scholarly journals Recent Advances in Pharmacotherapy Development for Abdominal Aortic Aneurysm

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Koichi Yoshimura ◽  
Hiroki Aoki
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Therapeutic Strategy ◽  
Unmet Need ◽  
Common Disease ◽  
Inflammatory Signaling ◽  
Proinflammatory Mediators ◽  
Abdominal Aortic ◽  
Tissue Degradation ◽  
Pharmacologic Inhibition

Abdominal aortic aneurysm (AAA) is a common disease causing segmental expansion and rupture of the aorta with a high mortality rate. The lack of nonsurgical treatment represents a large and unmet need in terms of pharmacotherapy. Advances in AAA research revealed that activation of inflammatory signaling pathways through proinflammatory mediators shifts the balance of extracellular matrix (ECM) metabolism toward tissue degradation. This idea is supported by experimental evidence in animal models that pharmacologic intervention at each pathological step can prevent AAA development. Previously, we identified c-Jun N-terminal kinase (JNK), a pro-inflammatory signaling molecule, as a therapeutic target for AAA. Abnormal activation of JNK in AAA tissue regulates multiple pathological processes in a coordinated manner. Pharmacologic inhibition of JNK tips the ECM balance back towards repair rather than degradation. Interventions targeting signaling molecules such as JNK in order to manipulate multiple pathological processes may be an ideal therapeutic strategy for AAA. Furthermore, the development of biomarkers as well as appropriate drug delivery systems is essential to produce clinically practical pharmacotherapy for AAA.

Smaller size is more suitable for pharmacotherapy among undersized abdominal aortic aneurysm: a systematic review and meta-analysis

2021 ◽  
pp. 1358863X2110616
Author(s):  
Takuro Shirasu ◽  
Hisato Takagi ◽  
Jun Yasuhara ◽  
Toshiki Kuno ◽  
K Craig Kent ◽  
...  
Keyword(s):  
Systematic Review ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Meta Analysis ◽  
Unmet Need ◽  
Secondary Outcome ◽  
Annual Growth Rate ◽  
Abdominal Aortic ◽  
Significant Difference ◽  
Baseline Diameter

Background: Pharmacotherapy for undersized abdominal aortic aneurysm (AAA) is a clinical unmet need. Randomized controlled trials (RCTs) have failed to show effectiveness despite countless promising data in preclinical studies. We aimed to identify the population with undersized AAAs (30–54 mm) who potentially benefit from pharmacotherapy. Methods: In accordance with the PRISMA statement, we conducted a systematic review and meta-analysis of placebo-controlled RCTs. The primary outcome was mean difference (MD) in annual growth rate (< 0 favors pharmacotherapy), and the secondary outcome was aneurysm-related events (diameters ⩾ 55 mm, ruptures, or referral to surgery). Results: Our search strategy identified eight RCTs (six trials on antibiotics [ABx], two on renin-angiotensin system inhibitors [RAS-I]) with a total of 1325 patients. The mean of baseline diameters ranged from 33.1 mm to 43.1 mm. Neither ABx nor RAS-I showed significant differences in MD. Multivariable random-effects restricted maximum likelihood meta-regression revealed a statistically significant linear relationship between baseline diameter and MD (coefficient 0.15 [95% CI 0.0011, 0.30], p = 0.049) but not for the follow-up period ( p = 0.28) and duration of treatment ( p = 0.11). In line with this result, ABx with baseline diameter < 40 mm significantly reduced MD (−1.03 mm/year [95% CI −1.64, −0.42], p = 0.001) and a borderline significant difference in aneurysm-related events (HR 0.53 [95% CI 0.28, 1.00], p = 0.05), whereas the other groups ⩾ 40 mm never demonstrated effectiveness. Fixed-effect models did not change the results. No evidence of publication bias was detected. Conclusion: Undersized AAAs < 40 mm can potentially benefit from pharmacotherapy. Future RCTs should consider preferentially including undersized AAA with smaller diameters.

scholarly journals Genomic Research to Identify Novel Pathways in the Development of Abdominal Aortic Aneurysm

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Seamus C. Harrison ◽  
Anastasia Z. Kalea ◽  
Michael V. Holmes ◽  
Obi Agu ◽  
Steve E. Humphries
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Genetic Variants ◽  
Association Studies ◽  
Complex Diseases ◽  
Genomic Research ◽  
Common Disease ◽  
Novel Treatment ◽  
Abdominal Aortic ◽  
Analytical Strategies

Abdominal aortic aneurysm (AAA) is a common disease with a large heritable component. There is a need to improve our understanding of AAA pathogenesis in order to develop novel treatment paradigms. Genomewide association studies have revolutionized research into the genetic variants that underpin the development of many complex diseases including AAA. This article reviews the progress that has been made to date in this regard, including mechanisms by which loci identified by GWAS may contribute to the development of AAA. It also highlights potential post-GWAS analytical strategies to improve our understanding of the disease further.

Mechanisms of abdominal aortic aneurysm progression: A review

2021 ◽  
pp. 1358863X2110211
Author(s):  
Jiang-Ping Gao ◽  
Wei Guo
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Treatment Method ◽  
Vasa Vasorum ◽  
Current Evidence ◽  
Common Disease ◽  
Perivascular Adipose Tissue ◽  
Abdominal Aortic ◽  
Cardiovascular Morbidity And Mortality ◽  
Choice Of Treatment

Abdominal aortic aneurysm (AAA) is a common disease associated with significant cardiovascular morbidity and mortality. Up to now, there is still controversy on the choice of treatment method of AAA. Even so, the mechanisms of AAA progression are poorly defined, making targeting new therapies problematic. Current evidence favors an interaction of the hemodynamic microenvironment with local and systemic immune responses. In this review, we aim to provide an update of mechanisms in AAA progression, involving hemodynamics, perivascular adipose tissue, adventitial fibroblasts, vasa vasorum remodeling, intraluminal thrombus, and distribution of macrophage subtypes.

scholarly journals Pharmacologic inhibition of transient receptor channel vanilloid 4 attenuates abdominal aortic aneurysm formation

2020 ◽  
Vol 34 (7) ◽  
pp. 9787-9801
Author(s):  
Alexander H. Shannon ◽  
Craig T. Elder ◽  
Guanyi Lu ◽  
Gang Su ◽  
Alexis Mast ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Aneurysm Formation ◽  
Abdominal Aortic ◽  
Transient Receptor ◽  
Pharmacologic Inhibition ◽  
Receptor Channel

Abstract 106: Prevention of Abdominal Aortic Aneurysm by Anti-MiRNA-712 or Anti-miR-205 in Angiotensin II--Infused Mice

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Chanwoo Kim ◽  
Sandeep Kumar ◽  
Dong Ju Son ◽  
In-Hwan Jang ◽  
Hanjoong Jo
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Therapeutic Strategy ◽  
Vascular Wall ◽  
Matrix Metalloproteases ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Cysteine Rich Protein ◽  
Endogenous Inhibitors ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is characterized by weakening of the vessel wall, followed by progressive expansion of the diseased aortic segment. MicroRNAs (miRNAs) have emerged as key regulator of gene expression in the cardiovascular diseases and may play a key role in therapeutically targeting AAA development. Although,vascular wall degradation by matrix metalloproteases (MMPs) is the key mechanism in AAA development, their targeting through miRNAs have never been studied. We identified microRNA-712 (miR-712) as a novel Angiotensin II(AngII)-sensitive miRNA which is upregulated in the abdominal aortic endothelium of AngII-infused mice. Mechanistically, we identified that miR-712 directly regulates two key endogenous inhibitors of MMP: tissue inhibitor of metalloproteinase 3 (TIMP3) and reversion inducing cysteine-rich protein with kazal motifs (RECK). Furthermore, inhibition of miR-712 by subcutaneous injection of anti-miR-712 significantly decreased MMP activity in the AngII-infused abdominal aorta wall, prevented the dilatation of aortae and significantly reduced AAA incidence from 80% (8/10) to 20% (2/10), compared to its mismatched control in ApoE -/- mice. Interestingly, based on the seeding sequence, we identified miR-205 as the human homolog of miR-712. miR-205 was also upregulated by AngII treatment and like miR-712 regulated MMPs activity via TIMP3 and RECK. Moreover, inhibition of miR-205 dramatically inhibits AngII-induced AAA development. We also found that miR-205 was significantly upregulated in the aortic sections of AAA patients in comparison to the healthy controls. Our findings demonstrate that AngII-sensitive miRNAs, miR-712 and miR-205, regulate MMP activity through TIMP3 and RECK and play important role in the pathogenesis of AAA. These results suggest that targeting these miRNAs using their inhibitors may hold promise as a therapeutic strategy to prevent the development of AAA.

Abstract 65: Interleukin-6 Signaling and Abdominal Aortic Aneurysm

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Seamus C Harrison ◽  
Andrew J Smith ◽  
Gregory T Jones ◽  
Michael V Holmes ◽  
Daniel Swerdlow ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Interleukin 6 ◽  
Meta Analysis ◽  
Common Disease ◽  
Expression Studies ◽  
Abdominal Aortic ◽  
Synonymous Variant ◽  
Reduced Risk

Introduction Abdominal aortic aneurysm (AAA) is a common disease that predisposes to aortic rupture, which has a high mortality. The only intervention that is proven to reduce rupture is invasive surgery. Understanding causal disease pathways may allow development of non-surgical therapies to target AAA formation, progression or rupture. In this study we investigate the role of interleukin-6 and AAA. Methods We performed systematic review and meta-analysis of the published literature in order to determine the association between circulating interleukin-6 (IL-6) and presence of AAA. We then investigated the association between a common non-synonymous variant in the interleukin-6 receptor gene (IL6R) and presence of AAA, performed in vitro functional analyses of this variant, and expression studies in aortic tissue. Results Meta-analysis of seven case-control studies of AAA (infra-renal aortic diameter ≥ 3cm), pooling data from 869 cases and 851 controls demonstrated consistently higher levels of circulating IL-6 in AAA compared to controls (standardised mean difference (SMD) = 0.42 units, 95% CI = 0.32-0.52, I2 = 69.4%, P for fixed effects = 1.29 x 10-16, P for random effects = 1.2 x10-5). There was less heterogeneity when comparing large AAA (>5cm, n = 547), to disease free controls (n = 712) (SMD = 0.46 units, 95% CI 0.34-0.57, I2=31.5, P = 2.2 x 10-14). The rare allele of rs7529229, which tags the non-synonymous variant (p.Asp358Ala, rs2228154) was consistently associated with reduced risk of AAA in meta-analysis of 4 studies, pooling data from 4,708 cases and 15,816 (per allele odds ratio 0.84, 95% CI 0.80-0.89, P = 2.7 x 10-11, I2=0). This variant was also associated with reduced risk incident AAA endpoints (rupture +/- repair) in prospective analysis of 7,888 individuals with known arterial disease (hazard ratio = 0.81, 95% CI 0.67 - 0.99, P = 0.043). Expression studies revealed strong correlation between IL-6 expression target genes (STAT3, MYC, ATF3, BCL3 and ICAM1) in aortic adventitia. In vitro analyses demonstrate that in lymphoblastoid cells, there is a genotype specific reduction in expression of downstream mediators of IL-6 signalling in response to IL-6 stimulation. Conclusions These data indicate that signalling via the IL-6 receptor is likely to be causal in the development of AAA. This suggests that this pathway may represent a novel target for pharmacological treatment of AAA with biological agents such as Tocilizumab, and clinical trials to assess this may be warranted.

Current evidence and prospects for medical treatment of abdominal aortic aneurysms

VASA ◽  
2005 ◽  
Vol 34 (4) ◽  
pp. 217-223 ◽  
Author(s):  
Diehm ◽  
Schmidli ◽  
Dai-Do ◽  
Baumgartner
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Medical Treatment ◽  
Endovascular Treatment ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Current Evidence ◽  
Significant Morbidity ◽  
Abdominal Aortic ◽  
Risk Of Rupture

Abdominal aortic aneurysm (AAA) is a potentially fatal condition with risk of rupture increasing as maximum AAA diameter increases. It is agreed upon that open surgical or endovascular treatment is indicated if maximum AAA diameter exceeds 5 to 5.5cm. Continuing aneurysmal degeneration of aortoiliac arteries accounts for significant morbidity, especially in patients undergoing endovascular AAA repair. Purpose of this review is to give an overview of the current evidence of medical treatment of AAA and describe prospects of potential pharmacological approaches towards prevention of aneurysmal degeneration of small AAAs and to highlight possible adjunctive medical treatment approaches after open surgical or endovascular AAA therapy.

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