KLF15 maintains contractile phenotype of vascular smooth muscle cells and prevents thoracic aortic dissection by interacting with MRTFB.

Thoracic aortic dissection (TAD) is a highly dangerous cardiovascular disorder caused by weakening of the aortic wall, resulting in a sudden tear of the internal face. Progressive loss of the contractile apparatus in vascular smooth muscle cells (VSMCs) is a major event in TAD. Exploring the endogenous regulators essential for the contractile phenotype of VSMCs may aid the development of strategies to prevent TAD. Krüppel-like factor 15 (KLF15) overexpression was reported to inhibit TAD formation; however, the mechanisms by which KLF15 prevents TAD formation and whether KLF15 regulates the contractile phenotype of VSMCs in TAD are not well understood. Therefore, we investigated these unknown aspects of KLF15 function. We found that KLF15 expression was reduced in human TAD samples and ß-aminopropionitrile monofumarate-induced TAD mouse model. Klf15KO mice are susceptible to both ß-aminopropionitrile monofumarate- and angiotensin II-induced TAD. KLF15 deficiency results in reduced VSMC contractility and exacerbated vascular inflammation and extracellular matrix degradation. Mechanistically, KLF15 interacts with myocardin-related transcription factor B (MRTFB), a potent serum response factor coactivator that drives contractile gene expression. KLF15 silencing represses the MRTFB-induced activation of contractile genes in VSMCs. Thus, KLF15 cooperates with MRTFB to promote the expression of contractile genes in VSMCs, and its dysfunction may exacerbate TAD. These findings indicate that KLF15 may be a novel therapeutic target for the treatment of TAD.

X-linked genetic associations in sporadic thoracic aortic dissection.

The male predominance in sporadic thoracic aortic aneurysm and dissection (TAD) suggests that the X chromosome contributes to TAD, but this has not been tested. We investigated whether X-linked variation-common (minor allele frequency [MAF] ≥0.01) and rare (MAF <0.01)-was associated with sporadic TAD in three cohorts of European descent (Discovery: 364 cases, 874 controls; Replication: 516 cases, 440,131 controls, and ARIC [Atherosclerosis Risk in Communities study]: 753 cases, 2247 controls). For analysis of common variants, we applied a sex-stratified logistic regression model followed by a meta-analysis of sex-specific odds ratios. Furthermore, we conducted a meta-analysis of overlapping common variants between the Discovery and Replication cohorts. For analysis of rare variants, we used a sex-stratified optimized sequence kernel association test model. Common variants results showed no statistically significant findings in the Discovery cohort. An intergenic common variant near SPANXN1 was statistically significant in the Replication cohort (p = 1.81 × 10-8). The highest signal from the meta-analysis of the Discovery and Replication cohorts was a ZNF182 intronic common variant (p = 3.5 × 10-6). In rare variants results, RTL9 reached statistical significance (p = 5.15 × 10-5). Although most of our results were statistically insignificant, our analysis is the most comprehensive X-chromosome association analysis of sporadic TAD to date.

Causal Role for Neutrophil Elastase in Thoracic Aortic Dissection in Mice.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening aortic disease without effective medical treatment. Increasing evidence has suggested a role for NE (neutrophil elastase) in vascular diseases. In this study, we aimed at investigating a causal role for NE in TAD and exploring the molecular mechanisms involved. METHODS: ß-aminopropionitrile monofumarate was administrated in mice to induce TAD. NE deficiency mice, pharmacological inhibitor GW311616A, and adeno-associated virus-2-mediated in vivo gene transfer were applied to explore a causal role for NE and associated target gene in TAD formation. Multiple functional assays and biochemical analyses were conducted to unravel the underlying cellular and molecular mechanisms of NE in TAD. RESULTS: NE aortic gene expression and plasma activity was significantly increased during ß-aminopropionitrile monofumarate-induced TAD and in patients with acute TAD. NE deficiency prevents ß-aminopropionitrile monofumarate-induced TAD onset/development, and GW311616A administration ameliorated TAD formation/progression. Decreased levels of neutrophil extracellular traps, inflammatory cells, and MMP (matrix metalloproteinase)-2/9 were observed in NE-deficient mice. TBL1x (F-box-like/WD repeat-containing protein TBL1x) has been identified as a novel substrate and functional downstream target of NE in TAD. Loss-of-function studies revealed that NE mediated inflammatory cell transendothelial migration by modulating TBL1x-LTA4H (leukotriene A4 hydrolase) signaling and that NE regulated smooth muscle cell phenotype modulation under TAD pathological condition by regulating TBL1x-MECP2 (methyl CpG-binding protein 2) signal axis. Further mechanistic studies showed that TBL1x inhibition decreased the binding of TBL1x and HDAC3 (histone deacetylase 3) to MECP2 and LTA4H gene promoters, respectively. Finally, adeno-associated virus-2-mediated Tbl1x gene knockdown in aortic smooth muscle cells confirmed a regulatory role for TBL1x in NE-mediated TAD formation. CONCLUSIONS: We unravel a critical role of NE and its target TBL1x in regulating inflammatory cell migration and smooth muscle cell phenotype modulation in the context of TAD. Our findings suggest that the NE-TBL1x signal axis represents a valuable therapeutic for treating high-risk TAD patients.

18F-fluorodeoxyglucose uptake patterns in positron emission tomography/computed tomography caused by inflammation and/or infection after graft surgery for thoracic aortic dissection.

BACKGROUND: To identify 18F-fluorodeoxyglucose (FDG) uptake patterns in positron emission tomography/computed tomography (PET/CT) caused by infection, inflammation, surgical material, and/or graft coating. METHODS AND RESULTS: Of 610 consecutive patients with thoracic aortic graft surgery, 60 patients with 187 PET/CT were retrospectively included. We quantified FDG uptake in all grafts using maximum standardized uptake value (SUVmax) alone and in relation to liver background (SUVratio) and determined the uptake pattern. Mixed linear regression models with random slope and intercept were applied for the analysis of SUVratio over time and generalized estimating equations to analyze the associations with anastomosis uptake. FDG uptake was frequently focal (90%), higher in infected than in noninfected grafts (mean SUVratio 2.19; 95% CI 2.05-2.32 vs. 1.63; 1.46-1.79, P < 0.001), and decreasing slowly over time (SUVratio per year since surgery -0.048; 95% CI -0.15- 0.051, P = 0.34), without a difference in slope between infected and noninfected grafts (P = 0.52). There was no evidence of an interaction between SUVratio and use of BioGlue® surgical adhesive (intercept P = 0.73, slope P = 0.71), or graft coating (gelatin and collagen, all P > 0.7). FDG uptake at the anastomosis was more frequent in noninfected grafts than in infected grafts (66% vs. 21%, odds ratio (OR) 11.34; 95% CI 3.61-35.66, P < 0.001). This effect was attenuated by the use of BioGlue® (OR 5.05; 95% CI 0.45-56.9, P = 0.19). CONCLUSIONS: FDG uptake in PET/CT after thoracic aortic graft surgery is higher in infected grafts than in noninfected grafts. In noninfected grafts, focal uptake is also frequent, mostly anastomosis-associated, not associated with graft coating, and possibly affected by the use of BioGlue®.

PUM2 regulates the formation of thoracic aortic dissection through EFEMP1.

Thoracic aortic dissection (TAD) is a severe cardiovascular disease attributed to the abnormal phenotypic switch of vascular smooth muscle cells (VSMCs). We found that the RNA-binding protein PUM2 and the fibulin protein EFEMP1 were significantly decreased at the TAD anatomical site. Therefore, we constructed expression and silencing vectors for PUM2 and EFEMP1 to analyze differential expression. Overexpression of PUM2 inhibited VSMC proliferation and migration. Western blot analysis indicated that PUM2 overexpression in VSMCs upregulated α-SMA and SM22α and downregulated OPN and MMP2. Immunofluorescence demonstrated that PUM2 and EFEMP1 were co-expressed in VSMCs. Immunoprecipitation confirmed that PUM2 bound to EFEMP1 mRNA to promote EFEMP1 expression. An Ang-II-induced aortic dissection mouse model showed that PUM2 impedes the development of aortic dissection in vivo. Our study demonstrates that PUM2 inhibits the VSMC phenotypic switch to prevent aortic dissection by targeting EFEMP1 mRNA. These findings could assist the development of targeted therapy for TAD.

A harmful MYH11 variant detected in a family with thoracic aortic dissection and patent ductus arteriosus.

Thoracic aortic dissection (TAD) is an important cause of sudden cardiac death and is characterized by high morbidity, mortality, and a poor prognosis. Patent ductus arteriosus (PDA) is a common congenital heart disease. The pathogenesis of both TAD and PDA has been reported to be related to genetic factors. The MYH11 gene, which encodes myosin heavy chain 11, has been reported in individuals with both TAD and PDA. Herein, we first detected a harmful MYH11 missense variant (c. T3728C, p. L1243P) in a TAD and PDA family. This missense variant co-segregated with the TAD/PDA phenotype in this family of four individuals, providing evidence of its harmfulness. Histopathological examinations revealed the presence of fragmented, broken, and lessened elastic fibers and the deposition of proteoglycans in the median of aortic dissection. Moreover, the immunofluorescence results showed that the labeled MYH11 protein in the tissue of the aortic dissection was weaker than that in the normal aorta. We present this familial case to stress the necessity of postmortem genetic testing in such cases among forensic practices. Identifying those culprit gene variants can direct effective genetic counseling and personalized health management in family members (especially first-degree relatives) with high-risk genotypes.

Tomo-seq identifies NINJ1 as a potential target for anti-inflammatory strategy in thoracic aortic dissection.

BACKGROUND: Thoracic aortic dissection (TAD) is a life-threatening disease caused by an intimal tear in the aorta. The histological characteristics differ significantly between the tear area (TA) and the distant area. Previous studies have emphasized that certain specific genes tend to cluster at the TA. Obtaining a thorough understanding of the precise molecular signatures near the TA will assist in discovering therapeutic strategies for TAD. METHODS: We performed a paired comparison of the pathological patterns in the TA with that in the remote area (RA). We used Tomo-seq, genome-wide transcriptional profiling with spatial resolution, to obtain gene expression signatures spanning from the TA to the RA. Samples from multiple sporadic TAD patients and animal models were used to validate our findings. RESULTS: Pathological examination revealed that the TA of TAD exhibited more pronounced intimal hyperplasia, media degeneration, and inflammatory infiltration compared to the RA. The TA also had more apoptotic cells and CD31+α-SMA+ cells. Tomo-seq revealed four distinct gene expression patterns from the TA to the RA, which were inflammation, collagen catabolism, extracellular matrix remodeling, and cell stress, respectively. The spatial distribution of genes allowed us to identify genes that were potentially relevant with TAD. NINJ1 encoded the protein-mediated cytoplasmic membrane rupture, regulated tissue remodeling, showed high expression levels in the tear area, and co-expressed within the inflammatory pattern. The use of short hairpin RNA to reduce NINJ1 expression in the beta-aminopropionitrile-induced TAD model led to a significant decrease in TAD formation. Additionally, it resulted in reduced infiltration of inflammatory cells and a decrease in the number of CD31+α-SMA+ cells. The NINJ1-neutralizing antibody also demonstrated comparable therapeutic effects and can effectively impede the formation of TAD. CONCLUSIONS: Our study showed that Tomo-seq had the advantage of obtaining spatial expression information of TAD across the TA and the RA. We pointed out that NINJ1 may be involved in inflammation and tissue remodeling, which played an important role in the formation of TAD. NINJ1 may serve as a potential therapeutic target for TAD.

[Latest Findings on the Pathogenic Mechanisms of Thoracic Aortic Dissection].

Thoracic aortic dissection (TAD) is a cardiovascular disease entailing a high lethality between 65% and 85%. Surgery-assissed implant/interventional stenting is the prevailing treatment of TAD. However, surgical treatment can cause severe postoperative complications and patients incur a relatively higher risk of postoperative mortality. Since the pathogenic mechanism underlying TAD is not clear, effective medication therapies are still not available. In recent years, along with advances in single-cell sequencing and other molecular biological technologies, there have been prelimiary findings suggesting the special role of dysfunctional vascular smooth muscle cells (VSMCs) in the pathogenesis and development of TAD. Furthermore, the molecular mechanisms regulating the dysfunction of VSMCs have been initially explored. It is expected that these new findings will contribute to the development of new strategies to prevent TAD and lead to new ideas for the identifiction of potential drug therapeutic targets. Herein, we summarized the critical role of dysfunctional VSMCs in the pathogenesis and development of TAD and presented in detail the biological factors and the related molecular mechanisms that regulate the dysfunction of VSMCs. We hope this review will provide a reference for further investigation into the central role of dysfunctional VSMCs in the pathogenesis and development of TAD and exploration for effective molecular drug targets for TAD.

Management of Thoracic Aortic Dissection.

This JAMA Clinical Guidelines Synopsis summarizes the 2021 guidelines from the American Association for Thoracic Surgery and the Society of Thoracic Surgeons on management of type A and type B thoracic aortic dissection.

Elucidating thoracic aortic dissection pathogenesis: The interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis.

The underlying molecular mechanisms of thoracic aortic dissection (TAD) remain incompletely understood. Recent insights into RNA methylation and microRNA-mediated gene regulation offer new avenues for exploring how these processes contribute to the pathophysiology of TAD, particularly through the modulation of pyroptosis and smooth muscle cell viability. This research aimed to elucidate the interplay of m1A-related gene expressions and miR-16-5p/YTHDC1 Axis in NLRP3-dependent pyroptosis, a mechanism implicated in the pathogenesis of TAD. We collected tissue samples from 28 human TAD patients and 8 healthy aortic group, as well as utilized a mouse model to replicate the disease. A combination of computational, in vitro, and in vivo methods was applied, including CIBERSORTx analysis, Pearson correlation, gene transfection using antagomiR-16-5p, siRNA, and several staining as well as cell culture techniques. Our analysis indicated two differentially expressed genes, ALKBH2 and YTHDC1. We found significant upregulation of has-miR-16-5p and downregulation of YTHDC1 at mRNA level in AD samples. Immune cell infiltration in TAD samples was examined using the CIBERSORTx database. We confirmed that YTHDC1 was a target of miR-16-5p, as evidenced by an inhibitory effect on luciferase activity. Inhibition of miR-16-5p enhanced SMC proliferation and promoted cell viability whilst downregulating NLRP3-pyroptosis. YTHDC1 expression was increased, and NLRP3-pyroptosis expressions were inhibited, suggesting miR-16-5p/YTHDC1 axis may involve the NLRP3-pyroptosis of the SMC. In vivo analyses confirmed the prevention of NLRP3-pyroptosis in middle layer of the thoracic aorta, implying that the miR-16-5p/YTHDC1 axis regulated SMC proliferation via NLRP3-pyroptosis signaling. Our findings underscored the anti-pyroptotic role of miR-16-5p/YTHDC1 axis in the pathogenesis of TAD, suggesting a potential therapeutic strategy via targeting YTHDC1 and suppressing miR-16-5p to inhibit NLRP3-dependent pyroptosis. Although further investigation is needed, these results relating to SMC proliferation are a significant step forward in understanding TAD.

S100A4 Is a Key Facilitator of Thoracic Aortic Dissection.

Background: Thoracic aortic dissection (TAD) is one of the cardiovascular diseases with high incidence and fatality rates. Vascular smooth muscle cells (VSMCs) play a vital role in TAD formation. Recent studies have shown that extracellular S100A4 may participate in VSMCs regulation. However, the mechanism(s) underlying this association remains elusive. Consequently, this study investigated the role of S100A4 in VSMCs regulation and TAD formation. Methods: Hub genes were screened based on the transcriptome data of aortic dissection in the Gene Expression Synthesis database. Three-week-old male S100A4 overexpression (AAV9- S100A4 OE) and S100A4 knockdown (AAV9- S100A4 KD) mice were exposed to ß-aminopropionitrile monofumarate through drinking water for 28 days to create the murine TAD model. Results: S100A4 was observed to be the hub gene in aortic dissection. Furthermore, overexpression of S100A4 was exacerbated, whereas inhibition of S100A4 significantly improved TAD progression. In the TAD model, the S100A4 was observed to aggravate the phenotypic transition of VSMCs. Additionally, lysyl oxidase (LOX) was an important target of S100A4 in TAD. S100A4 interacted with LOX in VSMCs, reduced mature LOX (m-LOX), and decreased elastic fiber deposition, thereby disrupting extracellular matrix homeostasis and promoting TAD development. Elastic fiber deposition in human aortic tissues was negatively correlated with the expression of S100A4, which in turn, was negatively correlated with LOX. Conclusions: Our data showed that S100A4 modulates TADprogression, induces lysosomal degradation of m-LOX, and reduces the deposition of elastic fibers by interacting with LOX, thus contributing to the disruption of extracellular matrix homeostasis in TAD. These findings suggest that S100A4 may be a new target for the prevention and treatment of TAD.

Branched-chain amino acid catabolic defect in vascular smooth muscle cells drives thoracic aortic dissection via mTOR hyperactivation.

Metabolic reprogramming of vascular smooth muscle cell (VSMC) plays a critical role in the pathogenesis of thoracic aortic dissection (TAD). Previous researches have mainly focused on dysregulation of fatty acid or glucose metabolism, while the impact of amino acids catabolic disorder in VSMCs during the development of TAD remains elusive. Here, we identified branched-chain amino acid (BCAA) catabolic defect as a metabolic hallmark of TAD. The bioinformatics analysis and data from human aorta revealed impaired BCAA catabolism in TAD individuals. This was accompanied by upregulated branched-chain α-ketoacid dehydrogenase kinase (BCKDK) expression and BCKD E1 subunit alpha (BCKDHA) phosphorylation, enhanced vascular inflammation, and hyperactivation of mTOR signaling. Further in vivo experiments demonstrated that inhibition of BCKDK with BT2 (a BCKDK allosteric inhibitor) treatment dephosphorylated BCKDHA and re-activated BCAA catabolism, attenuated VSMCs phenotypic switching, alleviated aortic remodeling, mitochondrial reactive oxygen species (ROS) damage and vascular inflammation. Additionally, the beneficial actions of BT2 were validated in a TNF-α challenged murine VSMC cell line. Meanwhile, rapamycin conferred similar beneficial effects against VSMC phenotypic switching, cellular ROS damage as well as inflammatory response. However, co-treatment with MHY1485 (a classic mTOR activator) reversed the beneficial effects of BT2 by reactivating mTOR signaling. Taken together, the in vivo and in vitro evidence showed that impairment of BCAA catabolism resulted in aortic accumulation of BCAA and further caused VSMC phenotypic switching, mitochondrial ROS damage and inflammatory response via mTOR hyperactivation. BCKDK and mTOR signaling may serve as the potential drug targets for the prevention and treatment of TAD.

Targeted genetic analysis in a cohort of sporadic death from spontaneous rupture of thoracic aortic dissection in Han Chinese population.

PURPOSE: Thoracic aortic dissection (TAD) is a life-threatening cardiovascular disease that often results in sudden cardiac death (SCD). However, the genetic characteristics of individuals with TAD confirmed at autopsy have been rarely studied. Our objective was to determine the prevalence of pathogenic variants in TAD-associated genes in a cohort of sporadic deaths resulting from spontaneous rupture of TAD and identify relevant genotype-phenotype relationships in Han Chinese population. METHODS: We included sixty-one consecutive sporadic decedents whose primary cause of death was spontaneous rupture of TAD, and performed a whole exome sequencing based strategy comprising 26 known TAD-associated genes. RESULTS: We identified 7 pathogenic or likely pathogenic (P/LP) variants in 7 cases (11.48 %) and 22 variants of uncertain significance (VUS) in 22 cases (36.07 %). The FBN1 gene was found to be the major disease-causing gene. Notably, TAD decedents with P/LP variant exhibited significantly earlier mortality. Moreover, we reported for the first time that TAD decedents with P/LP variant had a shorter diagnosis and treatment time. CONCLUSION: Our study investigated the genetic characteristics of TAD individuals confirmed until autopsy in Han Chinese population. The findings enhanced the understanding of the genetic underpinnings of TAD and have significant implications for clinical management and forensic investigations.

Costunolide mitigates inflammation and promotes extracellualr matrix integrity of thoracic aortic dissection by inhibiting NF-κB signaling.

BACKGROUND: Thoracic aortic dissection (TAD) is one of the most fatal cardiovascular diseases. One of its important pathological characteristics is the local inflammatory response. Many studies have found that Macrophage polarization plays an extremely critical role in the inflammatory progression and tissue remodeling of TAD. Costunolide (CTD) has an improving effect on oxidative stress and inflammation in the body. However, whether it can promote the integrity of extracellular matrix in Aortic dissection and its mechanism are still unclear. METHODS: The male C57BL/6J mice were used to construct an animal model of TAD with ß-aminopropionitrile (BAPN) (100 mg/kg/day, lasting for 28 days), and then CTD (10 mg/kg or 100 mg/kg) was injected intraperitoneally for 28 days to check the survival rate, TAD incidence, aortic morphology and other indicators of the mice. Using hematoxylin-eosin (HE), Masson, Elastin van Gieson (EVG) staining, immunofluorescence (IF), and immunohistochemical staining, the study aimed to determine the therapeutic effects of CTD on an animal model with BAPN-induced TAD. To enhance the examination of the regulatory mechanism of CTD, we conducted transcriptome sequencing on arterial tissues of mice in both the BAPN group and the BAPN + CTD100 group. Next, ANG II were used to construct TAD model in vascular smooth muscle cells (VMSCs). The effects of CTD on the proliferation, migration, invasion, and apoptosis of ANG II-induced cells are to be detected. The expression of MMP2, MMP9, P65, and p-P65 in each group will be examined using Western blot. Finally, the overexpression of IκB kinaseß (IKKß) will be established in VMSCs cells to further explore the protective function of CTD. RESULTS: The result showed that CTD significantly inhibited BAPN induced mortality and TAD incidence in the animal model, improved aortic vascular morphology, promoted the integrity of extracellular matrix in TAD, reduced tissue inflammation, reduced the accumulation of M1 macrophage, promoted M2 macrophage polarization, and reduced the expression of NF-κB pathway related proteins. Mechanistically, CTD significantly weakened the proliferation, migration, invasion, and apoptosis. p-P65 protein expression of TAD cells were induced by ANG II and IKK-ß. CONCLUSION: CTD has the potential to alleviate inflammation, VSMC apoptosis, MMP2/9 levels, and enhance extracellular matrix integrity in TAD by inhibiting the NF-κB signaling pathway.

KIF6 Trp719Arg Genetic Variant Increases Risk for Thoracic Aortic Dissection.

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).

Genetic architecture of thoracic aortic dissection in the female population.

BACKGROUND: Sex-related differences in cardiovascular disease are now gaining much more attention and their importance is increasingly being recognized, but little is known about the genetic distribution, genotype-phenotype correlation, and outcomes in the female population with thoracic aortic dissection (TAD). METHODS: One hundred seventy-nine Chinese female probands with TAD were enrolled from Tongji Hospital between October 2009 and October 2020. Genetic analysis was performed among 12 genes, and participants were subsequently followed up for a median of 38.2 months for TAD-related death. RESULTS: We identified 18 pathogenic or likely pathogenic variants among 18 (10.1%) probands and 21 variants of uncertain significance in 21 (11.7%) patients. Individuals with positive variants presented with a significant risk of TAD (OR: 12.0, 95% CI: 5.87-26.8), and an association between FBN1 (p = 2.60E-11, OR = 19.8), MYLK (p = 0.006, OR = 14.0) variants and an increased risk for female TAD was identified as well. Furthermore, nearly half of the variants were found in the FBN1 gene, which was significantly linked to early aortic dissection and tended to cause death at a young age. CONCLUSION: This study revealed the monogenic contribution of known TAD genes to the female TAD population with East Asian ancestry. Patients who tested positive for FBN1 were significantly younger at the time of aortic dissection and had a higher probability of dying at an early age.

Molecular genetic characterization of sudden deaths due to thoracic aortic dissection or rupture.

BACKGROUND: Sudden deaths due to thoracic aortic dissection or rupture (TADR) are often investigated by forensic pathologists in the United States. Up to a quarter of reported TADR result from a highly penetrant autosomal dominant single gene variant. Testing genes associated with familial TADR provides an underlying etiology for the cause of death and informs effective sudden death prevention for at-risk family members. At the New York City Office of Chief Medical Examiner (NYC-OCME), TADR cases are routinely tested by the in-house, CAP-accredited Molecular Genetics Laboratory. In this retrospective study, TADR and cardiovascular cases were reviewed to understand the burden of TADR in sudden deaths, value of molecular diagnostic testing in TADR, and genotype-phenotype correlations in a demographically diverse TADR cohort. METHODS: Between July 2019 and June 2022, cases with in-house cardiovascular genetic testing at NYC-OCME were retrospectively reviewed. Twenty genes associated with familial TADR were analyzed using high throughput massive parallel sequencing on postmortem tissues or bloodspot cards. Variant interpretation was conducted according to ACMG/AMP guidelines. RESULTS: A total of 1078 cases were tested for cardiovascular genetic conditions, of which 34 (3%) had TADR. Eight of those TADR cases had a pathogenic or likely pathogenic variant (P/LPV), 4 had a variant of uncertain significance (VUS), and 22 cases were negative for variants in TADR genes. The molecular diagnostic yield using the TADR subpanel was 23.5%. The genes with the greatest prevalence of P/LPV were FBN1 (6), followed by TGFBR2 (2), TGFBR1 (1), and MYLK (1). Highly penetrant P/LPV in TGFBR2, FBN1, and TGFBR1 were found in TADR individuals who died younger than 34 years old. Two P/LPV in FBN1 were secondary findings unrelated to cause of death. P/LPV in FBN1 included five truncating variants located in the N-terminal domains and one missense variant involved in the disulfide bonds of the EGF-like domain. All P/LPV in TGFBR1 and TGFBR2 were missense or in-frame deletion variants located in the protein kinase catalytic domain. Three variants were first reported in this study. CONCLUSIONS: Molecular testing of familial TADR-associated genes is a highly effective tool to identify the genetic cause of TADR sudden deaths and benefits surviving at-risk families.

Surgical treatment of double aortic arch malformation combined with descending aortic arch dissection in adults: a case series.

BACKGROUND: Double aortic arch (DAA) combined with descending aortic arch dissection (DAAD) in adults is a rare aorta vascular disease. Due to the abnormal anatomy of the double arch and arch vessels, the clinical symptoms and surgical methods differ from those of typical aortic dissection. METHODS: This study was retrospective analysis of a case series involving three patients (mean age, 47.3 years) with DAA combined DAAD underwent total arch replacement or hybrid aortic repair from September 2010 to June 2019. The patients' demographics, initial symptoms, comorbidities, surgical procedures, and outcomes are summarized. RESULTS: Total arch replacement plus frozen stent implantation under deep hypothermic circulatory arrest was performed for 2 patients, one of them developed disseminated intravascular coagulation and multiple organ failure postoperatively. Case 3 underwent a hybrid procedure with left subclavian artery revascularization and thoracic endovascular aortic repair. The symptoms of hoarseness and dysphagia were obviously improved during the follow up. CONCLUSION: In addition to typical sudden chest and back pain, patients with DAA and DAAD may have hoarseness and dysphagia. Based on the development of DAA, total arch replacement or hybrid surgery may be is an optional treatment.