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Circular RNA (circRNA) has been found to be differentially expressed and involved in regulating the processes of human diseases, including thoracic aortic dissection (TAD). However, the role and mechanism of circNRIP1 in the TAD process are still unclear. GEO database was used to screen the differentially expressed circRNA and mRNA in type A TAD patients and age-matched normal donors. Angiotensin II (Ang II)-induced human aortic vascular smooth muscle cells (HA-VSMCs) were used to construct TAD cell models. The expression levels of circNRIP1, NRIP1, CXC-motif chemokine 5 (CXCL5) and IGF2BP1 were detected by quantitative real-time PCR. Cell proliferation and migration were determined by EdU assay, transwell assay and wound healing assay. The protein levels of synthetic phenotype markers, contractile phenotype markers, CXCL5 and IGF2BP1 were tested by western blot analysis. The interaction between IGF2BP1 and circNRIP1/CXCL5 was confirmed by RIP assay, and CXCL5 mRNA stability was assessed by actinomycin D assay. CircNRIP1 was upregulated in TAD patients and Ang II-induced HA-VSMCs. Knockdown of circNRIP1 suppressed Ang II-induced proliferation, migration and phenotypic switch of HA-VSMCs. Also, high expression of CXCL5 was observed in TAD patients, and its knockdown could inhibit Ang II-induced HA-VSMCs proliferation, migration and phenotypic switch. Moreover, CXCL5 overexpression reversed the regulation of circNRIP1 knockdown on Ang II-induced HA-VSMCs functions. Mechanistically, circNRIP1 could competitively bind to IGF2BP1 and subsequently enhance CXCL5 mRNA stability. CircNRIP1 might contribute to TAD progression by promoting CXCL5 mRNA stability via recruiting IGF2BP1. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the efficacy and clinical outcomes of accurate embolization of endoleaks after fenestrated thoracic endovascular aortic repair (F-TEVAR) for thoracic aortic dissections. Methods: Twenty patients with endoleaks (17 type I and 3 type II) after fenestrated thoracic endovascular aortic repair (F-TEVAR) were embolized using detachable and ordinary coils. We assessed the success rate and complications of the operation, and its effects, through clinical and CT follow-up. Results: The mean clinical follow-up duration was 25.68 ± 11.07 months (3–44 months). During follow-up, all endoleaks were completely embolized and aortic remodeling was improved. Secondary endoleaks occurred in four patients who were embolized twice. No other complications or death were reported. Conclusion: Embolization using detachable and ordinary coils is effective and safe for the treatment of endoleaks after fenestrated thoracic endovascular aortic repair. [ABSTRACT FROM AUTHOR]

Thoracic aortic dissection (TAD) is a life-threatening vascular disease manifested as intramural bleeding in the medial layers of the thoracic aorta. The key histopathologic feature of TAD is medial degeneration, characterized by depletion of vascular smooth muscle cells (VSMCs) and degradation of extracellular matrix (ECM). MicroRNA, as essential epigenetic regulators, can inhibit the protein expression of target genes without modifying the sequences. This study aimed to elucidate the role and underlying mechanism of miR-20a, a member of the miR-17-92 cluster, in regulating ECM degradation during the pathogenesis of TAD. The expression of the miR-17-92 cluster was significantly increased in synthetic VSMCs derived from TAD lesions compared to contractile VSMCs isolated from normal thoracic aortas. Notably, the expression of miR-20a was increased in VSMCs in response to serum exposure and various stimuli. In TAD lesions, the expression of miR-20a was significantly negatively correlated with that of elastin. Elevated expression of miR-20a was also observed in thoracic aortas of TAD mice induced by β-aminopropionitrile fumarate and angiotensin II. Overexpression of miR-20a via mimic transfection enhanced the growth and invasive capabilities of VSMCs, with no significant impact on their migratory activity or the expression of phenotypic markers (α-SMA, SM22, and OPN). Silencing of miR-20a with inhibitor transfection mitigated the hyperactivation of MMP2 in VSMCs stimulated by PDGF-bb, as evidenced by reduced levels of active-MMP2 and increased levels of pro-MMP2. Subsequently, TIMP2 was identified as a novel target gene of miR-20a. The role of miR-20a in promoting the activation of MMP2 was mediated by the suppression of TIMP2 expression in VSMCs. In addition, the elevated expression of miR-20a was found to be directly driven by Nanog in VSMCs. Collectively, these findings indicate that miR-20a plays a crucial role in maintaining the homeostasis of the thoracic aortic wall during TAD pathogenesis and may represent a potential therapeutic target for TAD.

Abstract Background Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in β-aminopropionitrile fumarate (BAPN)-induced TAD. Methods A mouse model of TAD induced by BAPN and IL-1β -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. Results We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. Conclusion ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target.

Background: Thoracic aortic dissection (TAD) is an irreversible cardiovascular disorder with high mortality and morbidity. However, the molecular mechanisms remain elusive. Thus, identifying an effective therapeutic target to prevent TAD is especially critical. The purpose of this study is to elucidate the potential mechanism of inflammation and vascular smooth muscle cell (VSMCs) phenotypic switch in β-aminopropionitrile fumarate (BAPN)-induced TAD. Methods: A mouse model of TAD induced by BAPN and IL-1β -stimulated HVSMCs in vivo and in vitro models, respectively. ACE2 Knockdown mice treated with BAPN or without, and the TAD mouse model was treated with or without AAV-ACE2. Transthoracic ultrasound was conducted for assessment the maximum internal diameter of the thoracic aorta arch. RNA sequencing analysis was performed to recapitulate transcriptome profile changes. Western blot were used to detect the expression of MMP2, MMP9, ACE2, SIRT3, OPN, SM22α and other inflammatory markers. The circulating levels of ACE2 was measured by ELISA assay. Histological changes of thoracic aorta tissues were assessed by H&E, EVG and IHC analysis. Results: We found that circulating levels of and the protein levels of ACE2 were increased in the TAD mouse model and in patients with TAD. For further evidence, ACE2 deficiency decelerated the formation of TAD. However, overexpression of ACE2 aggravated BAPN-induced aortic injury and VSMCs phenotypic switch via lowered SIRT3 expression and elevated inflammatory cytokine expression. Conclusion: ACE2 deficiency prevented the development of TAD by inhibiting inflammation and VSMCs phenotypic switch in a SIRT3-dependent manner, suggesting that the ACE2/SIRT3 signaling pathway played a pivotal role in the pathological process of TAD and might be a potential therapeutical target. Highlights: This study demonstrated for the first time that ACE2 deficiency attenuates the development of TAD induced by BAPN. The inhibitory effect of ACE2 deficiency on phenotypic transformation of VSMCs and inflammation may be through SIRT3 signaling pathway. Specific inhibition of SIRT3 can speed the exacerbation of TAD induced by BAPN and SIRT3 may be an important target for drug therapy of TAD. [ABSTRACT FROM AUTHOR]

Aortic aneurysm/ dissection is the primary cause of mortality in patients with Marfan syndrome (MFS). Though aberrant activation of the transforming growth factor-β(TGF-β) pathway has been considered the central pathogenic mechanism for MFS aortic aneurysms, recent research has gradually revealed the involvement of other signaling pathways in MFS. This review summarizes the latest researches on the molecular mechanisms of MFS, including classical TGF-β and related signaling pathways such as Notch and nitric oxide(NO), as well as epigenetics and gene therapy, which provide new insights for the prevention and treatment of MFS. [ABSTRACT FROM AUTHOR]

Thoracic aortic dissection (TAD) is characterized by extracellular matrix (ECM) dysregulation. Aberrations in the ECM stiffness can lead to changes in cellular functions. However, the mechanism by which ECM softening regulates vascular smooth muscle cell (VSMCs) phenotype switching remains unclear. To understand this mechanism, we cultured VSMCs in a soft extracellular matrix and discovered that the expression of microRNA (miR)-143/145, mediated by activation of the AKT signalling pathway, decreased significantly. Furthermore, overexpression of miR-143/145 reduced BAPN-induced aortic softening, switching the VSMC synthetic phenotype and the incidence of TAD in mice. Additionally, high-throughput sequencing of immunoprecipitated RNA indicated that the TEA domain transcription factor 1 (TEAD1) is a common target gene of miR-143/145, which was subsequently verified using a luciferase reporter assay. TEAD1 is upregulated in soft ECM hydrogels in vitro, whereas the switch to a synthetic phenotype in VSMCs decreases after TEAD1 knockdown. Finally, we verified that miR-143/145 levels are associated with disease severity and prognosis in patients with thoracic aortic dissection. ECM softening, as a result of promoting the VSMCs switch to a synthetic phenotype by downregulating miR-143/145, is an early trigger of TAD and provides a therapeutic target for this fatal disease. miR-143/145 plays a role in the early detection of aortic dissection and its severity and prognosis, which can offer information for future risk stratification of patients with dissection. [Display omitted] • ECM softening down-regulates miR-143/145 expression via AKT phosphorylation. • TEAD1 as a target of miR-143/145 linking ECM softening to VSMC phenotype switching. • miR-143/145 levels correlate with TAD severity and prognosis, suggesting biomarker potential. [ABSTRACT FROM AUTHOR]

Circular RNA (circRNA) has been found to be differentially expressed and involved in regulating the processes of human diseases, including thoracic aortic dissection (TAD). However, the role and mechanism of circNRIP1 in the TAD process are still unclear. GEO database was used to screen the differentially expressed circRNA and mRNA in type A TAD patients and age-matched normal donors. Angiotensin II (Ang II)-induced human aortic vascular smooth muscle cells (HA-VSMCs) were used to construct TAD cell models. The expression levels of circNRIP1, NRIP1, CXC-motif chemokine 5 (CXCL5) and IGF2BP1 were detected by quantitative real-time PCR. Cell proliferation and migration were determined by EdU assay, transwell assay and wound healing assay. The protein levels of synthetic phenotype markers, contractile phenotype markers, CXCL5 and IGF2BP1 were tested by western blot analysis. The interaction between IGF2BP1 and circNRIP1/CXCL5 was confirmed by RIP assay, and CXCL5 mRNA stability was assessed by actinomycin D assay. CircNRIP1 was upregulated in TAD patients and Ang II-induced HA-VSMCs. Knockdown of circNRIP1 suppressed Ang II-induced proliferation, migration and phenotypic switch of HA-VSMCs. Also, high expression of CXCL5 was observed in TAD patients, and its knockdown could inhibit Ang II-induced HA-VSMCs proliferation, migration and phenotypic switch. Moreover, CXCL5 overexpression reversed the regulation of circNRIP1 knockdown on Ang II-induced HA-VSMCs functions. Mechanistically, circNRIP1 could competitively bind to IGF2BP1 and subsequently enhance CXCL5 mRNA stability. CircNRIP1 might contribute to TAD progression by promoting CXCL5 mRNA stability via recruiting IGF2BP1.

BackgroundThoracic Aortic Dissection (TAD) is a life-threatening disease without effective drug treatments. The disruption of HASMCs homeostasis is one direct histopathologic alteration in TAD pathological process. Several miRNAs have been shown abnormally expressed in TAD and to regulate HASMCs homeostasis. The primary goal of this study is to identify the miRNAs and the specific mechanisms that lead to HASMCs homeostasis disruption.MethodsBulk miRNA sequencing was performed to explore the aberrantly expressed miRNA profile in TAD, and differentially expressed miRNAs were verified with qRT-PCR. To explore the role of the key miRNAs (miR-3529) in HASMCs homeostasis, we overexpressed this miRNA with lentivirus in HASMCs. Integrative transcriptomics and metabolomics analysis were used to uncover the functional roles of this miRNA in regulating HASMCs homeostasis. Further, the target gene of miR-3529 was predicted by bioinformatics and verified through a dual-luciferase reporter assay.ResultsBulk miRNA sequencing showed miR-3529 was elevated in TAD tissues and confirmed by qRT-PCR. Further experimental assay revealed miR-3529 upregulation induced HASMCs homeostasis disruption, accompanied by reducing contractile markers and increasing pro-inflammatory cytokines. Integrative transcriptomics and metabolomics analysis showed that miR-3529 overexpression altered the metabolic profile of HASMC, particularly lipid metabolism. ABCA1 was found to be a direct target of miR-3529. Mechanistically, the miR-3529/ABCA1 axis disrupted HASMCs homeostasis through the JAK2/STAT3 signaling pathway.ConclusionsmiR-3529 is elevated in TAD patients and disrupts HASMCs homeostasis by reprogramming metabolism through the JAK2/STAT3 signaling pathway. These findings favor a role for miR-3529 as a novel target for TAD therapy.

This case report elucidates the presentation and management of a 54-year-old man with type A aortic dissection (TAAD) in the emergency department. The patient, a known diabetic with uncontrolled hypertension and a history of heavy smoking, presented with severe central chest pain radiating to the back, accompanied by diaphoresis. Clinical evaluation revealed tachycardia and normotension. An immediate computed tomography angiogram confirmed the diagnosis of TAAD. The patient received timely medical intervention with intravenous beta-blockers and was prepared for a surgical consultation. This report underscores the critical importance of rapid diagnosis, effective blood pressure control, and multidisciplinary collaboration in the management of TAAD in the emergency setting, emphasizing contemporary evidence-based practices. While the article omits details on operative procedures, it notes that the patient was discharged in stable condition postsurgery, and at the 3-month follow-up, he is progressing well.

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. [ABSTRACT FROM AUTHOR]

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. [Display omitted] • Aortic BCAA catabolic defect is a previously unrecognized contributor to the pathogenesis of TAD. • Aortic BCAA catabolic defect results from the inhibitory phosphorylation of BCKDHA by BCKDK. • Aortic BCAA catabolic defect induced VSMC phenotypic switching and inflammatory response via mTOR hyperactivation. • BCKDK and mTOR signaling may serve as the potential drug targets for the treatment of TAD. [ABSTRACT FROM AUTHOR]

Abstract 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.

Background Acute type B aortic dissection is a cardiovascular emergency with considerable mortality and morbidity risk. Male–female differences have been observed in cardiovascular disease; however, literature on type B aortic dissection is scarce. Methods and Results A retrospective cohort study was conducted including all consecutive patients with acute type B aortic dissection between 2007 and 2017 in 4 tertiary hospitals using patient files and questionnaires for late morbidity. In total, 384 patients were included with a follow‐up of 6.1 (range, 0.02–14.8) years, of which 41% (n=156) were female. Women presented at an older age than men (67 [interquartile range (IQR), 57–73] versus 62 [IQR, 52–71]; P=0.015). Prior abdominal aortic aneurysm (6% versus 15%; P=0.009), distally extending dissections (71 versus 85%; P=0.001), and clinical malperfusion (18% versus 32%; P=0.002) were less frequently observed in women. Absolute maximal descending aortic diameters were smaller in women (36 [IQR: 33–40] mm versus 39 [IQR, 36–43] mm; P

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES The aim of this study was to evaluate the suitability of a subclavian unibody single-branch endograft among patients treated with thoracic endovascular aortic repair (TEVAR) in landing zone 2 (LZ2). METHODS This is a pre-clinical, single-centre, real-world, all-comers, retrospective cohort study. Patients treated with TEVAR in LZ2 with an available preoperative computed tomography angiography were included. The primary outcome was the anatomical feasibility of the Castor endograft in patients receiving endovascular treatment in LZ2 between 1999 and 2022. Secondary outcomes were: a comparison of feasible and unfeasible patients; frequencies and description of exclusion causes; non-feasibility risk factor analysis; and analysis of the stent graft configurations necessary to treat 75% of the patients. A logistic regression model was used to find associations between baseline morphological data and non-feasibility. RESULTS A total of 473 procedures were performed and 72 patients fulfilling inclusion criteria were included. The mean distance between the left carotid artery and left subclavian artery (or between innominate artery and bovine trunk) was 12.4 ± 5.2 mm and its average diameter was 33.0 ± 10.6 mm. The pre-vertebral left subclavian artery's diameter and length were 11.3 ± 2.5 and 38.7 ± 10.8 mm. Forty-nine (68.1%) patients were suitable for Castor implantation. Twenty-one configurations were required to treat 75% of feasible patients and might be lowered to 12 configurations applying less strict criteria. CONCLUSIONS The Castor endograft was anatomically feasible in several patients requiring TEVAR in LZ2. Three-quarters of feasible patients could be treated with a reasonable number of configurations, paving the path for future off-the-shelf applications. [ABSTRACT FROM AUTHOR]

Background: Acute type A aortic dissection (ATAAD) is a highly lethal event, associated with aortic dilatation. It is not well known if patient height, weight or sex impact the thoracic aortic diameter (TAA) at ATAAD. The study aim was to identify male–female differences in TAA at ATAAD presentation. Methods: This retrospective cross-sectional study analysed all adult patients who presented with ATAAD between 2007 and 2017 in two tertiary care centres and underwent contrast enhanced computed tomography (CTA) before surgery. Absolute aortic diameters were measured at the sinus of Valsalva (SoV), ascending (AA) and descending thoracic aorta (DA) using double oblique reconstruction, and indexed for body surface area (ASI) and height (AHI). Z-scores were calculated using the Campens formula. Results: In total, 59 % (181/308) of ATAAD patients had CT-scans eligible for measurements, with 82 female and 99 male patients. Females were significantly older than males (65.5 ± 12.4 years versus 60.3 ± 2.3, p = 0.024). Female patients had larger absolute AA diameters than male patients (51.0 mm [47.0–57.0] versus 49.0 mm [45.0–53.0], p = 0.023), and larger ASI and AHI at all three levels. Z-scores for the SoV and AA were significantly higher for female patients (2.99 ± 1.66 versus 1.34 ± 1.77, p

We aimed to explore the feasibility of 4D flow magnetic resonance imaging (MRI) for patients undergoing thoracic aorta endovascular repair (TEVAR). We retrospectively evaluated ten patients (two female), with a mean (±standard deviation) age of 61 ± 20 years, undergoing MRI for a follow-up after TEVAR. All 4D flow examinations were performed using a 1.5-T system (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany). In addition to the standard examination protocol, a 4D flow-sensitive 3D spatial-encoding, time-resolved, phase-contrast prototype sequence was acquired. Among our cases, flow evaluation was feasible in all patients, although we observed some artifacts in 3 out of 10 patients. Three individuals displayed a reduced signal within the vessel lumen where the endograft was placed, while others presented with turbulent or increased flow. An aortic endograft did not necessarily hinder the visualization of blood flow through 4D flow sequences, although the graft could generate flow artifacts in some cases. A 4D Flow MRI may represent the ideal tool to follow up on both healthy subjects deemed to be at an increased risk based on their anatomical characteristics or patients submitted to TEVAR for whom a surveillance protocol with computed tomography angiography would be cumbersome and unjustified. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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. Conclusions: OXCT1 represents novel biomarkers for lysine succinylation of TAAD and might be a therapeutic target in the future. [ABSTRACT FROM AUTHOR]

Background: Sudden unexpected cardiac arrest is one of the life-threatening interventions of the pre hospital emergency medicine teams. Globally sudden cardiac death (SCD) accounts for 4-5 million deaths per year and is in most cases linked to coronary artery disease. Other causes include cardiomyopathies and channelopathies, but these are not always clear to the physician. Case Presentation: We present two unconscious patients with life-threatening cardiac arrests who were unsuccessfully resuscitated by the emergency team. As the cause of the sudden cardiac arrest was unclear an autopsy was performed. Conclusion: SCD can be the final stage of several pathologies. In acute myocardial infarction due to coronary artery disease, the underlying cause is clear. The situation is however more complex in drug abuse where the physician should be aware that underlying pathologies can be masked. If the cause of sudden cardiac arrest is unclear, a "molecular" autopsy is recommended to detect genetic susceptibility to dysrhythmias (long QT syndrome, Brugada syndrome), cardiomyopathies, thoracic aortic aneurysm, and dissection. Correlating significant clinical information, postmortem findings and genetic analysis can be used to detect underlying pathologies and to decide whether genetic screening and clinical follow up of relatives should be carried out. [ABSTRACT FROM AUTHOR]

Vascular inflammation triggers the development of thoracic aortic dissection (TAD). Zinc deficiency could dampen tissue inflammation. However, the role of zinc as a nutritional intervention in the progression of TAD remains elusive. In this study, we employed a classical β-aminopropionitrile monofumarate (BAPN)-induced TAD model in mice treated with low zinc and observed that the TAD progression was greatly ameliorated under low zinc conditions. Our results showed that low zinc could significantly improve aortic dissection and rupture (BAPN + low zinc vs. BAPN, 36% vs. 100%) and reduce mortality (BAPN + low zinc vs. BAPN, 22% vs. 57%). Mechanically, low zinc attenuated the infiltration of macrophages and inhibited the expression of inflammatory cytokines, suppressed the phenotype switch of vascular smooth muscle cells from contractile to synthetic types, and eventually alleviated the development of TAD. In conclusion, this study suggested that low zinc may serve as a potential nutritional intervention approach for TAD prevention. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the potential effect of EphrinB2 in human thoracic aortic dissection (TAD) and to illustrate the mechanisms governing the role of EphrinB2 in the growth of human aortic smooth muscle cells (HASMC). Methods: In the study, EphrinB2 expression was investigated by qRT-PCR and immunohistochemistry in 12 pairs of TAD and adjacent human tissues. HASMCs were used for in vitro experiments. Next, EphrinB2 overexpression and depletion in HASMCs were established by EphrinB2-overexpressing vectors and small interfering RNA, respectively. The transfection efficiency was evaluated by qRT-PCR and Western blot. The effects of overexpression and depletion of EphrinB2 on cell proliferation, migration, and invasion were tested in vitro. Cell Counting Kit-8, flow cytometry and transwell migration/invasion, and wound healing assay were used to explore the function of EphrinB2 on HASMC cell lines. The relationship between EphrinB2 and F-actin was assessed by Western blot, immunofluorescence, and Co-IP. Results: We found that EphrinB2 was a prognostic biomarker of TAD patients. Moreover, EphrinB2 expression negatively correlated to aortic dissection tissues, and disease incidence of males, suggesting that EphrinB2 might act as a TAD suppressor by promoting proliferation or decreasing apoptosis in HASMC. Next, over-expression of EphrinB2 in HASMC lines drove cell proliferation, migration, and invasion, and inhibited apoptosis while knockdown EphrinB2 showed the opposite phenomenon, respectively. Furthermore, the level of F-actin in mRNA, protein, and distribution in HASMC cell lines highly matched with the expression of EphrinB2, which indicated that EphrinB2 could mediate the HASMC cytoskeleton via inducing F-actin. Conclusions: In conclusion, our results first provided the pivotal role of EphrinB2 in HASMC proliferation initiated by mediating F-actin and demonstrated a prognostic biomarker and the potential targets for therapy to prevent thoracic aortic dissection. [ABSTRACT FROM AUTHOR]

Background: The molecular mechanisms associated with thoracic aortic dissection (TAD) remain poorly understood. A comprehensive high-throughput sequencing-based analysis of the circRNA–miRNA–mRNA competitive endogenous RNA (ceRNA) regulatory network in TAD has not been conducted. The purpose of this study is to identify and verify the key ceRNA networks which may have crucial biological functions in the pathogenesis of TAD. Methods: Gene expression profiles of the GSE97745, GSE98770, and GSE52093 datasets were acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the GEO2R tools. Protein–protein interaction (PPI) networks of the hub genes were constructed using STRING; the hub genes and modules were identified by MCODE and CytoHubba plugins of the Cytoscape. We analyzed the hub genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The functions of these hub genes were assessed using Cytoscape software. Our data—along with data from GSE97745, GSE98770, and GSE52093—were used to verify the findings. Results: Upon combined biological prediction, a total of 11 ce-circRNAs, 11 ce-miRNAs, and 26 ce-mRNAs were screened to construct a circRNA–miRNA–mRNA ceRNA network. PPI network and module analysis identified four hub nodes, including IGF1R, JAK2, CSF1, and GAB1. Genes associated with the Ras and PI3K-Akt signaling pathways were clustered in the four hub node modules in TAD. The node degrees were most significant for IGF1R, which were also the most significant in the two modules (up module and hub module). IGF1R was selected as a key gene, and the hsa_circ_0007386/miR-1271–5P/IGF1R/AKT regulatory axis was established. The relative expression levels of the regulatory axis members were confirmed by RT-PCR in 12 samples, including TAD tissues and normal tissues. Downregulation of IGF1R expression in smooth muscle cells (SMCs) was found to induce apoptosis by regulating the AKT levels. In addition, IGF1R showed high diagnostic efficacy in both AD tissue and blood samples. Conclusions: The hsa_circ_0007386/miR-1271-5P/IGF1R/AKT axis may aggravate the progression of TAD by inducing VSMCs apoptosis. CeRNA networks could provide new insights into the underlying molecular mechanisms of TAD. In addition, IGF1R showed high diagnostic efficacy in both tissue and plasma samples in TAD, which can be considered as a diagnostic marker for TAD. [ABSTRACT FROM AUTHOR]

Yue Shao,1 Jun Luo,1 Liu Ye,2 Hao-Yu Ran,1 Hao-Ming Shi,1 Cheng Zhang,1 Qing-Chen Wu1 1Department of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of China; 2The First Branch, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaCorrespondence: Cheng Zhang; Qing-Chen WuDepartment of Cardiothoracic Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People’s Republic of ChinaEmail zhangchengcqmu@126.com; wuqingchencqmu@126.comBackground: Long non-coding RNAs (lncRNAs) can act as a competitive endogenous RNA (ceRNA) to regulate gene expression by sequestering the microRNA (miRNA). However, the lncRNA-miRNA-mRNA ceRNA network in thoracic aortic dissection (TAD) has been rarely documented.Methods: Three Gene Expression Omnibus (GEO) datasets were used to detect differentially expressed mRNAs, miRNAs, and lncRNAs in TAD. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted for the differentially expressed mRNAs. A protein–protein interaction network for differentially expressed mRNAs was also constructed, and hub genes were identified. We established a ceRNA network of TAD based on the differentially expressed miRNAs, mRNAs and lncRNAs, and verified our results using an independent dataset and quantitative real-time PCR (qRT-PCR).Results: In TAD, 267 lncRNAs, 81 miRNAs, and 346 mRNAs were identified as differentially expressed. The established ceRNA network consisted of seven lncRNA nodes, three mRNA nodes, and three miRNA nodes, and the expression of miRNAs in TAD was opposite to that of lncRNAs and mRNAs. Subsequently, an independent GEO dataset and qRT-PCR were used to validate the expression of three mRNAs. In addition, the expression differences in SLC7A5, associated miRNA and lncRNA were verified. According to gene set enrichment analysis of SLC7A5, the most significant KEGG pathway was considerably enriched in spliceosome and pentose phosphate pathway.Conclusion: We established a novel ceRNA regulatory network in TAD, which provides valuable information for further research in the molecular mechanisms of TAD.Keywords: bioinformatics analysis, ceRNA, expression profile, thoracic aortic dissection

Thoracic aortic dissection (TAD) is the most common cause of sudden cardiac death associated with aortic diseases. The age of TAD victims in forensic studies is significantly younger than hospitalized patients with TAD, while only a few studies have been conducted on autopsy-diagnosed TAD deceased. A retrospective study was conducted at the Medicolegal Center of Sun Yat-sen University from 1999 to 2019 to address the characteristics of TAD victims. A total of 200 deceased from spontaneous rupture of TAD were assessed, with 165 (82.5%) males and 175 (87.5%) Stanford type A deceased. Our main results showed that compared with patients with TAD diagnosed during their lifetime, individuals diagnosed with TAD until an autopsy showed an earlier onset (43.80 years old) and less accompanied hypertension (

Altered proteoglycan (PG) and glycosaminoglycan (GAG) distribution within the aortic wall has been implicated in thoracic aortic aneurysm and dissection (TAAD). This review was conducted to identify literature reporting the presence, distribution and role of PGs and GAGs in the normal aorta and differences associated with sporadic TAAD to address the question; is there enough evidence to establish the role of GAGs/PGs in TAAD? 75 studies were included, divided into normal aorta (n = 51) and TAAD (n = 24). There is contradictory data regarding changes in GAGs upon ageing; most studies reported an increase in GAG sub-types, often followed by a decrease upon further ageing. Fourteen studies reported changes in PG/GAG or associated degradation enzyme levels in TAAD, with most increased in disease tissue or serum. We conclude that despite being present at relatively low abundance in the aortic wall, PGs and GAGs play an important role in extracellular matrix maintenance, with differences observed upon ageing and in association with TAAD. However, there is currently insufficient information to establish a cause-effect relationship with an underlying mechanistic understanding of these changes requiring further investigation. Increased PG presence in serum associated with aortic disease highlights the future potential of these biomolecules as diagnostic or prognostic biomarkers. [ABSTRACT FROM AUTHOR]

We aimed to explore the feasibility of 4D flow magnetic resonance imaging (MRI) for patients undergoing thoracic aorta endovascular repair (TEVAR). We retrospectively evaluated ten patients (two female), with a mean (±standard deviation) age of 61 ± 20 years, undergoing MRI for a follow-up after TEVAR. All 4D flow examinations were performed using a 1.5-T system (MAGNETOM Aera, Siemens Healthcare, Erlangen, Germany). In addition to the standard examination protocol, a 4D flow-sensitive 3D spatial-encoding, time-resolved, phase-contrast prototype sequence was acquired. Among our cases, flow evaluation was feasible in all patients, although we observed some artifacts in 3 out of 10 patients. Three individuals displayed a reduced signal within the vessel lumen where the endograft was placed, while others presented with turbulent or increased flow. An aortic endograft did not necessarily hinder the visualization of blood flow through 4D flow sequences, although the graft could generate flow artifacts in some cases. A 4D Flow MRI may represent the ideal tool to follow up on both healthy subjects deemed to be at an increased risk based on their anatomical characteristics or patients submitted to TEVAR for whom a surveillance protocol with computed tomography angiography would be cumbersome and unjustified.

Guidelines for surgical correction of patients with ascending thoracic aortic aneurysm (ATAA) with a bicuspid aortic valve (BAV) have oscillated over the years. In this study, we outline the natural history of the ascending aorta in patients with BAV and trileaflet aortic valve (TAV) ATAA followed over time, to ascertain if their behavior differs and to determine if a different threshold for intervention is required. Aortic diameters and long-term complications (ie, adverse aortic events) of 2428 patients (554 BAV and 1874 TAV) with ATAA before operative repair were reviewed. Growth rates, yearly complication rates, event-free survival, and risk of complications as a function of aortic size were calculated. Long-term follow-up and precise cause of death granularity was achieved via a comprehensive 6-pronged approach. Aortic growth rate in patients with BAV vs TAV ATAA was 0.20 and 0.17 cm/year, respectively (P =.009), with the rate increasing with increasing aortic size. Yearly adverse aortic events rates increased with ATAA size and were lower for patients with BAV. The relative risk of adverse aortic events exhibited an exponential increase with aortic diameter. Patients with BAV had a lower all-cause and ascending aorta-specific adverse aortic events hazard. Age-adjusted 10-year event-free survival was significantly better for patients with BAV, and BAV emerged as a protective factor against type A dissection, rupture, and ascending aortic death. The threshold for surgical repair of ascending aneurysm with BAV should not differ from that of TAV. Prophylactic surgery should be considered at 5.0 cm for patients with TAV (and BAV) at expert centers. [Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Our study is the largest genetic sequencing analysis of thoracic aortic dissection (TAD) decedents to date, finding that 11.48% carried pathogenic or likely pathogenic (P/LP) variants, primarily in the FBN1 gene. • Our study found a correlation between these P/LP variants and earlier mortality among TAD decedents, suggesting that genotype could influence the severity of TAD. • Our study reported for the first time that TAD decedents with P/LP variants exhibit a trend of shorter diagnosis and treatment time compared to those without such variants. [ABSTRACT FROM AUTHOR]

Chest pain is a common chief complaint in the emergency department. When looking at patients with chest pain cases of acute coronary syndrome, pulmonary embolism and aortic dissection account for the majority of cases that involve an allegation of malpractice. While it is likely impossible to catch all these cases having a structured approach to these patients may improve outcomes for both patients and clinicians., Competing Interests: Disclosure The authors have no financial disclosures or conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

AimsThoracic aortic dissection (TAD) is a life-threatening disease with no effective drug therapy thus far. New therapeutic targets and indications for timely surgical intervention are urgently needed. Our aim is to investigate new pathological mechanisms and potential biomarkers of TAD through global metabolomic profiling of aortic aneurysm and dissection patients.Methods and ResultsWe performed untargeted metabolomics to determine plasma metabolite concentrations in an aortic disease cohort, including 70 thoracic aortic aneurysm (TAA) and 70 TAD patients, as well as 70 healthy controls. Comparative analysis revealed that sphingolipid, especially its core metabolite C18-ceramide, was significantly distinguished in TAD patients but not in TAA patients, which was confirmed by subsequent quantitative analysis of C18-ceramide in a validation cohort. By analyzing our existing multiomics data in aortic tissue in a murine TAD model and TAD patients, we found that an enhanced ceramide de novo synthesis pathway in macrophages might contribute to the elevated ceramide. Inhibition of the ceramide de novo synthesis pathway by myriocin markedly alleviated BAPN-induced aortic inflammation and dissection in mice. In vitro studies demonstrated that exogenous C18-ceramide promoted macrophage inflammation and matrix metalloprotein (MMP) expression through the NLRP3-caspase 1 pathway. In contrast, inhibition of endogenous ceramide synthesis by myriocin attenuated lipopolysaccharide (LPS)-induced macrophage inflammation.ConclusionsOur findings demonstrated that ceramide metabolism disturbance might play a vital role in TAD development by aggravating aortic inflammation through the NLRP3 pathway, possibly providing a new target for pharmacological therapy and a potential biomarker of TAD.

Objective: To examine the feasibility, integrity, efficacy, and safety of endovascular repair of the aortic arch pathologies with the mini-cross prefenestration (MCPF) on stent grafts.Methods: First, to prove the feasibility of the MCPF, an in-vitro prefenestration experiment was conducted. Second, to examine the integrity of the MCPF stent grafts, a fatigue test was conducted. Then, the membranes and metal structures of stent grafts were examined by light microscopy and scanning electron microscopy (SEM). Third, a clinical experiment was conducted to investigate the efficacy and safety of this novel technique (ClinicalTrials.gov Identifier: NCT04544579).Results: All the 12 branch stents were successfully implanted and flared in vitro. After the fatigue test stimulating a 5-year cardiac cycle, no obvious disintegration or fracture was found in light microscopy or SEM. From December 2017 to February 2020, 26 patients with left subclavian arteries and/or left common carotid arteries involved received the novel technique. The endovascular repair with the MCPF was successfully performed on all the 26 (100%) patients. Eighteen (69.2%) patients underwent the reconstruction of the left subclavian artery (LSCA) only. The fenestrations of both the LSCA and left common carotid artery (LCCA) were conducted in 8 (30.8%) patients. Median operative time was 120 [interquartile range (IQR), 95–137.5] min and median revascularization time of the LSCA and LCCA was 30.5 (IQR, 22.8–42.0) s and 20.0 (IQR, 18.0–32.0) s separately. During the median follow-up duration of 38.9 (range, 18.8–44.2) months, one case needed an open surgery because of retrograde type A aortic dissection 3 months after implantation and no other complications or mortality occurred. The maximum aortic diameters were significantly decreased in patients with thoracic aortic dissection and thoracic aortic aneurysm (p < 0.05).Conclusion: The existing evidence demonstrated the safety, rapid branch artery revascularization, and positive aortic remodeling of the novel technique. Long-term observation is warranted to prove the durability.

Aim: Thoracic aortic dissection (TAD) is a high-risk vascular disease. The mortality rate of untreated TADs in 24 h was as high as 50%. Thus, rapid diagnosis of TAD in the emergency department would get patients to the right treatments to save their lives.Methods: We profiled the proteome of aortic tissues from TAD patients using a label-free quantification proteomics method. The differentially expressed proteins were screened and subjected to bioinformatics analysis. Candidate biomarkers were selected and validated in independent serum samples using enzyme-linked immunosorbent assays (ELISAs). The diagnostic values were further predicted via receiver operating characteristic (ROC) curve analysis.Results: A total of 1,141 differentially expressed proteins were identified in aortic tissues from 17 TAD patients and eight myocardial infarction (MI) patients. Six proteins were selected as candidate biomarkers for ELISAs in an independent training set of 20 serum samples (TAD = 10, MI = 10). Of these proteins, four with a P-value < 0.01 were further validated in another independent set of 64 serum samples (TAD = 32, MI = 32) via ELISAs. ITGA2, COL2A1, and MIF had P-values < 0.0001, and their areas under the curve (AUCs) were 0.801 (95% CI: 0.691–0.911), 0.773 (95% CI: 0.660–0.887), and 0.701 (95% CI: 0.574–0.828), respectively.Conclusion: ITGA2, COL2A1, and MIF were identified as promising biomarkers for discriminating TAD from emergency patients with severe chest pain. Biomarker-guided emergency triage could further shorten the time for patients to get more effective treatments.

Background: The molecular mechanisms associated with thoracic aortic dissection (TAD) remain poorly understood. A comprehensive high-throughput sequencing-based analysis of the circRNA–miRNA–mRNA competitive endogenous RNA (ceRNA) regulatory network in TAD has not been conducted. The purpose of this study is to identify and verify the key ceRNA networks which may have crucial biological functions in the pathogenesis of TAD. Methods: Gene expression profiles of the GSE97745, GSE98770, and GSE52093 datasets were acquired from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified using the GEO2R tools. Protein–protein interaction (PPI) networks of the hub genes were constructed using STRING; the hub genes and modules were identified by MCODE and CytoHubba plugins of the Cytoscape. We analyzed the hub genes using Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. The functions of these hub genes were assessed using Cytoscape software. Our data—along with data from GSE97745, GSE98770, and GSE52093—were used to verify the findings. Results: Upon combined biological prediction, a total of 11 ce-circRNAs, 11 ce-miRNAs, and 26 ce-mRNAs were screened to construct a circRNA–miRNA–mRNA ceRNA network. PPI network and module analysis identified four hub nodes, including IGF1R, JAK2, CSF1, and GAB1. Genes associated with the Ras and PI3K-Akt signaling pathways were clustered in the four hub node modules in TAD. The node degrees were most significant for IGF1R, which were also the most significant in the two modules (up module and hub module). IGF1R was selected as a key gene, and the hsa_circ_0007386/miR-1271–5P/IGF1R/AKT regulatory axis was established. The relative expression levels of the regulatory axis members were confirmed by RT-PCR in 12 samples, including TAD tissues and normal tissues. Downregulation of IGF1R expression in smooth muscle cells (SMCs) was found to induce apoptosis by regulating the AKT levels. In addition, IGF1R showed high diagnostic efficacy in both AD tissue and blood samples. Conclusions: The hsa_circ_0007386/miR-1271-5P/IGF1R/AKT axis may aggravate the progression of TAD by inducing VSMCs apoptosis. CeRNA networks could provide new insights into the underlying molecular mechanisms of TAD. In addition, IGF1R showed high diagnostic efficacy in both tissue and plasma samples in TAD, which can be considered as a diagnostic marker for TAD.

Background: Thoracic Aortic Dissection (TAD) is a life-threatening disease without effective drug treatments. The disruption of HASMCs homeostasis is one direct histopathologic alteration in TAD pathological process. Several miRNAs have been shown abnormally expressed in TAD and to regulate HASMCs homeostasis. The primary goal of this study is to identify the miRNAs and the specific mechanisms that lead to HASMCs homeostasis disruption., Methods: Bulk miRNA sequencing was performed to explore the aberrantly expressed miRNA profile in TAD, and differentially expressed miRNAs were verified with qRT-PCR. To explore the role of the key miRNAs (miR-3529) in HASMCs homeostasis, we overexpressed this miRNA with lentivirus in HASMCs. Integrative transcriptomics and metabolomics analysis were used to uncover the functional roles of this miRNA in regulating HASMCs homeostasis. Further, the target gene of miR-3529 was predicted by bioinformatics and verified through a dual-luciferase reporter assay., Results: Bulk miRNA sequencing showed miR-3529 was elevated in TAD tissues and confirmed by qRT-PCR. Further experimental assay revealed miR-3529 upregulation induced HASMCs homeostasis disruption, accompanied by reducing contractile markers and increasing pro-inflammatory cytokines. Integrative transcriptomics and metabolomics analysis showed that miR-3529 overexpression altered the metabolic profile of HASMC, particularly lipid metabolism. ABCA1 was found to be a direct target of miR-3529. Mechanistically, the miR-3529/ABCA1 axis disrupted HASMCs homeostasis through the JAK2/STAT3 signaling pathway., Conclusions: miR-3529 is elevated in TAD patients and disrupts HASMCs homeostasis by reprogramming metabolism through the JAK2/STAT3 signaling pathway. These findings favor a role for miR-3529 as a novel target for TAD therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Wang, Yu, Ding, Yang, Jiang, Gao, Liu, Shao and Shen.)

Background: Numerous pieces of evidence have indicated that thoracic aortic dissection (TAD) is an inflammatory disease. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling is a driver in multiple inflammatory diseases. Here, we examined the S1PR2 expression in TAD lesions and explored the effect of interfering with S1PR2 on TAD formation and progression.Methods: Aorta specimens and blood samples were collected from patients with TAD and matched controls. The expression of S1PR1, S1PR2, and S1PR3 was examined. The effect of inhibiting S1PR2 on TAD was evaluated in a TAD mouse model induced by β-aminopropionitrile fumarate (BAPN) and AngII. The presence of sphingosine kinase 1 (SPHK1), S1P, and neutrophil extracellular traps (NETs) was investigated. Further, the possible association between S1PR2 signaling and NETs in TAD was analyzed.Results: In the aortic tissues of patients with TAD and a mouse model, the S1PR2 expression was significantly up-regulated. In the TAD mouse model, JTE013, a specific S1PR2 antagonist, not only blunted the TAD formation and aortic rupture, but also preserved the elastic fiber architecture, reduced the smooth muscle cells apoptosis level, and mitigated the aortic wall inflammation. Augmented tissue protein expression of SPHK1, citrullinated histone H3 (CitH3, a specific marker of NETs), and serum S1P, CitH3 were detected in TAD patients. Surgical repair normalized the serum S1P and CitH3 levels. Immunofluorescence staining revealed that S1PR2 colocalized with NETs. The protein expression levels of SPHK1 and serum S1P levels positively correlated with the protein expression and serum levels of CitH3, separately. Furthermore, JTE013 treatment reduced NETs accumulation.Conclusion: Inhibiting S1PR2 attenuates TAD formation and prevents aortic rupture. Targeting S1PR2 may provide a promising treatment strategy against TAD.

• CTD significantly reduces the expression of inflammatory factors in the aortic tissue of TAD mice model. • CTD weakened the proliferation, migration, invasion, inflammation ANG II induced TAD cell model. • CTD attenuates ANG II induced TAD model by inhibiting the NF-κB signaling pathway in VMSCs. 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. The male C57BL/6J mice were used to construct an animal model of TAD with β-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 kinaseβ (IKKβ) will be established in VMSCs cells to further explore the protective function of CTD. 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-β. 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. [ABSTRACT FROM AUTHOR]

Cardiovascular societies have developed recommendations regarding the management of thoracic aortic diseases. While improvements in treatment have been observed during the past decade in regard to patient selection, thoracic endovascular aortic repair (TEVAR) and associated techniques, and high-volume centralization, the broad expansion of TEVAR has raised considerations about its indications, appropriateness, limitations, and application. The aim of this systematic review was to assess the similarities and differences among current cardiovascular societies' guidelines for the management of thoracic aortic diseases. The MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials were searched from January 2009 to May 2020. The initial search identified 990 articles. After exclusion of duplicate or inappropriate articles, the final analysis included 5 articles from cardiovascular societies published between 2010 and 2020. Selected controversial topics were analyzed, including diagnosis, imaging, spinal cord ischemia prevention, and management of the most important thoracic aortic pathologies. The analysis included data concerning the therapeutic approach in acute and chronic type B aortic dissection, penetrating aortic ulcer, intramural hematoma, thoracic aortic aneurysm, and traumatic aortic injury, as well a discussion of inflammatory aneurysms, aortitis, and genetic syndromes. The review presents consistent and controversial recommendations, as well as "gray zone" issues that need further investigation. There was significant overlap and agreement among the 5 societies regarding the management of thoracic aortic diseases. Especially in dissection and aneurysm management, TEVAR has established its role as the treatment of choice. However, robust evidence is still needed in many aspects of the management of thoracic aortic pathologies. [ABSTRACT FROM AUTHOR]

We document the elongation and shunting of a patent foramen ovale (PFO) after thoracic aortic dissection repair in a 63-year-old man. Initially, a presurgical echocardiogram showed insignificant PFO shunting; however, severe hypoxemia and inability to extubate after thoracic aortic dissection repair necessitated further investigation. A repeat transesophageal echocardiogram after cardiothoracic surgery revealed significant PFO elongation with bidirectional shunting. Subsequent urgent transcatheter PFO closure markedly improved oxygenation, allowing for successful weaning from mechanical ventilation. This case highlights the importance of recognizing dynamic PFO changes after thoracic surgery as a reversible cause of postoperative hypoxemia.

Thoracic aortic dissection (TAD) is a life-threatening vascular disease manifested as intramural bleeding in the medial layers of the thoracic aorta. The key histopathologic feature of TAD is medial degeneration, characterized by depletion of vascular smooth muscle cells (VSMCs) and degradation of extracellular matrix (ECM). MicroRNA, as essential epigenetic regulators, can inhibit the protein expression of target genes without modifying the sequences. This study aimed to elucidate the role and underlying mechanism of miR-20a, a member of the miR-17-92 cluster, in regulating ECM degradation during the pathogenesis of TAD. The expression of the miR-17-92 cluster was significantly increased in synthetic VSMCs derived from TAD lesions compared to contractile VSMCs isolated from normal thoracic aortas. Notably, the expression of miR-20a was increased in VSMCs in response to serum exposure and various stimuli. In TAD lesions, the expression of miR-20a was significantly negatively correlated with that of elastin. Elevated expression of miR-20a was also observed in thoracic aortas of TAD mice induced by β-aminopropionitrile fumarate and angiotensin II. Overexpression of miR-20a via mimic transfection enhanced the growth and invasive capabilities of VSMCs, with no significant impact on their migratory activity or the expression of phenotypic markers (α-SMA, SM22, and OPN). Silencing of miR-20a with inhibitor transfection mitigated the hyperactivation of MMP2 in VSMCs stimulated by PDGF-bb, as evidenced by reduced levels of active-MMP2 and increased levels of pro-MMP2. Subsequently, TIMP2 was identified as a novel target gene of miR-20a. The role of miR-20a in promoting the activation of MMP2 was mediated by the suppression of TIMP2 expression in VSMCs. In addition, the elevated expression of miR-20a was found to be directly driven by Nanog in VSMCs. Collectively, these findings indicate that miR-20a plays a crucial role in maintaining the homeostasis of the thoracic aortic wall during TAD pathogenesis and may represent a potential therapeutic target for TAD., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. ☐The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:, (© 2024 The Authors.)

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 β-aminopropionitrile monofumarate-induced TAD mouse model. Klf15KO mice are susceptible to both β-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., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Thoracic aortic dissection (TAD) is associated with matrix changes, biochemical changes, and inflammatory markers like interleukin-1 beta (IL-1β). However, the exact mechanism remains unknown. This study aimed to investigate the role of IL-1β, matrix metalloproteinase (MMP)-2, MMP-9, smooth muscle cell apoptosis, and elastic fibre fracture in the development of TAD in a rat model. The TAD rat model was induced by β-aminopropionitrile (BAPN). TAD was investigated in 112 male Sprague–Dawley rats, which were equally divided into four groups of 28 rats (Control, BAPN, BAPN + IL-1β, and BAPN + IL-1β antibody). Systolic blood pressure, survival, and the development of TAD were measured after six weeks. Expression of IL-1β, MMP-2, and MMP-9 was measured by Western blot. Apoptosis, aortic elastin concentration, and biomechanical characteristics were measured by the TdT mediated dUTP nick end labelling assay, Victoria blue staining, and in vitro testing. During six weeks, the mortality was 0% (0/28) in the control group, 53.6% (15/28) in the BAPN group (p <.001 compared with the control group), 75.0% (21/28) in the BAPN + IL-1β group (p =.007 compared with the BAPN group), and 35.7% (10/28) in the BAPN + IL-1β antibody group (p =.023 compared with BAPN group and p <.001 compared with the BAPN + IL-1β group). IL-1β treatment deteriorates BAPN induced mortality and aneurysm expansion, which were attenuated by anti-IL-1β treatment. In BAPN + IL-1β group, stress and strain parameters were decreased by 13.5%–53.5% and elastin content was decreased by 14%, and IL-1β, MMP-2, and MMP-9 were expressed higher by 117%, 108%, and 75% when compared with the rats in the BAPN group. Contrarily, in the BAPN + IL-1β antibody group, the above changes could be completely (strain, elastin content, and expression of MMP-2) or partly (elasticity modulus, stress, and expression of MMP-9) blocked by anti-IL-1β treatment. IL-1β plays a critical role in TAD formation by altering the expression of MMP-2 and MMP-9, degrading the aortic wall matrix, causing elastic fibre rupture, and changing the stress or strain of the aortic wall. Anti-IL-1β reduces the later effects and could be one of the molecular targets for prognosis and drug treatment of TAD in the future. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study?Insulin‐like growth factor 1 and its major binding protein insulin‐like growth factor binding protein 3 (IGFBP3) are involved in collagen deregulation in several cardiovascular diseases: what is the role of IGFBP3 in thoracic aortic dissection and does it regulate aortic smooth muscle cells' phenotypic switch?What is the main finding and its importance?IGFBP3 inhibits aortic smooth muscle cells' phenotypic switch from a contractile to a synthetic phenotype, decreases matrix metalloproteinase 9 activation and suppresses elastin degradation. These findings provide a better understanding of the pathogenesis of thoracic aortic dissection. Thoracic aortic dissection (TAD) is characterized by aortic media degeneration and is a highly lethal disease. An aortic smooth muscle cell (AoSMC) phenotypic switch is considered a key pathophysiological change in TAD. Insulin‐like growth factor binding protein 3 (IGFBP3) was found to be downregulated in aortic tissues of TAD patients. The present work aimed to study the function of IGFBP3 in AoSMCs' phenotypic switch and matrix metalloproteinase (MMP) expression. We established a mouse model of TAD by angiotensin (Ang) II infusion to β‐aminopropionitrile‐administrated mice, and found decreased IGFBP3 expression accompanied by aortic dilatation and elastin degradation in vivo. Further, mouse (m)AoSMCs were isolated from mouse thoracic aorta and treated with Ang II. Ang II induced downregulation of IGFBP3 in vitro. To further study the function of IGFBP3, primary mAoSMCs were infected with adenovirus expressing IGFBP3 followed by Ang II induction. Enforced upregulation of IGFBP3 decreased MMP9 expression and activation as well as increasing tissue inhibitor of metalloproteinase (TIMP) 1 expression in Ang II‐induced mAoSMCs. No difference was observed in MMP2 and TIMP3 expression. IGFBP3 suppressed subsequent Ang II‐induced elastin degradation in vitro. IGFBP3 inhibited Ang II‐induced mAoSMCs' phenotypic switch as evidenced by increased smooth muscle actin α‐2 (ACTA2) and myosin heavy chain 11 (MYH11) expression and decreased secreted phosphoprotein 1 (SPP1) and vimentin expression. Taken together, the present study demonstrates the role of IGFBP3 in preserving AoSMCs' contractile state and reducing MMP9 activation and thus promoting elastic fibre synthesis, which provides a better understanding of the pathogenesis of TAD. [ABSTRACT FROM AUTHOR]

Although much progress has been made in the diagnosis and treatment of thoracic aortic dissection (TAD), the overall morbidity and mortality rates of TAD are still high. Therefore, the molecular pathogenesis and etiology of TAD need to be elucidated. In this study, we found that histone deacetylase 1 (HDAC1) expression is dramatically higher in the aortic wall of patients with TAD (than that in a normal group) and negatively correlates with the levels of the vascular smooth muscle cell (SMC) contractile‐phenotype markers. Knockdown of HDAC1 upregulated both smooth muscle 22 α (SM22α) and α‐smooth muscle actin (α‐SMA) in platelet‐derived growth factor (PDGF)‐BB‐treated and ‐untreated SMCs. In addition, the knockdown of HDAC1 markedly decreased SMC viability and migration in contrast to the control group under the conditions of quiescence and PDGF‐BB treatment. We also showed that the expression of polycystic kidney disease 1 (PKD1) is decreased in the aortic wall of patients with TAD and negatively correlates with HDAC1 expression. Overexpressed PKD1 obviously increased SM22α and α‐SMA expression and reduced the viability and migration of SMCs, but these effects were attenuated by HDAC1. Furthermore, we demonstrated that HDAC1 serves as an important modulator of the migration and phenotypic switch of SMCs by suppressing the PKD1– mammalian target of the rapamycin signaling pathway. HDAC1 downregulation inhibited media degeneration and attenuated the loss of elastic–fiber integrity in a mouse model of TAD. Our results suggest that HDAC1 might be a new target for the treatment of a macrovascular disease such as TAD. [ABSTRACT FROM AUTHOR]

DNA methylation is known to regulate the expression of numerous genes but its role in the pathogenesis of thoracic aortic dissection (TAD) has remained largely elusive. In the present study, the DNA methylome of patients with TAD was analyzed using a methylation microarray and bisulfite pyrosequencing was used to determine whether the hypermethylation of matrix metalloproteinase 2 (MMP2) specifically is associated with TAD. Chip-based whole-DNA methylome analysis was performed on 4 male patients with TAD and 4 male healthy controls using an Illumina HumanMethylation EPIC 850K BeadChip. The resulting data were analyzed by clustering and principal component analysis, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed on the differentially methylated genes to interrogate their biological functions. Compared to the healthy controls, 3,362 loci were differentially methylated in the patients with TAD with a statistical significance of P<0.05, while 1,223 loci had a significance of P<0.01. Among these loci, 2,019 were hypermethylated and 1,343 were hypomethylated. From GO analysis within the biological process category, the MMP2, MMP14 and WNT2B genes were identified. enrichment was observed for loci involved in cellular component organization, enzyme-linked receptor protein signaling pathways (potentially having a key role in the development of cardiopulmonary function disorders) and vascular reconstruction. Bisulfite pyrosequencing of plasma samples indicated significantly increased methylation (P<0.01) of the CpG site at position 2 in the promoter of MMP2 in the TAD group relative to the healthy controls, and the mean methylation level of four CpG sites on the MMP2 gene in the TAD group was slightly higher than that in the control group, but not significantly. Hypermethylation of the MMP2 promoter may be a promising novel diagnostic and prognostic biomarker for TAD. Future studies on the epigenetics of biomarkers linked to vascular reconstruction and immune function may provide further insight into the pathogenesis and progression of TAD. [ABSTRACT FROM AUTHOR]

Thoracic aortic dissection (TAD) has a high mortality rate. Intermittent hypoxia (IH) triggers both harmful and beneficial effects in numerous physiological systems. The effects of IH on TAD development were explored in a mouse model. β-Aminopropionitrile monofumarate (BAPN) was used to induce TAD in C57BL/6 mice. Three week old male mice were treated with 1 g/kg/day BAPN in drinking water for four weeks and simultaneously subjected to IH (n = 30) (21%–5% O 2 , 90 s/cycle, 10 h/day, IH + BAPN group) or normoxia (n = 30) (21% O 2 , 24 h/day, BAPN group). Human VSMCs (HUASMCs) exposed to IH (30 min, 5% O 2)/re-oxygenation (30 min, 21% O2) cycles with a maximum of 60 min/cycle to detect the effect of IH on HIF-1α and LOX via HIF-1α-siRNA. It was found that BAPN administration significantly increased the lumen size and wall thickness of aortas compared with the normal group, but was significantly reversed by IH exposure. Additionally, IH exposure significantly increased the survival rate of BAPN induced TAD (70% vs. 40%). Furthermore, IH exposure reduced BAPN induced elastin breaks and apoptosis of vascular smooth muscle cells. IH exposure also reversed BAPN induced upregulation of inflammation and extracellular matrix (ECM) degradation. Real time polymerase chain reaction (RT-PCR) confirmed that IH inhibited inflammation and ECM degradation related genes interleukin (IL)-1β , IL-6 , cathepsin S (Cat S), and matrix metalloproteinase 9 (MMP-9), but upregulated the ECM synthesis related genes lysyl oxidase (LOX) and collagen type I alpha2 (Col1a2) compared with the BAPN group. In vitro results suggest that IH promotes the expression of LOX via HIF-1α. The results suggest that IH alleviates BAPN induced TAD in C57BL/6 mice. [ABSTRACT FROM AUTHOR]