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International Journal of Molecular... Jan 2024Thoracic aortic aneurysm (TAA) has a prevalence of 0.16-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1-2% of all deaths in Western countries.... (Review)
Review
Thoracic aortic aneurysm (TAA) has a prevalence of 0.16-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1-2% of all deaths in Western countries. Currently, no effective pharmacological therapies have been identified to slow TAA development and prevent TAA rupture. Large TAAs are treated with open surgical repair and less invasive thoracic endovascular aortic repair, both of which have high perioperative mortality risk. Therefore, there is an urgent medical need to identify the cellular and molecular mechanisms underlying TAA development and rupture to develop new therapies. In this review, we summarize animal TAA models including recent developments in porcine and zebrafish models: porcine models can assess new therapeutic devices or intervention strategies in a large mammal and zebrafish models can employ large-scale small-molecule suppressor screening in microwells. The second part of the review covers current views of TAA pathogenesis, derived from recent studies using these animal models, with a focus on the roles of the transforming growth factor-beta (TGFβ) pathway and the vascular smooth muscle cell (VSMC)-elastin-contractile unit. The last part discusses TAA treatment options as they emerge from recent preclinical studies.
Topics: Humans; Animals; Swine; Zebrafish; Aortic Aneurysm, Thoracic; Aortic Rupture; Models, Animal; Muscle Contraction; Mammals
PubMed: 38255976
DOI: 10.3390/ijms25020901 -
Arteriosclerosis, Thrombosis, and... Feb 2024Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our... (Review)
Review
Aortic disease, including dissection, aneurysm, and rupture, carries significant morbidity and mortality and is a notable cause of sudden cardiac death. Much of our knowledge regarding the genetic basis of aortic disease has relied on the study of individuals with Mendelian aortopathies and, until recently, the genetic determinants of population-level variance in aortic phenotypes remained unclear. However, the application of machine learning methodologies to large imaging datasets has enabled researchers to rapidly define aortic traits and mine dozens of novel genetic associations for phenotypes such as aortic diameter and distensibility. In this review, we highlight the emerging potential of genomics for identifying causal genes and candidate drug targets for aortic disease. We describe how deep learning technologies have accelerated the pace of genetic discovery in this field. We then provide a blueprint for translating genetic associations to biological insights, reviewing techniques for locus and cell type prioritization, high-throughput functional screening, and disease modeling using cellular and animal models of aortic disease.
Topics: Animals; Humans; Genomics; Aortic Diseases; Aortic Dissection; Phenotype; Aortic Aneurysm, Thoracic
PubMed: 38095107
DOI: 10.1161/ATVBAHA.123.318771 -
Frontiers in Immunology 2024The crucial role of inflammation in aortic aneurysm (AA) is gaining prominence, while there is still a lack of key cytokines or targets for effective clinical...
BACKGROUND
The crucial role of inflammation in aortic aneurysm (AA) is gaining prominence, while there is still a lack of key cytokines or targets for effective clinical translation.
METHODS
Mendelian randomization (MR) analysis was performed to identify the causal relationship between 91 circulating inflammatory proteins and AA and between 731 immune traits and AA. Bulk RNA sequencing data was utilized to demonstrate the expression profile of the paired ligand-receptor. Gene enrichment analysis, Immune infiltration, and correlation analysis were employed to deduce the potential role of CX3CR1. We used single-cell RNA sequencing data to pinpoint the localization of CX3CL1 and CX3CR1, which was further validated by multiplex immunofluorescence staining. Cellchat analysis was utilized to infer the CX3C signaling pathway. Trajectory analysis and the Cytosig database were exploited to determine the downstream effect of CX3CL1-CX3CR1.
RESULTS
We identified 4 candidates (FGF5, CX3CL1, IL20RA, and SCF) in multiple two-sample MR analyses. Subsequent analysis of the expression profile of the paired receptor revealed the significant upregulation of CX3CR1 in AA and its positive correlation with pro-inflammatory macrophages. Two sample MR between immune cell traits and AA demonstrated the potential causality between intermediate monocytes and AA. We finally deciphered in single-cell sequencing data that CX3CL1 sent by endothelial cells (ECs) acted on CX3CR1 of intermediated monocytes, leading to its recruitment and pro-inflammatory responses.
CONCLUSION
Our study presented a genetic insight into the pathogenetic role of CX3CL1-CX3CR1 in AA, and further deciphered the CX3C signaling pathway between ECs and intermediate monocytes.
Topics: CX3C Chemokine Receptor 1; Humans; Chemokine CX3CL1; Mendelian Randomization Analysis; Aortic Aneurysm; Gene Expression Profiling; Transcriptome; Signal Transduction; Genetic Predisposition to Disease
PubMed: 38715600
DOI: 10.3389/fimmu.2024.1383607 -
Frontiers in Immunology 2023Aortic aneurysms (AA) are prevalent worldwide with a notable absence of drug therapies. Thus, identifying potential drug targets is of utmost importance. AA often...
INTRODUCTION
Aortic aneurysms (AA) are prevalent worldwide with a notable absence of drug therapies. Thus, identifying potential drug targets is of utmost importance. AA often presents in the elderly, coupled with consistently raised serum inflammatory markers. Given that ageing and inflammation are pivotal processes linked to the evolution of AA, we have identified key genes involved in the inflammaging process of AA development through various bioinformatics methods, thereby providing potential molecular targets for further investigation.
METHODS
The transcriptome data of AA was procured from the datasets GSE140947, GSE7084, and GSE47472, sourced from the NCBI GEO database, whilst gene data of ageing and inflammation were obtained from the GeneCards Database. To identify key genes, differentially expressed analysis using the "Limma" package and WGCNA were implemented. Protein-protein intersection (PPI) analysis and machine learning (ML) algorithms were employed for the screening of potential biomarkers, followed by an assessment of the diagnostic value. Following the acquisition of the hub inflammaging and AA-related differentially expressed genes (IADEGs), the TFs-mRNAs-miRNAs regulatory network was established. The CIBERSORT algorithm was utilized to investigate immune cell infiltration in AA. The correlation of hub IADEGs with infiltrating immunocytes was also evaluated. Lastly, wet laboratory experiments were carried out to confirm the expression of hub IADEGs.
RESULTS
342 and 715 AA-related DEGs (ADEGs) recognized from GSE140947 and GSE7084 datasets were procured by intersecting the results of "Limma" and WGCNA analyses. After 83 IADEGs were obtained, PPI analysis and ML algorithms pinpointed 7 and 5 hub IADEGs candidates respectively, and 6 of them demonstrated a high diagnostic value. Immune cell infiltration outcomes unveiled immune dysregulation in AA. In the wet laboratory experiments, 3 hub IADEGs, including BLNK, HLA-DRA, and HLA-DQB1, finally exhibited an expression trend in line with the bioinformatics analysis result.
DISCUSSION
Our research identified three genes - BLNK, HLA-DRA, and HLA-DQB1- that play a significant role in promoting the development of AA through inflammaging, providing novel insights into the future understanding and therapeutic intervention of AA.
Topics: Aged; Humans; HLA-DR alpha-Chains; Genes, MHC Class II; Aortic Aneurysm; Cancer Vaccines; Computational Biology; Inflammation
PubMed: 37744379
DOI: 10.3389/fimmu.2023.1260688 -
Heart (British Cardiac Society) Oct 2023In patients with abdominal aortic aneurysms, sodium [F]fluoride positron emission tomography identifies aortic microcalcification and disease activity. Increased uptake...
OBJECTIVE
In patients with abdominal aortic aneurysms, sodium [F]fluoride positron emission tomography identifies aortic microcalcification and disease activity. Increased uptake is associated with aneurysm expansion and adverse clinical events. The effect of endovascular aneurysm repair (EVAR) on aortic disease activity and sodium [F]fluoride uptake is unknown. This study aimed to compare aortic sodium [F]fluoride uptake before and after treatment with EVAR.
METHODS
In a preliminary proof-of-concept cohort study, preoperative and post-operative sodium [F]fluoride positron emission tomography-computed tomography angiography was performed in patients with an infrarenal abdominal aortic aneurysm undergoing EVAR according to current guideline-directed size treatment thresholds. Regional aortic sodium [F]fluoride uptake was assessed using aortic microcalcification activity (AMA): a summary measure of mean aortic sodium [F]fluoride uptake.
RESULTS
Ten participants were recruited (76±6 years) with a mean aortic diameter of 57±2 mm at time of EVAR. Mean time from EVAR to repeat scan was 62±21 months. Prior to EVAR, there was higher abdominal aortic AMA when compared with the thoracic aorta (AMA 1.88 vs 1.2; p<0.001). Following EVAR, sodium [F]fluoride uptake was markedly reduced in the suprarenal (ΔAMA 0.62, p=0.03), neck (ΔAMA 0.72, p=0.02) and body of the aneurysm (ΔAMA 0.69, p=0.02) while it remained unchanged in the thoracic aorta (ΔAMA 0.11, p=0.41).
CONCLUSIONS
EVAR is associated with a reduction in AMA within the stented aortic segment. This suggests that EVAR can modify aortic disease activity and aortic sodium [F]fluoride uptake is a promising non-invasive surrogate measure of aneurysm disease activity.
Topics: Humans; Aortic Aneurysm, Abdominal; Fluorides; Endovascular Aneurysm Repair; Cohort Studies; Blood Vessel Prosthesis Implantation; Treatment Outcome; Endovascular Procedures; Calcinosis; Retrospective Studies; Risk Factors; Blood Vessel Prosthesis
PubMed: 37164479
DOI: 10.1136/heartjnl-2023-322514 -
BMC Cardiovascular Disorders Apr 2024One of the pathogenic causes of thoracic aortic aneurysm (TAA), a dangerous vascular condition that can cause aortic rupture, is autoimmune disorders. Currently, immune...
One of the pathogenic causes of thoracic aortic aneurysm (TAA), a dangerous vascular condition that can cause aortic rupture, is autoimmune disorders. Currently, immune cell clustering is becoming more and more refined, and the specific immune cell phenotypes involved are yet unknown. Here, we want to clarify the causal link between TAA risk and 731 immune cell traits. There was a Mendelian randomization analysis (MR). We discovered that the presence of TAA led to an increase in CD45 on CD33 HLA-DR myeloid cells, an increase in CD45 on natural killer cells, and a decrease in FSC-A on granulocytes after applying FDR correction. Our research also revealed a strong correlation between the incidence of TAA and an increase in immune cells with CD3 on CD39 CD4, and CD25 on IgD CD27 phenotypes. Through genetic techniques, our research has shown the intimate relationship between immune cells and TAA, offering direction for future clinical investigations.
Topics: Humans; Mendelian Randomization Analysis; Aortic Aneurysm, Thoracic; Aortic Rupture; Autoimmune Diseases; Cluster Analysis; Genome-Wide Association Study
PubMed: 38627614
DOI: 10.1186/s12872-024-03876-1 -
Current Problems in Cardiology Mar 2024In this study we correlated changes of risk factors for cardiovascular diseases with trends of age standardized mortality rates and burden for aortic aneurysms and... (Review)
Review
BACKGROUND
In this study we correlated changes of risk factors for cardiovascular diseases with trends of age standardized mortality rates and burden for aortic aneurysms and dissections.
METHODS
We analyzed data from the Global Burden of Diseases and EUROSTAT.
FINDINGS
There was a significant increase of expenditure for health from 1980 and 2019. In the period 1980-2000, despite higher health spending, age standardized mortality rates increased in almost all European countries. During the period 2000-2019, in Western European Countries and in Poland, Estonia, Latvia, Slovenia there was a correlation between higher health expenditure and decrease of ASMR. The most important changes between the period 1980-2000 and the period 2000-2019 was the proportion of health expenditure devoted to preventive care and to the increased use of aspirin and statins.
INTERPRETATION
Information about risk factors for cardiovascular diseases have leads to decreased aortic aneurysm related mortality and burden.
Topics: Humans; Aortic Aneurysm; Estonia; Aspirin; Risk Factors; Dissection
PubMed: 38184128
DOI: 10.1016/j.cpcardiol.2024.102384 -
Vascular Health and Risk Management 2024It has been documented that large-artery stiffness is independently associated with increased cardiovascular risk and may potentially lead to heart and kidney failure... (Review)
Review
It has been documented that large-artery stiffness is independently associated with increased cardiovascular risk and may potentially lead to heart and kidney failure and cerebrovascular disease. A systematic review of studies investigating changes in arterial stiffness in patients undergoing endovascular repair of aortic disease was conducted. In addition, a review of the available literature was performed, analyzing findings from studies using the cardio-ankle vascular index (CAVI) as a marker of arterial stiffness. Overall, 26 studies were included in the present analysis. Our research revealed a high heterogeneity of included studies regarding the techniques used to assess the aortic stiffness. Aortic stiffness was assessed by pulse wave velocity (PWV), elastic modulus (Ep), and augmentation index (AI). Currently a few studies exist investigating the role of CAVI in patients having an aortic aneurysm or undergoing endovascular aortic repair. The majority of studies showed that the treatment of an abdominal aortic aneurysm (AAA) either with open repair (OR) or endovascular aortic repair (EVAR) reduces aortic compliance significantly. Whether EVAR reconstruction might contribute a higher effect on arterial stiffness compared to OR needs further focused research. An increase of arterial stiffness was uniformly observed in studies investigating patients following thoracic endovascular aortic repair (TEVAR), and the effect was more pronounced in young patients. The effects of increased arterial stiffness after EVAR and TEVAR on the heart and the central hemodynamic, and an eventual effect on cardiac systolic function, need to be further investigated and evaluated in large studies and special groups of patients.
Topics: Humans; Vascular Stiffness; Blood Vessel Prosthesis Implantation; Pulse Wave Analysis; Endovascular Procedures; Aortic Aneurysm, Abdominal; Treatment Outcome; Retrospective Studies; Risk Factors
PubMed: 38374913
DOI: 10.2147/VHRM.S410736 -
European Radiology Aug 2023The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm... (Observational Study)
Observational Study
OBJECTIVE
The aim of this study was to assess whether aortic peak wall stress (PWS) and peak wall rupture index (PWRI) were associated with the risk of abdominal aortic aneurysm (AAA) rupture or repair (defined as AAA events) among participants with small AAAs.
METHODS
PWS and PWRI were estimated from computed tomography angiography (CTA) scans of 210 participants with small AAAs (≥ 30 and ≤ 50 mm) prospectively recruited between 2002 and 2016 from two existing databases. Participants were followed for a median of 2.0 (inter-quartile range 1.9, 2.8) years to record the incidence of AAA events. The associations between PWS and PWRI with AAA events were assessed using Cox proportional hazard analyses. The ability of PWS and PWRI to reclassify the risk of AAA events compared to the initial AAA diameter was examined using net reclassification index (NRI) and classification and regression tree (CART) analysis.
RESULTS
After adjusting for other risk factors, one standard deviation increase in PWS (hazard ratio, HR, 1.56, 95% confidence intervals, CI 1.19, 2.06; p = 0.001) and PWRI (HR 1.74, 95% CI 1.29, 2.34; p < 0.001) were associated with significantly higher risks of AAA events. In the CART analysis, PWRI was identified as the best single predictor of AAA events at a cut-off value of > 0.562. PWRI, but not PWS, significantly improved the classification of risk of AAA events compared to the initial AAA diameter alone.
CONCLUSION
PWS and PWRI predicted the risk of AAA events but only PWRI significantly improved the risk stratification compared to aortic diameter alone.
KEY POINTS
• Aortic diameter is an imperfect measure of abdominal aortic aneurysm (AAA) rupture risk. • This observational study of 210 participants found that peak wall stress (PWS) and peak wall rupture index (PWRI) predicted the risk of aortic rupture or AAA repair. • PWRI, but not PWS, significantly improved the risk stratification for AAA events compared to aortic diameter alone.
Topics: Humans; Risk Assessment; Aortography; Stress, Mechanical; Finite Element Analysis; Retrospective Studies; Aortic Aneurysm, Abdominal; Risk Factors; Aorta, Abdominal
PubMed: 36897345
DOI: 10.1007/s00330-023-09488-1 -
International Journal of Molecular... May 2024Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other... (Review)
Review
Abdominal aortic aneurysm (AAA) has been recognized as a serious chronic inflammatory degenerative aortic disease in recent years. At present, there is no other effective intervention except surgical treatment for AAA. With the aging of the human population, its incidence is increasing year by year, posing a serious threat to human health. Modern studies suggest that vascular chronic inflammatory response is the core process in AAA occurrence and development. Inflammasome, a multiprotein complex located in the cytoplasm, mediates the expression of various inflammatory cytokines like interleukin (IL)-1β and IL-18, and thus plays a pivotal role in inflammation regulation. Therefore, inflammasome may exert a crucial influence on the progression of AAA. This article reviews some mechanism studies to investigate the role of inflammasome in AAA and then summarizes several potential drugs targeting inflammasome for the treatment of AAA, aiming to provide new ideas for the clinical prevention and treatment of AAA beyond surgical methods.
Topics: Aortic Aneurysm, Abdominal; Humans; Inflammasomes; Animals; Inflammation
PubMed: 38732221
DOI: 10.3390/ijms25095001