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BACKGROUND: The common genetic signatures of ascending aortic dilation and acute type A aortic dissection (AAAD) remained unclear. This study aims to investigate the role of ESR1 in ascending aortic dilation and AAAD via a multi-omics approach combining transcriptome-wide association study (TWAS) and mRNA expression profiles. METHODS: The TWAS analysis was performed by integrating expression quantitative trait loci (eQTL) data of aorta and the GWAS dataset of ascending aortic diameter using the FUSION software. Joint/Conditional Analysis was used to screen conditionally independent genes from TWAS significant regions. mRNA expression profiles were used to confirm the differential expression of ESR1 in ascending aortic dilation and AAAD. An independent mRNA expression profile dataset was used to validate the diagnostic efficiency of ESR1 expression on thoracic aortic aneurysm (TAA). Gene set enrichment analysis (GSEA) was utilized to explore the potential molecular function of ESR1 in mouse aorta. Immune infiltration analysis was performed to evaluate the association between ESR1 and immune infiltration in AAAD. RESULTS: ESR1 was among the top 10 most significant genes identified by TWAS of ascending aortic diameter (Z score = -7.3, PTWAS = 3.30 × 10-13). mRNA expression profiles confirmed the low expression of ESR1 both in ascending aortic dilation (PmRNA = 0.0361) and AAAD (PmRNA = 0.0142). The diagnostic efficiency of peripheral blood ESR1 expression on TAA was further validated by an independent mRNA expression profile dataset. GSEA showed that GO terms and KEGG pathways mainly involved in metabolism and oxidoreductase activity were enriched in aortic tissue of ERα knockout mice. The immune infiltration ration of naive CD8 + T cells was significantly lower in AAAD compared with normal aorta, and was positively correlated with ESR1 expression. CONCLUSION: Low expression of ESR1 is associated with ascending aortic dilation and AAAD. Peripheral blood ESR1 expression may be a novel diagnostic biomarker of TAA. ESR1 expression is positively correlated with immune infiltration ration of naive CD8 + T cells in AAAD.

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Aneurisma de la Aorta Torácica , Disección Aórtica , Animales , Ratones , Dilatación , Perfilación de la Expresión Génica , Transcriptoma , Disección Aórtica/genética , ARN Mensajero/metabolismo , Aneurisma de la Aorta Torácica/genética , Ratones Noqueados

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Aortic procedures are associated with higher risks of bleeding, yet data regarding perioperative transfusion in this patient population are lacking. We evaluated transfusion patterns in patients undergoing proximal aortic surgery to provide a benchmark against which future standards can be assessed. Between June 2014 and July 2017, 247 patients underwent elective aortic reconstruction for aneurysm. Patients with acute aortic syndrome, endocarditis, and/or prior cardiac surgery were excluded. Transfusion data were analyzed by type of operation: ascending aorta replacement ± aortic valve procedure (group 1, n = 122, 49.4%); aortic root replacement with a composite valve-graft conduit ± ascending aorta replacement (group 2, n = 93, 37.7%); valve-sparing aortic root replacement (VSARR) ± ascending aorta replacement (group 3, n = 32, 13.0%). Thirty-day mortality for the entire cohort was 2.02% (5 deaths). Overall, 75 patients (30.4%) did not require any transfusion of blood or other products. Patients in groups 1 and 3 were significantly more likely to avoid transfusion than those in group 2. Mean transfusion volume for any individual patient was modest; those who underwent VSARR (group 3) required less intraoperative red blood cells (RBC) than others. Intraoperative transfusion of RBC was independently associated with an increased risk of death at 30 days. Elective proximal aortic reconstruction can be performed without the need for excessive utilization of blood products. Composite root replacement is associated with a greater need for transfusion than either VSARR or isolated replacement of the ascending aorta.

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Background: Ascending and abdominal aortic aneurysms (AAs) are asymptomatic, permanent dilations of the aorta with surgical intervention as the currently available therapy. Hippo-Yap signaling cascade plays a critical role in stem cell self-renewal, tissue regeneration and organ size control. By using XMU-MP-1, a pharmacological inhibitor of the key component of Hippo-Yap signaling, MST1/2, we examined the functional contribution of Hippo-Yap in the development of AAs in Angiotensin II (AngII)-infused hypercholesterolemic mice. Methods and Results: MST, p-MST, p-YAP, p-MOB and TAZ proteins in AngII-infused ascending and abdominal aortas were assessed by immunohistochemical and western blot analyses. To examine the effect of MST1/2 inhibition on AAs, western diet-fed low density lipoprotein (LDL) receptor -/- mice infused with AngII were administered with either vehicle or XMU-MP-1 for 5 weeks. Hippo-YAP signaling proteins were significantly elevated in AngII infused ascending and abdominal aortas. XMU-MP-1 administration resulted in the attenuation of AngII-induced ascending AAs without influencing abdominal AAs and aortic atherosclerosis. Inhibition of Hippo-YAP signaling also resulted in the suppression of AngII-induced matrix metalloproteinase 2 (MMP2) activity, macrophage accumulation, aortic medial hypertrophy and elastin breaks in the ascending aorta. Conclusions: The present study demonstrates a pivotal role for the Hippo-YAP signaling pathway in AngII-induced ascending AA development.

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To determine individual, expected normal diameters of the ascending aorta (AAo) and prevalence of dilations based upon an absolute cut-off point (≥ 40 mm) and individual cut-off point (≥ 25% than expected normal). Non-contrast computed tomography (CT) scans were obtained in 14,993 individuals (95.0% male, mean age 67.8 ± 3.8). A sub-group (n = 291) had AAo diameter measured by transthoracic echocardiography. A prediction formula for AAo diameters was created from multivariate linear regression analysis based upon gender, age, and body surface area. An index was made by dividing observed diameters with predicted diameters. A size-index ≥ 1.25 was defined as dilated. Prevalence of AAo dilations among males and females using 40 mm as cut-off point were 10.6% and 2.1% (p < 0.001), respectively, while 3.3% and 2.6% (p = 0.305) using the size-index ≥ 1.25, respectively. Proportion of agreement between cases of AAo dilations from the size-index and 40 mm was 93.0%. Using the size-index as 'golden standard' for dilation, the sensitivity and specificity using 40 mm as cut-off point for males were 100.0% and 92.4%, respectively, while 75.0% and 99.9%, respectively, for females. For males and females, the positive predicted values were 31.3% and 93.8%, respectively; the negative predicted values were 100.0% and 99.3%, respectively. An absolute echocardiographic size-criterion of 40 mm entails a significant number of females with missed AAo dilation, and a large number of males are mistaken to have dilated AAo. Thus, AAo diameters should be evaluated in relation to gender, age and BSA. This study provides a formula for potential clinical implementation.

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Aorta/diagnóstico por imagen , Aneurisma de la Aorta/diagnóstico por imagen , Aortografía , Angiografía por Tomografía Computarizada , Ecocardiografía , Factores de Edad , Anciano , Aneurisma de la Aorta/epidemiología , Superficie Corporal , Estudios Transversales , Dinamarca/epidemiología , Dilatación Patológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prevalencia , Estudios Prospectivos , Valores de Referencia , Factores Sexuales

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BACKGROUND: Ascending aortic aneurysm is a disease requiring surgical intervention. However, the timing of operation is still controversial. The purpose of this study is to compare the ascending aortic diameter and postoperative outcomes in hospital between patients with simple ascending aortic dissection and patients with simple ascending aortic dilation in China, and to investigate the accuracy of the timing of operation determined by ascending aortic diameter alone. METHODS: We reviewed the data from 2,520 hospitalized patients of aortic aneurysm and aortic dissection who underwent surgical treatment from January 2010 to June 2017 in our hospital. A total of 139 simple ascending aortic dissection and simple ascending aortic aneurysm hospitalized patients excluding Marfan syndrome and heart valve diseases etc. (56 in the aortic dilatation group and 83 in the aortic dissection group) were enrolled. The t-test and univariable analysis were used to compare the differences between two groups. RESULTS: For the aortic diameter, the group of aneurysm has greater ascending aortic diameter and the index of ascending aortic diameter compared with the group of dissection (P<0.001, P<0.001). For male patients, the result is the same (P<0.001, P<0.001). But for female patients, there was no significant statistical significance between the two groups (P=0.631, P=0.288). For the postoperative outcomes, the dissection group had higher mortality, incidence of tracheotomy and postoperative re-exploration for hemorrhage (P=0.040, P=0.011, P=0.028). CONCLUSIONS: The majority of patients with simple ascending aortic dissection present with aortic diameters <5.5 cm and this is not consistent with the current operation indications of aortic aneurysm. It is far from enough to predict aortic dissection with aortic diameter alone. More indicators are needed to do this.

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BACKGROUND: The bicuspid aortic valve (BAV) is the most common cardiac congenital disease and is associated with an increased risk of developing ascending aorta dilation; which can have fatal consequences. Currently; no established risk biomarkers exist to facilitate the diagnosis and prognosis of BAV. METHODS: Using an untargeted metabolomic approach; we identified the levels of metabolites in plasma samples and compared them depending on the bicuspid or tricuspid morphology of the aortic valve. Including those patients with ascending aortic dilation and/or aortic stenosis (n = 212), we analyzed the role possibly played by alpha-Tocopherol in BAV disease; considering its association with the pathophysiological characteristics of BAV and biomarkers related to inflammation, oxidative stress and endothelial damage, as well as characteristics related to alpha-Tocopherol functionality and metabolism. RESULTS: We found that BAV patients; especially those with ascending aortic dilation; presented lower antioxidant capacity; as determined by decreased plasma levels of alpha-Tocopherol; paraoxonase 1 and high-density lipoprotein (HDL), as well as increased levels of C-reactive protein (CRP; a biomarker of inflammation) and endothelial microparticles (EMPs; an endothelial damage biomarker). By applying random forest analyses; we evaluated the significant screening capacity of alpha-Tocopherol; CRP and EMPs to classify patients depending on the morphology of the aortic valve. DISCUSSION: Our findings support the role of decreased antioxidant capacity; increased inflammation and endothelial damage in the pathogenesis of BAV and the progression of aortic dilation. Moreover; determining the plasma levels of alpha-Tocopherol; CRP and EMPs could improve BAV diagnosis in large populations.

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@#Objective    To compare the ascending aortic diameter and postoperative outcomes of patients with simple ascending aortic dissection or simple ascending aortic dilatation and to study the reliability of the surgical indication in present guideline for Chinese patients with ascending aortic dilatation. Methods    The clinical data of patients with aortic aneurysm and aortic dissection who underwent surgery at Beijing Anzhen Hospital, Capital Medical University from 2010 to 2017 were retrospectively reviewed. After exclusion of patients with Marfan syndrome, heart valve and other diseases, 139 patients were divided into two groups: a simple ascending aorta dilatation group (56 patients) and a simple ascending aortic dissection group (83 patients). The ascending aortic diameter and postoperative outcomes of two groups were compared.  Results    The inner ascending aortic diameter (57.30±9.41 mm vs. 50.72±9.53 mm, P <0.001) and the inner ascending aortic diameter index (31.12±5.38 vs. 27.22±6.40, P<0.001) in the simple ascending aorta dilatation group were significantly greater than those in the simple ascending aortic dissection group. For male patients, the results were similar (60.28±10.80 mm vs. 47.40±6.53 mm; 30.00±6.33 vs. 23.60±3.72, both P<0.001). But for the female patients, there was no significant difference between the two groups (54.90±7.47 mm vs. 53.81±10.84 mm; 32.03±4.37 vs. 30.58±6.56, both P>0.05). The mortality, the incidence of tracheotomy and postoperative reopen rate in the simple ascending aortic dissection group were higher. Conclusion    In this study, the inner diameter of the ascending aorta in the group of ascending aorta is mostly < 5.5 cm. In our opinion, the present surgical indication for Chinese patients with ascending aortic dilatation is not enough. In the future clinical studies, we also need to find more reasonable surgical indications.

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Objective Atrial septal defect(ASD) or ventricular septal defect(VSD) To performe a retrospective analysis of ascending aortic dilation in adult patients with congenital ASD or VSD,and summarized the treatment experience and prognosis.Methods Retrospective analysis on preoperative data,intraoperative data,and postoperative data from the adult patients with ASD or VSD who developed ascending aortic dilation in our institution from February 2010 to January 2017.24 adult patients,19 males,5 females;aged(40.7 ± 14.4) years.Results All patients received surgical treatment.Their symptoms were all improved after surgery,no deaths occurred.Conclusion Surgery is safe for the ascending aortic dilation in adult patients with congenital ASD or VSD.Both proper perioperative treatment and close monitoring are required for the successful surgery.

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BACKGROUND: In patients with a dilated proximal ascending aorta and trileaflet aortic valve, we aimed to assess (1) factors independently associated with increased long-term mortality and (2) the incremental prognostic utility of indexing aortic root to patient height. METHODS: We studied consecutive patients with a dilated aortic root (≥4 cm) that underwent echocardiography and gated contrast-enhanced thoracic aortic computed tomography or magnetic resonance angiography between 2003 and 2007. A ratio of aortic root area over height was calculated (cm2/m) on tomography, and a cutoff of 10 cm2/m was chosen as abnormal, on the basis of previous reports. All-cause death was recorded. RESULTS: The cohort comprised 771 patients (63 years [interquartile range, 53-71], 87% men, 85% hypertension, 51% hyperlipidemia, 56% smokers). Inherited aortopathies, moderate to severe aortic regurgitation, and severe aortic stenosis were seen in 7%, 18%, and 2%, whereas 91% and 54% were on ß-blockers and angiotensin-converting enzyme inhibitors, respectively. Aortic root area/height ratio was ≥10 cm2/m in 24%. The Society of Thoracic Surgeons score and right ventricular systolic pressure were 3.3±3 and 31±7 mm Hg, respectively. At 7.8 years (interquartile range, 6.6-8.9), 280 (36%) patients underwent aortic surgery (76% within 1 year) and 130 (17%) died (1% in-hospital postoperative mortality). A lower proportion of patients in the surgical (versus nonsurgical) group died (13% versus 19%, P<0.01). On multivariable Cox proportional hazard analysis, aortic root area/height ratio (hazard ratio, 4.04; 95% confidence interval [CI], 2.69-6.231) was associated with death, whereas aortic surgery (hazard ratio, 0.47; 95% CI, 0.27-0.81) was associated with improved survival (both P<0.01). For longer-term mortality, the addition of aortic root area/height ratio ≥10 cm2/m to a clinical model (Society of Thoracic Surgeons score, inherited aortopathies, hypertension, hyperlipidemia, medications, aortic regurgitation, and right ventricular systolic pressure), increased the c-statistic from 0.57 (95% CI, 0.35-0.77) to 0.65 (95% CI, 0.52-0.73) and net reclassification index from 0.17 (95% CI, 0.02-0.31) to 0.23 (95% CI, 0.04-0.34), both P<0.01. Of the 327 patients with aortic root diameter between 4.5 and 5.5 cm, 44% had an abnormal aortic root area/height ratio, of which 78% died. CONCLUSIONS: In patients with dilated aortic root and trileaflet aortic valve, a ratio of aortic root area to height provides independent and improved stratification for prediction of death.

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Aorta/anomalías , Válvula Aórtica/anomalías , Anciano , Aorta/diagnóstico por imagen , Aorta/cirugía , Válvula Aórtica/diagnóstico por imagen , Válvula Aórtica/cirugía , Estudios de Cohortes , Ecocardiografía/métodos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo

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Thoracic aortic aneurysms (TAA) are a significant cause of morbidity and mortality in humans. While the exact etiology is unknown, genetic factors play an important role. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV) and aortopathy in humans. The aim of this study was to determine if haploinsufficiency of Notch1 contributes to aortopathy using Notch1+/-; Nos3-/- mice. Echocardiographic analysis of Notch1+/-; Nos3-/- mice reveals effacement of the sinotubular junction and a trend toward dilation of the aortic sinus. Furthermore, examination of the proximal aorta of Notch1+/-; Nos3-/- mice reveals elastic fiber degradation, a trend toward increased matrix metalloproteinase 2 expression, and increased smooth muscle cell apoptosis, features characteristic of aneurysmal disease. Although at a lower penetrance, we also found features consistent with aortopathic changes in Notch1 heterozygote mice and in Nos3-null mice. Our findings implicate a novel role for Notch1 in aortopathy of the proximal aorta.