Genetic Variation in LRP1 Associates with Stanford Type B Aortic Dissection Risk and Clinical Outcome.
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ABSTRACT:
SUBMITTER: Erhart P
PROVIDER: S-EPMC8780592 | biostudies-literature | 2022 Jan
REPOSITORIES: biostudies-literature
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Genetic Variation in <i>LRP1</i> Associates with Stanford Type B Aortic Dissection Risk and Clinical Outcome.
Erhart Philipp P Körfer Daniel D Grond-Ginsbach Caspar C Qiao Jia-Lu JL Bischoff Moritz S MS Hempel Maja M Schaaf Christian P CP Grau Armin A Böckler Dittmar D
Journal of cardiovascular development and disease 20220105 1
Genetic variation in <i>LRP1</i> (low-density lipoprotein receptor-related protein 1) was reported to be associated with thoracic aortic dissections and aneurysms. The aims of this study were to confirm this association in a prospective single-center patient cohort of patients with acute Stanford type B aortic dissections (STBAD) and to assess the impact of <i>LRP1</i> variation on clinical outcome. The single nucleotide variation (SNV) rs11172113 within the <i>LRP1</i> gene was genotyped in 113 ...[more]
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Project description:BackgroundStanford type B aortic dissection is a rare, life-threatening complex phenotype associated with several modifiable and genetic risk factors. In the current study of a hospital-based, consecutive series of aortic dissection patients we propose a selection based on age and family history of aortic disease for genetic testing and detection of causative gene variants.MethodsIn this single center cohort study from 2013 to 2018 patients with acute Stanford type B aortic dissections were consecutively treated and analyzed by next generation sequencing based on selection criteria (age of disease onset ≤45 years and/or positive familial history for aortic disease) to detect genome-wide pathogenic variants in protein-coding sequences and to identify large copy number variants (CNV). Variants in a predefined panel of 30 genes associated with the familial thoracic aortic aneurysm and dissection (TAAD) syndrome were evaluated.ResultsFrom 105 patients nine matched selection criteria for genetic testing. Next-generation sequencing analysis revealed causal variants in FBN1 (fibrillin-1) in three patients: a pathogenic missense variant [c.6661T>C, p.(Cys2221Arg)] and two truncating variants [c.4786C>T, p.(Arg1596Ter)] and [c.6366C>CA, p.(Asp2123GlufsTer5)]. A fourth patient carried a large (>1,000,000 bp) CNV in the long arm of chromosome 10, deleting eleven genes, including the whole ACTA2 (actin alpha 2) gene. The latter two genetic findings have not been reported before.ConclusionsSelection of patients on the basis of young age and familial inheritance of aortic disease favors the identification of disease-causing genetic variants in a clinical cohort of patients with Stanford type B aortic dissection.
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Project description:BackgroundGenetic disorders are strongly associated with aortic disease. However, the identities of genetic mutations in sporadic Stanford type A aortic dissection (STAAD) are not clear. The present study analysed the possible genetic mutations of the known pathogenic genes of aortic disease and the clinical characteristics in patients with sporadic STAAD.MethodsWe analysed genetic mutations in 26 genes that underlie aortic aneurysms and dissections in 100 sporadic STAAD patients and 568 healthy controls after whole-genome sequencing (WGS). Clinical features and in-hospital death were determined in all STAAD patients.ResultsIn total, 60 suspicious pathogenic mutations (56 novel and 4 previously reported) in 19 genes were identified in 50% (50/100) of patients, and 14 patients had more than 1 mutation. The ascending aortic diameter was extended in patients with mutations (49.1±12.3 vs. 43.7±11.2 mm, P=0.023), and the DeBakey type I phenotype was more common in patients with mutations in genes that coded extracellular matrix (ECM) components than in patients with mutations in other genes (96.6% vs. 66.7%, P=0.007). Patients with fibrillin-1 (FBN1) mutations were younger than patients without FBN1 mutations (44.7±11.0 vs. 53.5±12.1, P=0.030). Subgroup analyses revealed an increased risk of in-hospital mortality in mutation carriers (44.4% vs. 10.5%, P=0.029) but only in patients who received conservative treatment.ConclusionsHalf of Chinese patients with a sporadic form of STAAD may carry mutations in known pathogenic genes of aortic disease, and these patients may exhibit distinct clinical features and poor clinical outcomes with the use of conservative treatment.
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Project description:Background: Stanford type A aortic dissection (ATAAD) is a common life-threatening event in the aorta. Recently, immune disorder has been linked to the risk factors that cause ATAAD at the molecular level. However, the specific immune-related gene signature during the progression is unclear. Methods: The GSE52093 and GSE98770 datasets related to ATAAD from the Gene Expression Omnibus (GEO) database were acquired. The immune gene expression levels were analyzed by single sample gene set enrichment analysis (ssGSEA). The correlations between gene networks and immune scores were determined by weighted gene correlation network analysis (WGCNA). The different immune subgroups were finally divided by consensus clustering. The differentially expressed genes (DEGs) were identified and subsequent functional enrichment analyses were conducted. The hub genes were identified by protein-protein interaction (PPI) network and functional similarities analyses. The immune cell infiltration proportion was determined by the CIBERSORT algorithm. Results: According to the ssGSEA results, the 13 ATAAD samples from the GEO database were divided into high- and low-immune subgroups according to the ssGSEA, WGCNA, and consensus clustering analysis results. Sixty-eight immune-related DEGs (IRDEGs) between the two subgroups were enriched in inflammatory-immune response biological processes, including leukocyte cell-cell adhesion, mononuclear cell migration, and myeloid leukocyte migration. Among these IRDEGs, 8 genes (CXCR4, LYN, CCL19, CCL3L3, SELL, F11R, DPP4, and VAV3) were identified as hub genes that represented immune-related signatures in ATAAD after the PPI and functional similarities analyses. The proportions of infiltrating CD8 T cells and M1 macrophages were significantly higher in ATAAD patients in the immune-high group than the immune-low group. Conclusion: Eight immune-related genes were identified as hub genes representing potential biomarkers and therapeutic targets linked to the immune response in ATAAD patients.
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Project description:BACKGROUND:The purpose of the study was to examine the association between white blood cell count (WBCc) on admission and early outcome in patients with the acute Stanford type A aortic dissection (TAAD). METHODS:From January 2012 to December 2018, we retrospectively evaluated a series of 331 consecutive patients underwent surgery for TAAD in Tongji Hospital. The patients were divided into 2 groups based on the WBCc, i.e. the normal WBCc group (WBCc?11?×?109/L) and leukocytosis group (WBCc>?11?×?109/L). The perioperative data were compared between the 2 groups. The in-hospital mortality and the compositive adverse event including multi-organ dysfunction syndrome, postoperative stroke, tracheotomy, and re-exploration for stopping bleeding were set as end points. Cox regression were used to assess the potential risk factors. RESULTS:The in-hospital mortality was nearly 3 time higher in the leukocytosis group than in the normal WBCc group (20.9% vs.8.1%, P =?0.001), and 15.1% overall. For the circulatory arrest, there was significant higher mortality in patients with leukocytosis than normal WBCc group (26.1%vs.8.9%, P?=?0.001). After adjustment for confounding factors, the leukocytosis was found to be a strong independent predictor of in-hospital mortality (odds ratio?=?3.10; 95% confidence interval 1.38 to 6.97, P?=?0.006). The leukocytosis was also a risk factor of adverse events (odds ratio?=?1.80; 95% confidence interval 1.07 to 3.04, P?=?0.027). CONCLUSIONS:The WBCc within 24?h of admission for TAAD is a strong and independent predictor of in-hospital mortality as well as short-term clinical events. The results of this study have important clinical implications for risk-stratifying patients with TAAD.
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Project description:Total arch replacement using the frozen elephant trunk procedure is performed for true lumen expansion of the descending aorta in patients with type A acute aortic dissection. However, the remodelling effect of the frozen elephant trunk on the dissected descending aorta is unclear. We aimed to evaluate the effect of the frozen elephant trunk on postoperative descending aortic remodelling after surgery. Between December 2012 and January 2020, we retrospectively investigated 24 patients who underwent total arch replacement using the frozen elephant trunk for type A acute aortic dissection. Remodelling of the descending aorta was evaluated using computed tomography. The aortic remodelling effect, based on aortic true lumen ratio, was determined for (i) DeBakey type (type I versus type III retrograde); (ii) thoracic endovascular aneurysm repair reintervention status (reintervention versus no reintervention); and (iii) stent length of the frozen elephant trunk (60 vs 90 mm). Postoperative true lumen ratio significantly increased in the type I dissection group. The true lumen ratio in the no-reintervention group, which had many patients with the type I dissection, significantly increased after the frozen elephant trunk. Aortic remodelling due to the frozen elephant trunk can be expected after type I acute aortic dissections.
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Project description:Background: Aortic dissection (AD) is a life-threatening cardiovascular disease. Pathophysiologically, it has been shown that aortic wall inflammation promotes the occurrence and development of aortic dissection. Thus, the aim of the current research was to determine the inflammation-related biomarkers in AD. Methods: In this study, we conducted differentially expressed genes (DEGs) analysis using the GSE153434 dataset containing 10 type A aortic dissection (TAAD) and 10 normal samples downloaded from the Gene Expression Omnibus (GEO) database. The intersection of DEGs and inflammation-related genes was identified as differential expressed inflammation-related genes (DEIRGs). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed for DEIRGs. We then constructed the protein-protein interaction (PPI) network using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database and identified hub genes using the Cytoscape plugin MCODE. Finally, least absolute shrinkage and selection operator (LASSO) logistic regression was used to construct a diagnostic model. Results: A total of 1728 DEGs were identified between the TAAD and normal samples. Thereafter, 61 DEIRGs are obtained by taking the intersection of DEGs and inflammation-related genes. The GO indicated that DEIRGs were mainly enriched in response to lipopolysaccharide, in response to molecules of bacterial origin, secretory granule membrane, external side of plasma, receptor ligand activity, and signaling receptor activator activity. KEGG analysis indicated that DEIRGs were mainly enriched in cytokine-cytokine receptor interaction, TNF signaling pathway, and proteoglycans in cancer. We identified MYC, SELL, HIF1A, EDN1, SERPINE1, CCL20, IL1R1, NOD2, TLR2, CD69, PLAUR, MMP14, and HBEGF as hub genes using the MCODE plug-in. The ROC indicated these genes had a good diagnostic performance for TAAD. Conclusion: In conclusion, our study identified 13 hub genes in the TAAD. This study will be of significance for the future development of a preventive therapy of TAAD.
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Project description:ObjectivesTo compare the efficacy and prognosis of one-stop hybrid surgery using the elephant trunk procedure for treatment of complex Stanford type B aortic dissection.MethodsWe retrospectively analyzed patients who underwent surgical treatment from January 2014 to July 2019. The patients were divided into those who underwent the elephant trunk procedure (n = 10) and those who underwent one-stop hybrid surgery (n = 10). The cardiopulmonary bypass time, mechanical ventilation time, length of hospital stay, and red blood cell usage were compared between the two groups. All patients' 3-month postoperative aortic computed tomography angiography (CTA) findings were also reviewed.ResultsThe cardiopulmonary bypass time, mechanical ventilation time, and length of hospital stay were significantly shorter and red blood cell usage was significantly lower in the one-stop hybridization group. The aortic cross-clamp time was not significantly different between the two groups. Aortic CTA review after hybrid surgery showed that the true lumen of the descending aorta was almost completely restored at 3 months.ConclusionOne-stop hybrid surgery effectively alleviated the occlusion of the aortic dissection, prevented the need for additional surgery, and expanded the indications for covered-stent endovascular repair.
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Project description:BackgroundThe expression levels of long noncoding RNAs (lncRNAs) and mRNAs in human acute Stanford type A aortic dissecting aneurysm and normal active vascular tissues were compared using the array lncRNA/mRNA expression profile chip technology.MethodsThe tissue samples of 5 patients who presented with Stanford type A aortic dissections and the normal ascending aorta tissues from 5 donor heart transplantation patients receiving surgical treatment in Ganzhou People's Hospital were collected. Hematoxylin and eosin (HE) staining were performed to investigate the structural features of the ascending aortic vascular tissue. Nanodropnd-100 was used to detect the surface level of RNA in 10 samples included in the experiment, to ensure that the quality of the standard was consistent with the core plate detection. NanoDrop ND-1000 was used to detect the RNA expression levels in 10 specimens included in the experiment to ensure that the quality of specimens satisfied the requirements of the microarray detection experiment. The Arraystar Human LncRNA/mRNAV3.0 expression profile chip (8×60K, Arraystar) was used to detect the expression levels of lncRNAs and mRNAs in the tissue samples.ResultsA total of 29,198 lncRNAs and 22,959 mRNA target genes could be detected in the above tissue samples after the initial data were standardized and low-expression information was filtered. The data in the middle of the range of 50% value consistency was higher. The scatterplot results preliminarily suggested that there were large numbers of lncRNAs with increased and decreased expression in Stanford type A aortic dissection tissues compared with normal aortic tissues. The differentially expressed lncRNAs were enriched in BPs including apoptosis, nitric oxide synthesis, estradiol response, angiogenesis, inflammatory response, oxidative stress, and acute response; cell components (CCs) including cytoplasm, nucleus, cytoplasmic matrix, extracellular space, protein complex, and platelet α granule lumen; and MFs including protease binding, zinc ion binding, steroid compound binding, steroid hormone receptor activity, heme binding, protein kinase, cytokine, superoxide dismutase, and nitric oxide synthase activities.ConclusionsGene ontology analysis demonstrated that many genes in Stanford type A aortic dissection were involved in cell biological functions, cell components, and molecular functions through upregulating and downregulating the levels of expression.
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Project description:BackgroundAcute Stanford type A aortic dissection is often fatal, with a high mortality rate and requiring emergency intervention. Salvage surgery aims to keep the patient alive by addressing severe aortic regurgitation, tamponade, primary tear, and organ malperfusion and, if possible, prevent the late dissection-related complications in the proximal and downstream aorta. Unfortunately, no optimal standard treatment or technique to treat this disease exists. Total arch replacement with frozen elephant trunk technique plays an important role in treating acute type A aortic dissection. We aim to describe a modified elephant trunk technique and report its short-term outcomes.MethodsFrom February 2018 to August 2019, 16 patients diagnosed with acute Stanford type A aortic dissection underwent surgery with the modified frozen elephant trunk technique at Xiamen Heart Center (male/female: 9/7; average age: 56.1 ± 7.6 years). All perioperative variables were recorded and analyzed. We measured the diameters of the ascending aorta, aortic arch, and descending aorta on the bifurcation of the pulmonary and abdominal aortas and compared the diameters at admission, before discharge, and 3 months after discharge.ResultsFifteen patients (93.8%) had hypertension. The primary tears were located in the lesser curvature of the aortic arch and ascending aorta in 5 (31.3%) and 9 patients (56.3%), respectively, and no entry was found in 2 patients (12.5%). The dissection extended to the iliac artery and distal descending aorta in 14 (87.6%) and 2 patients (12.5%), respectively. The duration of cardiopulmonary bypass (CPB), cross-clamping, and antegrade cerebral perfusion were 215.8 ± 40.5, 140.8 ± 32.3, and 55.1 ± 15.2 min, respectively. Aortic valve repair was performed in 15 patients (93.8%). Bentall procedure was performed in one patient (6.3%). Another patient received coronary artery repair (6.3%). The diameters at all levels were greater on discharge than those on admission, except the aortic arch. After 3 months, the true lumen diameter distal to the frozen elephant trunk increased, indicating false lumen thrombosis and/or aortic remodeling.ConclusionsThe modified frozen elephant trunk technique for acute Stanford type A aortic dissection is safe and feasible and could be used for organ malperfusion. Short-term outcomes are encouraging, but long-term outcomes require further investigation.
| S-EPMC7579979 | biostudies-literature
Project description:BackgroundReintubation is a serious adverse respiratory event after Stanford type A aortic dissection surgery (AADS), however, published studies focused on reintubation after AADS are very limited worldwide. The objectives of the current study were to establish an early risk prediction model for reintubation after AADS and to clarify its relationship with short-term and long-term prognosis.MethodsPatients undergoing AADS between 2016-2019 in a single institution were identified and divided into two groups based on whether reintubation was performed. Independent predictors were identified by univariable and multivariable analysis and a clinical prediction model was then established. Internal validation was performed using bootstrap method with 1,000 replications. The relationship between reintubation and clinical outcomes was determined by univariable and propensity score matching analysis.ResultsReintubation were performed in 72 of the 492 included patients (14.6%). Three preoperative and one intraoperative predictors for reintubation were identified by multivariable analysis, including older age, smoking history, renal insufficiency and transfusion of intraoperative red blood cells. The model established using the above four predictors showed moderate discrimination (AUC = 0.753, 95% CI, [0.695-0.811]), good calibration (Hosmer-Lemeshow χ2 value = 3.282, P = 0.915) and clinical utility. Risk stratification was performed and three risk intervals were identified. Reintubation was closely associated with poorer in-hospital outcomes, however, no statistically significant association between reintubation and long-term outcomes has been observed in patients who were discharged successfully after surgery.ConclusionsThe requirement of reintubation after AADS is prevalent, closely related to adverse in-hospital outcomes, but there is no statistically significant association between reintubation and long-term outcomes. Predictors were identified and a risk model predicting reintubation was established, which may have clinical utility in early individualized risk assessment and targeted intervention.
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