Thoracic Aortic Aneurysms And Dissections Research Articles

Evaluation of the Value of Histological Examination for the Prediction of Genetic Thoracic Proximal Aortopathies.

Background: Heritable connective tissue disorders are often accompanied by an increased risk for thoracic aortic aneurysm and dissection (TAAD). Profound knowledge of the underlying pathology may have an impact on individual treatment, systematic follow-up, and early detection by the screening of offspring. The aim of this study, based in a single high-volume tertiary center, was an analysis of the diagnostic validity of histopathologic findings in patients with TAAD due to these findings' accuracy in diagnosing heritable connective tissue disorders. Methods: Therefore, genetic testing by next-generation sequencing (NGS) was performed to evaluate the correlations. In total, 65 patients with TAAD undergoing surgical treatment before the age of 60 years or with age up to 80 years if they had offspring at the time of the procedure were included in the analysis. Results: In our cohort, no certain correlation of histological findings to the results of genetic diagnostics in patients with clinically relevant aortic pathology could be shown. Patients with histopathologic findings for heritable connective tissue disorder and a positive gene variant were 11.6 years younger than patients without mutation and without histological evidence for connective tissue disorder. Conclusions: Genetic clarification is useful to define the specific genotype of the disease of the aortic wall in the case of non-specific histological characteristics.

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Nerve growth factor (Ngf) gene-driven semaphorin 3a (Sema3a) expression exacerbates thoracic aortic aneurysm dissection in mice.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf -driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely NgfSema3a/Sema3a mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by β-aminopropionitrile monofumarate (BAPN) both in NgfSema3a/Sema3a mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in NgfSema3a/Sema3a mice than in wild-type (WT) mice. In addition, NgfSema3a/Sema3a mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from NgfSema3a/Sema3a mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf -driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of NgfSema3a/Sema3a mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies.

In search of genetic modifiers that explain the phenotypic variability in SMAD3-related aortopathy

Abstract Introduction Loeys-Dietz Syndrome (LDS) is an autosomal dominant connective tissue disorder presenting with thoracic aortic aneurysm and dissection (TAAD). Remarkably, some LDS patients remain cardiovascularly unaffected throughout life, while others carrying the exact same genetic variant die early because of an aortic dissection. We hypothesize that genetic modifiers are the basis of this observation. Objectives Identify genetic modifiers that explain the variability in LDS-related aortopathy. Generate a patient-specific iPSC-vascular smooth muscle cell (VSMC) model to allow functional validation of genetic modifiers. Material and Methods We have access to a large LDS family segregating a pathogenic SMAD3 (p.Arg287Gln) variant. Identification of candidate modifiers in this family encompasses genome-wide SNP-based linkage analysis (n=19, available mutation carriers) and WGS (3 affected (AMC) and 4 unaffected mutation carriers (UMC)). Subsequent functional validation involves CRISPR/Cas-based modifier correction in iPSC-VSMCs of an affected variant carrier, which are created using the CytoTune iPS 2.0 Kit and the Granata et al. VSMC differentiation protocols. Results Linkage analysis suggests the presence of an aggravating modifier at chr2 (LOD: 2.68). The region of 6 Mb contains 19 protein coding genes of which the TNFAIP6 gene was ToppGene prioritized. There were no exonic variants in any of the genes that segregate with affection status at MAF 0.01%. However, we are currently adapting the the filtering strategy and will look into more common variants, MAF 10% for exonic and MAF 5% for intronic variants. iPSCs of an AMC and its isogenic control were created. They express core pluripotency markers and possess trilineage differentiation potential in the absence of the Sendai vectors. SNP array confirmed the genomic stability and identity of the cells. Conclusion and Future Work The obtained data suggest the presence of an aggravating modifier at chr2. Further analyses are ongoing to pinpoint the exact modifier variant explaining the linkage signal. Subsequently, the identified modifier(s) will be modelled in an in-vitro created iPSC-VSMC model.

Epigenetic Induction of Smooth Muscle Cell Phenotypic Alterations in Aortic Aneurysms and Dissections.

Smooth muscle cell (SMC) phenotypic switching has been increasingly detected in aortic aneurysm and dissection (AAD) tissues. However, the diverse SMC phenotypes in AAD tissues and the mechanisms driving SMC phenotypic alterations remain to be identified. We examined the transcriptomic and epigenomic dynamics of aortic SMC phenotypic changes in mice with angiotensin II-induced AAD by using single-cell RNA sequencing and single-cell sequencing assay for transposase-accessible chromatin. SMC phenotypic alteration in aortas from patients with ascending thoracic AAD was examined by using single-cell RNA sequencing analysis. Single-cell RNA sequencing analysis revealed that aortic stress induced the transition of SMCs from a primary contractile phenotype to proliferative, extracellular matrix-producing, and inflammatory phenotypes. Lineage tracing showed the complete transformation of SMCs to fibroblasts and macrophages. Single-cell sequencing assay for transposase-accessible chromatin analysis indicated that these phenotypic alterations were controlled by chromatin remodeling marked by the reduced chromatin accessibility of contractile genes and the induced chromatin accessibility of genes involved in proliferation, extracellular matrix, and inflammation. IRF3 (interferon regulatory factor 3), a proinflammatory transcription factor activated by cytosolic DNA, was identified as a key driver of the transition of aortic SMCs from a contractile phenotype to an inflammatory phenotype. In cultured SMCs, cytosolic DNA signaled through its sensor STING (stimulator of interferon genes)-TBK1 (tank-binding kinase 1) to activate IRF3, which bound and recruited EZH2 (enhancer of zeste homolog 2) to contractile genes to induce repressive H3K27me3 modification and gene suppression. In contrast, double-stranded DNA-STING-IRF3 signaling induced inflammatory gene expression in SMCs. In Sting-/- mice, the aortic stress-induced transition of SMCs into an inflammatory phenotype was prevented, and SMC populations were preserved. Finally, profound SMC phenotypic alterations toward diverse directions were detected in human ascending thoracic AAD tissues. Our study reveals the dynamic epigenetic induction of SMC phenotypic alterations in AAD. DNA damage and cytosolic leakage drive SMCs from a contractile phenotype to an inflammatory phenotype.

Emerging role of radiogenomics in genetically triggered thoracic aortic aneurysm and dissection: a narrative review.

Thoracic aortic aneurysm and dissection (TAAD) and its complications are life-threatening conditions. Hypertension and atherosclerosis had all along been recognized as the predominant risk factors for the development of TAAD. However, it was increasingly reported that genetic factors, such as single nucleotide polymorphisms (SNPs), are playing an important role in the disease development. The development of next-generation sequencing (NGS) and the rapid growth in radiomics provide a promising new platform to evaluate genetically triggered thoracic aortic aneurysm and dissection (GTAAD) from a new angle. This review is to present an overview of currently available knowledge regarding the use of radiomics and radiogenomics in GTAAD. We performed literature searches in PubMed, EMBASE and Cochrane database from 2012 to 2022 regarding the use of radiomics and radiogenomics in GTAAD. There were only 13 studies on radiomics and 4 studies on radiogenomics integration retrieved from the search and it signifies there is still a significant knowledge gap in this field of translational medicine. An overview of the current knowledge of GTAAD, the workflow and role of radiomics, the radiogenomics integration for GTAAD including its potential role in the development of polygenic scores, as well as the implications, challenges, and limitations of radiogenomics research were discussed. In the contemporary era, radiogenomics has been emerging as a state-of-the art approach to establish statistical correlation with radiomics features with genomic information in diagnosis, risk modeling and prediction and treatment decision in TAAD.

The Role of ADAMTS Proteoglycanases in Thoracic Aortic Disease.

Thoracic aortic aneurysm and dissection (TAAD) are complex disease states with high morbidity and mortality that pose significant challenges to early diagnosis. Patients with an aneurysm are asymptomatic and typically present to the emergency department only after the development of a dissection. The extracellular matrix (ECM) plays a crucial role in regulating the aortic structure and function. The histopathologic hallmark termed medial degeneration is characterised by smooth muscle cell (SMC) loss, the degradation of elastic and collagen fibres and proteoglycan (PG) accumulation. Covalently attached to the protein core of PGs are a number of glycosaminoglycan chains, negatively charged molecules that provide flexibility, compressibility, and viscoelasticity to the aorta. PG pooling in the media can produce discontinuities in the aortic wall leading to increased local stress. The accumulation of PGs is likely due to an imbalance between their synthesis by SMCs and decreased proteolysis by A Disintegrin-like and Metalloproteinase with Thrombospondin motifs (ADAMTS) proteoglycanases in the ECM. Mouse models of TAAD indicated that these proteases exert a crucial, albeit complex and not fully elucidated, role in this disease. This has led to a mounting interest in utilising ADAMTS proteoglycanases as biomarkers of TAAD. In this review, we discuss the role of ADAMTSs in thoracic aortic disease and their potential use in facilitating the clinical diagnosis of TAAD and disease progression.

Genome-wide association study of thoracic aortic aneurysm and dissection in the Million Veteran Program

The current understanding of the genetic determinants of thoracic aortic aneurysms and dissections (TAAD) has largely been informed through studies of rare, Mendelian forms of disease. Here, we conducted a genome-wide association study (GWAS) of TAAD, testing ~25 million DNA sequence variants in 8,626 participants with and 453,043 participants without TAAD in the Million Veteran Program, with replication in an independent sample of 4,459 individuals with and 512,463 without TAAD from six cohorts. We identified 21 TAAD risk loci, 17 of which have not been previously reported. We leverage multiple downstream analytic methods to identify causal TAAD risk genes and cell types and provide human genetic evidence that TAAD is a non-atherosclerotic aortic disorder distinct from other forms of vascular disease. Our results demonstrate that the genetic architecture of TAAD mirrors that of other complex traits and that it is not solely inherited through protein-altering variants of large effect size.

68Ga-labeled WVP peptide as a novel PET probe for molecular biological diagnosis of unstable thoracic aortic aneurysm and early dissection: an animal study.

Type IV collagen (Col-IV) is a prospective biomarker for diagnosing and treating of unstable thoracic aortic aneurysm and dissection (TAAD). This study aims to evaluate the feasibility of 68Ga-labeled WVP peptide (68Ga-DOTA-WVP) as a novel Col-IV-targeted probe for TAAD biological diagnosis using PET/CT. WVP peptide was modified with bifunctional chelator DOTA for 68Ga radiolabeling. Immunohistochemical staining was used to evaluate the expression and location of Col-IV and elastin in aortas treated with 3-aminopropionitrile fumarate (BAPN) at different time points (0, 2, and 4 weeks). The imaging performance of 68Ga-DOTA-WVP was investigated using Micro-PET/CT in a BAPN-induced TAAD mouse model. The relationship between 68Ga-DOTA-WVP uptake in aortic lesions and the serum levels of TAAD-related biomarkers including D-dimer, C-reactive protein (CRP), and serum soluble suppression of tumorigenicity-2 (sST2) was also analyzed. 68Ga-DOTA-WVP was readily prepared with high radiochemical purity and stability in vitro. 68Ga-DOTA-WVP Micro-PET/CT could detect Col-IV exposure of unstable aneurysms and early dissection in BAPN-induced TAAD mice, but little 68Ga-DOTA-WVP uptake was shown in the control group at each imaging time point. The differences of Col-IV expression and distribution of 68Ga-DOTA-WVP both in TAAD and control groups further verified the imaging efficiency of 68Ga-DOTA-WVP PET/CT. Additionally, a higher sST2 level was found in the imaging positive (n = 14) than the negative (n = 8) group (9.60 ± 1.14 vs. 8.44 ± 0.52, P = 0.014). 68Ga-DOTA-WVP could trace the exposure and abnormal deposition of Col-IV in enlarged and early injured aortas, showing a potential for biological diagnosis, whole-body screening, and progression monitoring of TAAD.

Thoracic aneurysm and dissection gene variants increase the risk of aortic-related adverse events in early-onset isolated Stanford type B aortic dissection after endovascular aortic repair.

Researches on Marfan syndrome and Ehlers-Danlos syndrome leading to early-onset aortic dissection (AD) emphasize the importance of gene variants, but the genetic pathogenesis, clinical characteristics and outcomes of early-onset isolated Stanford type B aortic dissection (iTBAD) patients remain unclear and need to be further elucidated. Isolated type B AD patients with an onset age of less than 50 years were enrolled in this study. Whole exome sequencing (WES) was performed to detect 11 known thoracic aortic aneurysm and dissection (TAAD) gene variants. Clinical characteristics and outcomes were compared between patients with and without gene variants. Multivariate Cox regression analysis was performed to identify independent risk factors for aortic-related adverse events (ARAEs) after endovascular aortic repair. A total of 37 patients were included. Ten patients carried 10 variants in five TAAD genes, four of whom carried pathogenic or likely pathogenic variants. Compared to patients without the variants, patients with variants had a lower incidence of hypertension (50.0% vs. 88.9%, P=0.021), a higher incidence of other vascular abnormalities (60.0% vs. 18.5%, P=0.038), all-cause mortality (40.0% vs. 3.7%, P=0.014) and aortic related mortality (30.0% vs. 3.7%, P=0.052). Multivariate analysis confirmed the presence of TAAD gene variants as the only independent risk factor for ARAEs [hazard ratio (HR) =4.00; 95% confidence interval (CI): 1.26-12.74; P=0.019]. Routine genetic testing is necessary for early-onset iTBAD patients. Individuals with a high risk of ARAEs can be identified by detecting TAAD gene variants, which is important for risk stratification and proper management.

Tandem mass tag-based quantitative proteomic analysis identification of succinylation related proteins in pathogenesis of thoracic aortic aneurysm and aortic dissection.

Thoracic aortic aneurysm and dissection (TAAD) are devastating cardiovascular diseases with a high rate of disability and mortality. Lysine succinylation, a newly found post-translational modification, has been reported to play an important role in cardiovascular diseases. However, how succinylation modification influences TAAD remains obscure. Ascending aortic tissues were obtained from patients with thoracic aortic aneurysm (TAA, n = 6), thoracic aortic dissection (TAD) with pre-existing aortic aneurysm (n = 6), and healthy subjects (n = 6). Global lysine succinylation level was analyzed by Western blotting. The differentially expressed proteins (DEPs) were analyzed by tandem mass tag (TMT) labeling and mass spectrometry. Succinylation-related proteins selected from the literature review and AmiGO database were set as a reference inventory for further analysis. Then, the pathological aortic sections were chosen to verify the proteomic results by Western blotting and qRT-PCR. The level of global lysine succinylation significantly increased in TAA and TAD patients compared with healthy subjects. Of all proteins identified by proteomic analysis, 197 common DEPs were screened both in TAA and TAD group compared with the control group, of which 93 proteins were significantly upregulated while 104 were downregulated. Among these 197 DEPs, OXCT1 overlapped with the succinylation-related proteins and was selected as the target protein involved in thoracic aortic pathogenesis. OXCT1 was further verified by Western blotting and qRT-PCR, and the results showed that OXCT1 in TAA and TAD patients was significantly lower than that in healthy donors (p < 0.001), which was consistent with the proteomic results. OXCT1 represents novel biomarkers for lysine succinylation of TAAD and might be a therapeutic target in the future.

Urate-Lowering Therapy Inhibits Thoracic Aortic Aneurysm and Dissection Formation in Mice.

Thoracic aortic aneurysm and dissection (TAAD) is a highly lethal vascular disease without effective drug therapy. Whether elevated serum concentrations of uric acid are involved in TAAD development remains unclear. Serum uric acid levels were detected in different TAAD mouse models and patients. The urate-lowering drug allopurinol was administered in the drinking water of TAAD mice. Adenine diet-induced mice were established to investigate the role of hyperuricemia in TAAD formation and RNA-sequencing of thoracic aortas from these mice was performed. We found serum uric acid levels were elevated in various mouse TAAD models, including mice fed a β-aminopropionitrile diet, Marfan mice with fibrillin-1 haploinsufficiency (Fbn1C1041G/+), and ApoE-/- mice infused with Ang II (angiotensin II), as well as in patients with TAAD. Administration of urate-lowering drug allopurinol in the drinking water significantly alleviated TAAD formation in β-aminopropionitrile-treated mice, Fbn1C1041G/+ mice, and Ang II-infused ApoE-/- mice. Moreover, an adenine diet was used to induce hyperuricemia in mice. Intriguingly, a 4-week adenine diet feeding directly induced TAAD formation characterized by increased maximal thoracic aortic diameters and severe elastin degradation, which were ameliorated by allopurinol. Unbiased RNA-sequencing in mouse thoracic aortas suggested that FcγR (Fc gamma receptor) was upregulated upon adenine diet, but reciprocally repressed by allopurinol. Mechanistically, hyperuricemia activated FcγR-mediated ERK1/2 (extracellular signal-regulated kinase 1/2) phosphorylation to induce macrophage inflammation and TAAD development, which was abrogated by allopurinol or FcγR deficiency. This study uncovered an important and previously unrecognized role of hyperuricemia in mediating the pathogenesis of TAAD, and uric acid-lowering drug may represent a promising therapeutic approach for TAAD.

ADAMTS-7 deficiency attenuates thoracic aortic aneurysm and dissection in mice.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening cardiovascular disease with severe extracellular matrix (ECM) remodeling that lacks efficient early stage diagnosis and nonsurgical therapy. A disintegrin and metalloproteinase with thrombospondin motif 7 (ADAMTS-7) is recognized as a novel locus for human coronary artery atherosclerosis. Previous work by us and others showed that ADAMTS-7 promoted atherosclerosis, postinjury neointima formation, and vascular calcification. However, whether ADAMTS-7 is involved in TAAD pathogenesis is unknown. We aimed to explore the alterations in ADAMTS-7 expression in human and mouse TAAD, and investigate the role of ADAMTS-7 in TAAD formation. A case-control study of TAAD patients (N = 86) and healthy participants (N = 88) was performed. The plasma ADAMTS-7 levels were markedly increased in TAAD patients within 24h and peaked in 7days. A TAAD mouse model was induced with 0.5% β-aminopropionitrile (BAPN) in drinking water. ELISA analysis of mouse plasma, Western blotting, and immunohistochemical staining of aorta showed an increase in ADAMTS-7 in the early stage of TAAD. Moreover, ADAMTS-7-deficient mice exhibited significantly attenuated TAAD formation and TAAD rupture-related mortality in both male and female mice, which was accompanied by reduced artery dilation and inhibited elastin degradation. ADAMTS-7 deficiency caused repressed inflammatory response and complement system activation during TAAD formation. An increase in plasma ADAMTS-7 is a novel biomarker for human TAAD. ADAMTS-7 deficiency attenuates BAPN-induced murine TAAD. ADAMTS-7 is a potential novel target for TAAD diagnosis and therapy. KEY MESSAGES: A case-control study revealed increased plasma ADAMTS-7 is a risk factor for TAAD. ADAMTS-7 was elevated in plasma and aorta at early stage of mouse TAAD. ADAMTS-7 knockout attenuated mouse TAAD formation and mortality in both sexes.

The matrix reloaded – Addressing structural integrity of the aortic wall in aneurysmal disease

Thoracic aortic aneurysms and dissections (TAADs) involve dilation of the aortic wall that can lead to tearing or rupture. Progressive extracellular matrix (ECM) degradation is common in TAAD, regardless of the underlying cause. TAAD treatments typically target cellular signaling pathways, rather than the ECM itself, due to the complex assembly process and long half-life of ECM proteins. Compounds that stabilize the ECM are proposed as an alternative TAAD therapy that addresses the underlying cause of aortic wall failure, namely compromised structural integrity. Compounds are discussed that revisit historical approaches to maintain and preserve structural integrity of biological tissues.

Targeting endothelial tight junctions to predict and protect thoracic aortic aneurysm and dissection.

Whether changes in endothelial tight junctions (TJs) lead to the formation of thoracic aortic aneurysm and dissection (TAAD) and serve as an early indicator and therapeutic target remains elusive. Single-cell RNA sequencing analysis showed aberrant endothelial TJ expressions in the thoracic aortas of patients with TAAD. In a β-aminopropionitrile (BAPN)-induced TAAD mouse model, endothelial TJ function was disrupted in the thoracic aortas at an early stage (5 and 10 days) as observed by a vascular permeability assay, while the intercellular distribution of crucial TJ components was significantly decreased by en face staining. For the non-invasive detection of endothelial TJ function, two dextrans of molecular weights 4 and 70 kDa were conjugated with the magnetic resonance imaging (MRI) contrast agent Gd-DOTA to synthesize FITC-dextran-DOTA-Gd and rhodamine B-dextran-DOTA-Gd. MRI images showed that both probes accumulated in the thoracic aortas of the BAPN-fed mice. Particularly, the mice with increased accumulated signals from 5 to 10 days developed TAAD at 14 days, whereas the mice with similar signals between the two time points did not. Furthermore, the protease-activated receptor 2 inhibitor AT-1001, which seals TJs, alleviated the BAPN-induced impairment of endothelial TJ function and expression and subsequently reduced TAAD incidence. Notably, endothelial-targeted ZO-1 conditional knockout increased TAAD incidence. Mechanistically, vascular inflammation and edema were observed in the thoracic aortas of the BAPN-fed mice, whereas these phenomena were attenuated by AT-1001. The disruption of endothelial TJ function is an early event prior to TAAD formation, herein serving as a potential indicator and a promising target for TAAD.

Unraveling the Genetic Complexity: A Case Report of MYLK Gene Mutation in a Patient with SCAD

Spontaneous Coronary Artery Dissection (SCAD) is a rare and potentially fatal disorder characterized by a tear in the wall of a coronary artery, leading to reduced blood flow to the heart. Although its exact cause remains elusive, SCAD is often associated with fibromuscular dysplasia and other connective tissue disorders. Here, we present a case of a 34-year-old African-American male with SCAD, hypertension, and obesity, whose family history included myocardial infarction, hypertension, and diabetes mellitus. Extensive imaging and cardiovascular evaluation revealed severe stenosis in the left anterior descending artery and a dissection flap in the left main coronary artery. Further genetic testing identified a variant of uncertain significance (VUS) in the MYLK gene, which has been linked to aortic dissections. While MYLK gene mutations have been reported in some SCAD and thoracic aortic aneurysm and dissection (TAAD) patients, they appear to be relatively rare. This case underscores the potential genetic basis of SCAD and highlights the importance of continued research to understand the role of MYLK gene mutations in SCAD and TAAD pathogenesis. Further investigation is warranted to determine the significance of the VUS identified in this patient

PM2.5 exposure exacerbates mice thoracic aortic aneurysm and dissection by inducing smooth muscle cell apoptosis via the MAPK pathway

Air pollution is a major public health concern worldwide. Exposure to fine particulate matter (PM2.5) is closely associated with cardiovascular diseases. However, the effect of PM2.5 exposure on thoracic aortic aneurysm and dissection (TAAD) has not been fully elucidated. Diesel exhaust particulate (DEP) is an important component of PM2.5, which causes health effects and is closely related to the incidence of cardiovascular disease. In the current study, we found that DEP exposure increased the incidence of aortic dissection (AD) in β-aminopropionitrile (BAPN)-induced thoracic aortic aneurysm (TAA). In addition, exposure to PM2.5 increased the diameter of the thoracic aorta in mice models. The number of apoptotic cells increased in the aortic wall of PM2.5-treated mice, as did the protein expression level of BAX/Bcl2 and cleaved caspase3/caspase3. Using a rhythmically stretching aortic mechanical simulation model, fluorescent staining indicated that PM2.5 administration could induce mitochondrial dysfunction and increase reactive oxygen species (ROS) levels in human aortic smooth muscle cells (HASMCs). Furthermore, ERK1/2 mitogen-activated protein kinase (MAPK) signaling pathways participated in the apoptosis of HASMCs after PM2.5 exposure. Therefore, we concluded that PM2.5 exposure could exacerbate the progression of TAAD, which could be induced by the increased apoptosis in HASMCs through the ERK1/2 MAPK signaling pathway.

Phospholipase Cε insufficiency causes ascending aortic aneurysm and dissection.

Phospholipase Cε (PLCε) is a phospholipase C isoform with a wide range of physiological functions. It has been implicated in aortic valve disorders, but its role in frequently associated aortic disease remains unclear. To determine the role of PLCε in thoracic aortic aneurysm and dissection (TAAD) we used PLCε-deficient mice, which develop aortic valve insufficiency and exhibit aortic dilation of the ascending thoracic aorta and arch without histopathological evidence of injury. Fourteen days of infusion of Plce1+/+ and Plce1-/- mice with angiotensin II (ANG II), which induces aortic dilation and dissection, led to sudden death secondary to ascending aortic dissection in 43% of Plce1-/- versus 5% of Plce1+/+ mice (P < 0.05). Medial degeneration and TAAD were detected in 80% of Plce1-/- compared with 10% of Plce1+/+ mice (P < 0.05) after 4 days of ANG II. Treatment with ANG II markedly increased PLCε expression within the ascending aortic adventitia. Total RNA sequencing demonstrated marked upregulation of inflammatory and fibrotic pathways mediated by interleukin-1β, interleukin-6, and tumor necrosis factor-α. In silico analysis of whole exome sequences of 258 patients with type A dissection identified 5 patients with nonsynonymous PLCE1 variants. Our data suggest that PLCε deficiency plays a role in the development of TAAD and aortic insufficiency.NEW & NOTEWORTHY We describe a novel phenotype by which PLCε deficiency predisposes to aortic valve insufficiency and ascending aortic aneurysm, dissection, and sudden death in the setting of ANG II-mediated hypertension. We demonstrate PLCE1 variants in patients with type A aortic dissection and aortic insufficiency, suggesting that PLCE1 may also play a role in human aortic disease. This finding is of very high significance because it has not been previously demonstrated that PLCε directly mediates aortic dissection.

Abstract 10884: X-Linked Genetic Associations in Sporadic Thoracic Aortic Aneurysm and Dissection

Introduction: The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) and the high prevalence of TAD in Turner syndrome patients suggest the contribution of X chromosome genes to TAD. However, such role has not been explored. Methods: We investigated whether X-linked variation, both common (Minor Allele Frequency (MAF) ≥0.01) and rare (MAF &lt;0.01), was associated with sporadic TAD in three datasets of European descent (dataset-1: 753 cases, 2247 controls; dataset-2: 253 cases, 282 controls; dataset-3: 364 cases, 874 controls). All cases were obtained from McGovern School of Medicine and Baylor College of Medicine; however, controls were obtained from the Atherosclerosis Risk in Communities study (dataset-1), the University of Washington Center for Mendelian Genomics (dataset-2), and the National Institute of Neurological Disorders and Stroke Repository (dataset-3). We applied a sex-stratified logistic regression model, followed by a meta-analysis of sex specific odds ratios for common variants, and an optimized sequence kernel association test model for rare variants. For top (P≤1x10 -3 ) common X-linked variants from the three datasets, we performed tissue enrichment analysis using a hypergeometric test. Results: The majority of cases (75%) were males. In dataset-2, common variant, rs55936630, in IGSF1 (P meta-analysis: 2.43x10 -7 ), reached X chromosome-wide significance. An additional 125 variants were suggestive of an association (P meta-analysis ≤1x10 -3 ) in at least one of the three datasets. Tissue enrichment identified a set of 12 X-linked genes that was significantly enriched in blood vessels (P: 3x10 -2 ). RTL9 (P: 5.15x10 -5 ; dataset-1) reached X chromosome-wide significance in rare variants analyses. Conclusions: This is the most comprehensive X-chromosome association analysis of TAD to date. Although most of our common variants did not reach X chromosome-wide significance, collectively testing these variants in tissue enrichment analysis identified a set of 12 X-linked genes that was significantly enriched in blood vessels. Among these 12 X-linked genes were C1GALT1C1 and DMD which were previously associated with vasculitis and arterial stiffness, respectively, both of which are risk factors for TAD.

Risk Factors for Thoracic Aortic Dissection.

Thoracic aortic aneurysms involving the root and/or the ascending aorta enlarge over time until an acute tear in the intimal layer leads to a highly fatal condition, an acute aortic dissection (AAD). These Stanford type A AADs, in which the tear occurs above the sinotubular junction, leading to the formation of a false lumen in the aortic wall that may extend to the arch and thoracoabdominal aorta. Type B AADs originate in the descending thoracic aorta just distal to the left subclavian artery. Genetic variants and various environmental conditions that disrupt the aortic wall integrity have been identified that increase the risk for thoracic aortic aneurysms and dissections (TAD). In this review, we discuss the predominant TAD-associated risk factors, focusing primarily on the non-genetic factors, and discuss the underlying mechanisms leading to TAD.