscle cells and pathogenesis of aortic dissection, as revealed through comprehensive, multi-omic analyses of familial thoracic aortic aneurysm and dissection models. While L-type voltage-gated calcium channels have been extensively investigated for their roles in smooth muscle contraction, more recent investigations have suggested that downregulation of T-type voltage-gated calcium channels, rather than their L-type counterparts, may be more closely associated with impaired contractility observed in vascular smooth muscle cells. This review provides a detailed examination of T-type voltage-gated calcium channels, highlighting their structure, electrophysiology, biophysics, expression patterns, functional roles, and potential mechanisms through which their downregulation may contribute to reduced contractile function. Furthermore, the application of multi-omic approaches in investigating calcium channels is discussed. Full article

Hereditary thoracic aorta diseases (HTADs) are a heterogeneous group of rare disorders whose major manifestation is represented by aneurysm and/or dissection frequently located at the level of the ascending thoracic aorta. The diseases have an insidious evolution and can be encountered as an isolated manifestation or can also be associated with systemic, extra-aortic manifestations (syndromic HTADs). Along with the development of molecular testing technologies, important progress has been made in deciphering the heterogeneous etiology of HTADs. The aim of this study is to identify the genetic variants associated with a group of patients who presented clinical signs suggestive of a syndromic form of HTAD. Genetic testing based on next-generation sequencing (NGS) technology was performed using a gene panel (Illumina TruSight Cardio Sequencing Panel) or whole exome sequencing (WES). In the majority of cases (8/10), de novo mutations in the FBN1 gene were detected and correlated with the Marfan syndrome phenotype. In another case, a known mutation in the TGFBR2 gene associated with Loeys–Dietz syndrome was detected. Two other pathogenic heterozygous variants (one de novo and the other a known mutation) in the SLC2A10 gene (compound heterozygous genotype) were identified in a patient diagnosed with arterial tortuosity syndrome (ATORS). We presented the genotype–phenotype correlations, especially related to the clinical evolution, highlighting the particularities of each patient in a family context. We also emphasized the importance of genetic testing and patient monitoring to avoid acute aortic events. Full article

Background: There is a paucity of evidence on people with thoracic aortic aneurysm and dissection. We aimed to determine the prevalence of genetic variants and their associations with phenotypes. Methods: In this cross-sectional single-centre cohort study of consecutive patients who underwent endovascular or open-surgical repair of thoracic aortic aneurysm and dissection, genetic analysis was performed using four-stage Next Generation Sequencing, and findings were confirmed with Sanger sequencing. We collected personal and family history on comorbidities, clinical examination, anthropometrics, skeletal deformities, joint function, and ophthalmological measures. Cardiovascular risk and phenotype scores were calculated. Results: Ninety-five patients were eligible (mean age 54 ± 9 years, 70% males, 56% aortic dissection). One-fifth had a family history of aortic disease. Furthermore, 95% and 54% had a phenotype score of ≤5 and ≤2, respectively. There were no significant differences in the distribution of phenotype characteristics according to age, sex, aortic pathology, or performed invasive procedures. Genetic variants of uncertain significance were detected in 40% of patients, with classic mutations comprising 18% of all variants. We observed no significant association with cardiovascular and phenotype scores but with higher joint function scores (p = 0.015). Conclusion: Genetic variants are highly present in clinically relevant aortic pathologies. Variants appear to play a larger role than previously described. The different variants do not correlate with specific phenotypes, age, pathology, sex, or family history. Full article

Objective: Thoracic aortic aneurysm dissection (TAAD) represents a cardiac surgery emergency characterized by the disrupted integrity of the aortic wall and is associated with poor prognosis. In this context, the identification of biomarkers implicated in the pathobiology of TAAD is crucial. Our aim in the present original in silico study is to assess the differential gene expression profile of the tight junction proteins (TJPs) in patients with TAAD and to propose novel biomarkers for the diagnosis and prognosis of this disease. Methods: We implemented bioinformatics methodology in order to construct the gene network of the TJPs family, identify the differentially expressed genes (DEGs) in pathologic aortic tissue excised from patients with TAAD as compared to healthy aortic tissue, and assess the related biological functions and the associated miRNA families. Results: Data regarding the transcriptomic profile of selected genes were retrieved and incorporated from three microarray datasets, including 23 TAAD and 20 healthy control samples. A total of 32 TJPs were assessed. The zona occludens 2 (ZO-2) protein encoded by the gene TJP2 was significantly under-expressed in patients with TAAD compared to the control group (p = 0.009). ZO-2 was associated with fair discrimination and calibration traits in predicting the TAAD presentation. CpG islands of ZO-2 were demonstrated. No important difference was found regarding ZO-2 expression between aneurysmal non-dissected and healthy control aortic tissue. Finally, we performed gene set enrichment analysis (GSEA) and uncovered the major biological functions and miRNA families (hsa-miR-155-5p, hsa-miR-1-3p, hsa-miR-2118-5p, hsa-miR-4691-3p, and hsa-miR-1229-3p) relevant to ZO-2. Conclusions: These outcomes demonstrated the important role of ZO-2 in the pathobiology of TAAD. Full article

Familial thoracic aortic aneurysms and dissections may occur as an isolated hereditary trait or as part of connective tissue disorders with Mendelian inheritance, but severe cardiovascular disease in pediatric patients is extremely rare. There is growing knowledge on pathogenic variants causing the disease; however, much of the phenotypic variability and gene–gene interactions remain to be discovered. We present a case report of a 5.5-year-old girl with an aortic aneurysm and concomitant polycystic kidney disease. Whole exome sequencing was performed, followed by family screening by amplicon deep sequencing and diagnostic imaging studies. In the proband, two pathogenic variants were identified: p.Tyr257Ter in the LOX gene inherited from her mother, and p.Thr2977Ile in the PKD1 gene inherited from her father. All adult carriers of either of these variants showed symptoms of aortic disease. We conclude that the coexistence of two independent genetic variants in the proband may be the reason for an early onset of disease. Full article

Several genetic defects, including a mutation in myosin heavy chain 11 (Myh11), are reported to cause familial thoracic aortic aneurysm and dissection (FTAAD). We recently showed that mice lacking K1256 of Myh11 developed aortic dissection when stimulated with angiotensin II, despite the absence of major pathological phenotypic abnormalities prior to stimulation. In this study, we used a comprehensive, data-driven, unbiased, multi-omics approach to find underlying changes in transcription and metabolism that predispose the aorta to dissection in mice harboring the Myh11 K1256del mutation. Pathway analysis of transcriptomes showed that genes involved in membrane transport were downregulated in homozygous mutant (Myh11^ΔK/ΔK) aortas. Furthermore, expanding the analysis with metabolomics showed that two mechanisms that raise the cytosolic Ca²⁺ concentration—multiple calcium channel expression and ADP–ribose synthesis—were attenuated in Myh11^ΔK/ΔK aortas. We suggest that the impairment of the Ca²⁺ influx attenuates aortic contraction and that suboptimal contraction predisposes the aorta to dissection. Full article

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. Full article

Background: KIF6 (kinesin family member 6), a protein coded by the KIF6 gene, serves an important intracellular function to transport organelles along microtubules. In a pilot study, we found that a common KIF6 Trp719Arg variant increased the propensity of thoracic aortic aneurysms (TAA) to suffer dissection (AD). The present study aims for a definite investigation of the predictive ability of KIF6 719Arg vis à vis AD. Confirmatory findings would enhance natural history prediction in TAA. Methods: 1108 subjects (899 aneurysm and 209 dissection patients) had KIF6 719Arg variant status determined. Results: The 719Arg variant in the KIF6 gene correlated strongly with occurrence of AD. Specifically, KIF6 719Arg positivity (homozygous or heterozygous) was substantially more common in dissectors (69.8%) than non-dissectors (58.5%) (p = 0.003). Odds ratios (OR) for suffering aortic dissection ranged from 1.77 to 1.94 for Arg carriers in various dissection categories. These high OR associations were noted for both ascending and descending aneurysms and for homozygous and heterozygous Arg variant patients. The rate of aortic dissection over time was significantly higher for carriers of the Arg allele (p = 0.004). Additionally, Arg allele carriers were more likely to reach the combined endpoint of dissection or death (p = 0.03). Conclusions: We demonstrate the marked adverse impact of the 719Arg variant of the KIF6 gene on the likelihood that a TAA patient will suffer aortic dissection. Clinical assessment of the variant status of this molecularly important gene may provide a valuable “non-size” criterion to enhance surgical decision making above and beyond the currently used metric of aortic size (diameter). Full article

Aortic diseases are a rare but potentially life-threatening condition. We present a serum proteomic study for a spectrum of aortic diseases including thoracic aortic aneurysms (n = 11), chronic dissections (n = 9), acute aortic dissections (n = 11), and surgically treated dissections (n = 19) as well as healthy controls (n = 10) and patients of coronary heart disease (n = 10) to represent non-aortic cardiovascular disease. In total, we identified and quantified 425 proteins across all 70 samples. The different aortic diseases represented distinguishable proteome profiles. We identified protein clusters that positively or negatively correlate with disease severity, including increase of cytosolic tissue leakage proteins and decrease of components of the coagulation and complement system. Further, we identified a serum proteome fingerprint of acute aortic dissections, consisting, among others, of enriched inflammatory markers such as C-reactive protein and members of the S100 protein family. The study underlines the applicability of serum proteomics for the investigation of aortic diseases and highlights the possibility to establish disease-specific prognostic markers. Full article