-
Signal Transduction and Targeted Therapy Feb 2023Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high... (Review)
Review
Aortic aneurysm is a chronic aortic disease affected by many factors. Although it is generally asymptomatic, it poses a significant threat to human life due to a high risk of rupture. Because of its strong concealment, it is difficult to diagnose the disease in the early stage. At present, there are no effective drugs for the treatment of aneurysms. Surgical intervention and endovascular treatment are the only therapies. Although current studies have discovered that inflammatory responses as well as the production and activation of various proteases promote aortic aneurysm, the specific mechanisms remain unclear. Researchers are further exploring the pathogenesis of aneurysms to find new targets for diagnosis and treatment. To better understand aortic aneurysm, this review elaborates on the discovery history of aortic aneurysm, main classification and clinical manifestations, related molecular mechanisms, clinical cohort studies and animal models, with the ultimate goal of providing insights into the treatment of this devastating disease. The underlying problem with aneurysm disease is weakening of the aortic wall, leading to progressive dilation. If not treated in time, the aortic aneurysm eventually ruptures. An aortic aneurysm is a local enlargement of an artery caused by a weakening of the aortic wall. The disease is usually asymptomatic but leads to high mortality due to the risk of artery rupture.
Topics: Animals; Humans; Aortic Aneurysm, Abdominal; Aortic Rupture; Cohort Studies
PubMed: 36737432
DOI: 10.1038/s41392-023-01325-7 -
Circulation Jan 2020Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal...
BACKGROUND
Sporadic aortic aneurysm and dissection (AAD), caused by progressive aortic smooth muscle cell (SMC) loss and extracellular matrix degradation, is a highly lethal condition. Identifying mechanisms that drive aortic degeneration is a crucial step in developing an effective pharmacologic treatment to prevent disease progression. Recent evidence has indicated that cytosolic DNA and abnormal activation of the cytosolic DNA sensing adaptor STING (stimulator of interferon genes) play a critical role in vascular inflammation and destruction. Here, we examined the involvement of this mechanism in aortic degeneration and sporadic AAD formation.
METHODS
The presence of cytosolic DNA in aortic cells and activation of the STING pathway were examined in aortic tissues from patients with sporadic ascending thoracic AAD. The role of STING in AAD development was evaluated in -deficient () mice in a sporadic AAD model induced by challenging mice with a combination of a high-fat diet and angiotensin II. We also examined the direct effects of STING on SMC death and macrophage activation in vitro.
RESULTS
In human sporadic AAD tissues, we observed the presence of cytosolic DNA in SMCs and macrophages and significant activation of the STING pathway. In the sporadic AAD model, mice showed significant reductions in challenge-induced aortic enlargement, dissection, and rupture in both the thoracic and abdominal aortic regions. Single-cell transcriptome analysis revealed that aortic challenge in wild-type mice induced the DNA damage response, the inflammatory response, dedifferentiation and cell death in SMCs, and matrix metalloproteinase expression in macrophages. These changes were attenuated in challenged mice. Mechanistically, nuclear and mitochondrial DNA damage in SMCs and the subsequent leak of DNA to the cytosol activated STING signaling, which induced cell death through apoptosis and necroptosis. In addition, DNA from damaged SMCs was engulfed by macrophages in which it activated STING and its target interferon regulatory factor 3, which directly induced matrix metalloproteinase-9 expression. We also found that pharmacologically inhibiting STING activation partially prevented AAD development.
CONCLUSIONS
Our findings indicate that the presence of cytosolic DNA and subsequent activation of cytosolic DNA sensing adaptor STING signaling represent a key mechanism in aortic degeneration and that targeting STING may prevent sporadic AAD development.
Topics: Aortic Dissection; Animals; Aortic Rupture; Cytosol; DNA; Female; Male; Membrane Proteins; Mice; Mice, Knockout; Signal Transduction
PubMed: 31887080
DOI: 10.1161/CIRCULATIONAHA.119.041460 -
Deutsches Arzteblatt International Oct 2020
Topics: Aortic Aneurysm, Abdominal; Aortic Rupture; Humans
PubMed: 33568257
DOI: 10.3238/arztebl.2020.0811 -
Deutsches Arzteblatt International Oct 2020This review presents the surgical indications, surgical procedures, and results in the treatment of asymptomatic and ruptured abdominal aortic aneurysms (AAA). (Review)
Review
BACKGROUND
This review presents the surgical indications, surgical procedures, and results in the treatment of asymptomatic and ruptured abdominal aortic aneurysms (AAA).
METHODS
An updated search of the literature on screening, diagnosis, treatment, and follow-up of AAA, based on the German clinical practice guideline published in 2018.
RESULTS
Surgery is indicated in men with an asymptomatic AAA ≥ 5.5 cm and in women, ≥ 5.0 cm. The indication in men is based on four randomized trials, while in women the data are not conclusive. The majority of patients with AAA (around 80%) meanwhile receive endovascular treatment (endovascular aortic repair, EVAR). Open surgery (open aneurysm repair, OAR) is reserved for patients with longer life expectancy and lower morbidity. The pooled 30-day mortality is 1.16% (95% confidence interval [0.92; 1.39]) following EVAR, 3.27% [2.7; 3.83] after OAR. Women have higher operative/interventional mortality than men (odds ratio 1.67%). The mortality for ruptured AAA is extremely high: around 80% of women and 70% of men die after AAA rupture. Ruptured AAA should, if possible, be treated via the endovascular approach, ideally with the patient under local anesthesia. Treatment at specialized centers guarantees the required expertise and infrastructure. Long-term periodic monitoring by mean of imaging (duplex sonography, plus computed tomography if needed) is essential, particularly following EVAR, to detect and (if appropriate) treat endoleaks, to document stable diameter of the eliminated aneurysmal sac, and to determine whether reintervention is necessary (long-term reintervention rate circa 18%).
CONCLUSION
Vascular surgery now offers a high degree of safety in the treatment of patients with asymptomatic AAA. Endovascular intervention is preferred.
Topics: Aortic Aneurysm, Abdominal; Aortic Rupture; Endovascular Procedures; Female; Humans; Male; Odds Ratio; Retrospective Studies; Risk Factors; Treatment Outcome
PubMed: 33568258
DOI: 10.3238/arztebl.2020.0813 -
Revue Medicale de Liege May 2018Ruptured abdominal aortic aneurysm is a cardiovascular emergency associated with a 30 day mortality as high as 70 %. However, recent progresses in the management of... (Review)
Review
Ruptured abdominal aortic aneurysm is a cardiovascular emergency associated with a 30 day mortality as high as 70 %. However, recent progresses in the management of these patients have improved the results. From a surgical point of view, endovascular methods such as balloon occlusion and endovascular repair (EVAR) in patients with suitable anatomy are recommended in order to reduce mortality.
Topics: Aortic Aneurysm, Abdominal; Aortic Rupture; Cardiac Surgical Procedures; Endovascular Procedures; Humans
PubMed: 29926569
DOI: No ID Found -
Clinical Science (London, England :... Aug 2023Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a... (Review)
Review
Abdominal aortic aneurysm (AAA) is a severe vascular disease and a major public health issue with an unmet medical need for therapy. This disease is featured by a progressive dilation of the abdominal aorta, boosted by atherosclerosis, ageing, and smoking as major risk factors. Aneurysm growth increases the risk of aortic rupture, a life-threatening emergency with high mortality rates. Despite the increasing progress in our knowledge about the etiopathology of AAA, an effective pharmacological treatment against this disorder remains elusive and surgical repair is still the unique available therapeutic approach for high-risk patients. Meanwhile, there is no medical alternative for patients with small aneurysms but close surveillance. Clinical trials assessing the efficacy of antihypertensive agents, statins, doxycycline, or anti-platelet drugs, among others, failed to demonstrate a clear benefit limiting AAA growth, while data from ongoing clinical trials addressing the benefit of metformin on aneurysm progression are eagerly awaited. Recent preclinical studies have postulated new therapeutic targets and pharmacological strategies paving the way for the implementation of future clinical studies exploring these novel therapeutic strategies. This review summarises some of the most relevant clinical and preclinical studies in search of new therapeutic approaches for AAA.
Topics: Humans; Aortic Aneurysm, Abdominal; Aorta, Abdominal; Doxycycline; Aortic Rupture; Hydroxymethylglutaryl-CoA Reductase Inhibitors
PubMed: 37559446
DOI: 10.1042/CS20220795 -
Experimental & Molecular Medicine Dec 2023Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta.... (Review)
Review
Aortic aneurysm is a chronic disease characterized by localized expansion of the aorta, including the ascending aorta, arch, descending aorta, and abdominal aorta. Although aortic aneurysms are generally asymptomatic, they can threaten human health by sudden death due to aortic rupture. Aortic aneurysms are estimated to lead to 150,000 ~ 200,000 deaths per year worldwide. Currently, there are no effective drugs to prevent the growth or rupture of aortic aneurysms; surgical repair or endovascular repair is the only option for treating this condition. The pathogenic mechanisms and therapeutic targets for aortic aneurysms have been examined over the past decade; however, there are unknown pathogenic mechanisms involved in cellular heterogeneity and plasticity, the complexity of the transforming growth factor-β signaling pathway, inflammation, cell death, intramural neovascularization, and intercellular communication. This review summarizes the latest research findings and current pathogenic mechanisms of aortic aneurysms, which may enhance our understanding of aortic aneurysms.
Topics: Humans; Aortic Aneurysm, Thoracic; Chronic Disease; Aortic Rupture; Aorta
PubMed: 38036736
DOI: 10.1038/s12276-023-01130-w -
Hypertension (Dallas, Tex. : 1979) Apr 2022
Topics: Aldosterone; Aortic Dissection; Aortic Aneurysm; Aortic Rupture; Humans
PubMed: 35263159
DOI: 10.1161/HYPERTENSIONAHA.122.18888 -
British Journal of Pharmacology Mar 2022Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only... (Review)
Review
Abdominal aortic aneurysm (AAA) rupture is estimated to cause 200,000 deaths each year. Currently, the only treatment for AAA is surgical repair; however, this is only indicated for large asymptomatic, symptomatic or ruptured aneurysms, is not always durable, and is associated with a risk of serious perioperative complications. As a result, patients with small asymptomatic aneurysms or who are otherwise unfit for surgery are treated conservatively, but up to 70% of small aneurysms continue to grow, increasing the risk of rupture. There is thus an urgent need to develop drug therapies effective at slowing AAA growth. This review describes the commonly used mouse models for AAA. Recent research in these models highlights key roles for pathways involved in inflammation and cell turnover in AAA pathogenesis. There is also evidence for long non-coding RNAs and thrombosis in aneurysm pathology. Further well-designed research in clinically relevant models is expected to be translated into effective AAA drugs. LINKED ARTICLES: This article is part of a themed issue on Preclinical Models for Cardiovascular disease research (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.5/issuetoc.
Topics: Animals; Aortic Aneurysm, Abdominal; Aortic Rupture; Disease Models, Animal; Humans; Mice
PubMed: 32914434
DOI: 10.1111/bph.15260 -
The Journal of Thoracic and... Mar 2022Aortic aneurysm and dissection are major life-threatening complications of Marfan syndrome. Avoiding factors that promote aortic damage is critical in managing the care...
OBJECTIVE
Aortic aneurysm and dissection are major life-threatening complications of Marfan syndrome. Avoiding factors that promote aortic damage is critical in managing the care of these patients. Findings from clinical and animal studies raise concerns regarding fluoroquinolone use in patients at risk for aortic aneurysm and dissection. Therefore, we examined the effects of ciprofloxacin on aortic aneurysm and dissection development in Marfan mice.
METHODS
Eight-week-old Marfan mice (Fbn1) were given ciprofloxacin (100 mg/kg/d; n = 51) or vehicle (n = 59) for 4 weeks. Mice were monitored for 16 weeks. Aortic diameters were measured by using ultrasonography, and aortic structure was examined by using histopathologic and immunostaining analyses.
RESULTS
Vehicle-treated Fbn1 mice showed progressive aortic enlargement, with aortic rupture occurring in 5% of these mice. Compared with vehicle-treated Fbn1 mice, ciprofloxacin-treated Fbn1 mice showed accelerated aortic enlargement (P = .01) and increased incidences of aortic dissection (25% vs 47%, P = .03) and rupture (5% vs 25%, P = .005). Furthermore, ciprofloxacin-treated Fbn1 mice had higher levels of elastic fiber fragmentation, matrix metalloproteinase expression, and apoptosis than did vehicle-treated Fbn1 mice.
CONCLUSIONS
Ciprofloxacin accelerates aortic root enlargement and increases the incidence of aortic dissection and rupture in Marfan mice, partially by suppressing lysyl oxidase expression and further compromising the inherited defect in aortic elastic fibers. Our findings substantiate that ciprofloxacin should be avoided in patients with Marfan syndrome.
Topics: Aortic Dissection; Animals; Anti-Bacterial Agents; Aorta; Aortic Aneurysm; Aortic Rupture; Apoptosis; Ciprofloxacin; Dilatation, Pathologic; Disease Progression; Elastic Tissue; Extracellular Matrix Proteins; Female; Fibrillin-1; Genetic Predisposition to Disease; Male; Matrix Metalloproteinases; Mice, Knockout; Phenotype; Protein-Lysine 6-Oxidase; Vascular Remodeling; Mice
PubMed: 34586071
DOI: 10.1016/j.jtcvs.2020.09.069