scholarly journals Pharmacological inhibition of Factor XIIa attenuates abdominal aortic aneurysm, reduces atherosclerosis, and stabilizes atherosclerotic plaques

2021 ◽  
Author(s):  
Amy K Searle ◽  
Yung Chih Chen ◽  
Maria Wallert ◽  
James McFadyen ◽  
Ana Maluenda ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Abdominal Aortic Aneurysm ◽  
Cardiovascular Diseases ◽  
Aortic Aneurysm ◽  
Mouse Models ◽  
Atherosclerotic Plaque ◽  
Plaque Burden ◽  
Markers Of Inflammation ◽  
Abdominal Aortic ◽  
Tandem Stenosis

Background: 3F7 is a monoclonal antibody targeting the enzymatic pocket of FXIIa, thereby inhibiting its catalytic activity. Given the emerging role of FXIIa in promoting thrombo-inflammation, along with its apparent redundancy for haemostasis, the selective inhibition of FXIIa represents a novel and highly attractive approach targeting pathogenic processes that cause thromboinflammation-driven cardiovascular diseases. Methods: The effects of FXIIa inhibition were investigated using three distinct mouse models of cardiovascular disease - angiotensin II-induced abdominal aortic aneurysm (AAA), an ApoE-/- model of atherosclerosis, and a tandem stenosis model of atherosclerotic plaque instability. 3F7 or its isotype control, BM4, were administered to mice (10 mg/kg) on alternate days for 4 to 8 weeks, depending on the experimental model. Mice were examined for the development and size of AAAs, or the burden and instability of atherosclerosis and associated markers of inflammation. Results: Inhibition of FXIIa resulted in a reduced incidence of larger AAAs, with less acute aortic ruptures and an associated fibro-protective phenotype. FXIIa inhibition also decreased stable atherosclerotic plaque burden and achieved plaque stabilization associated with increased deposition of fibrous structures, a >2-fold thicker fibrous cap, increased cap-to-core ratio, and reduction in localized and systemic inflammatory markers. Conclusions: Inhibition of FXIIa attenuates disease severity across three mouse models of thromboinflammation-driven cardiovascular diseases. Specifically, the FXIIa-inhibiting monoclonal antibody 3F7 reduces AAA severity, inhibits the development of atherosclerosis, and stabilizes vulnerable plaques. Ultimately, clinical trials in patients with cardiovascular diseases such as AAA and atherosclerosis are warranted to demonstrate the therapeutic potential of FXIIa inhibition.

scholarly journals Systematic Review and Meta-Analysis of Interventions to Slow Progression of Abdominal Aortic Aneurysm in Mouse Models

2021 ◽  
Author(s):  
James Phie ◽  
Shivshankar Thanigaimani ◽  
Jonathan Golledge
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Mouse Models ◽  
Meta Analysis ◽  
Renin Angiotensin System ◽  
Angiotensin System ◽  
Renin Angiotensin ◽  
Model Studies ◽  
Abdominal Aortic ◽  
Meta Analyses

Objective: There are no current effective abdominal aortic aneurysm (AAA) drug therapies. An important limitation of most preclinical studies is that they test the effect of drugs on AAA formation rather than AAA progression. The aim of this study was to systematically review AAA mouse model studies that have tested the effect of interventions in limiting the progression of preestablished AAA. Approach and Results: The literature search identified 35 studies meeting eligibility, and 30 (n=935 mice) contributed to the meta-analyses. AAAs were induced with angiotensin II (n=745 mice), calcium chloride (n=91 mice), or elastase (n=99 mice). Anti-inflammatory drugs (standardized mean difference [SMD], 1.62 [95% CI, 0.93–2.30]), protease inhibitors (SMD, 1.23 [95% CI, 0.52–1.95]), stem cells (SMD, 1.64 [95% CI, 1.05–2.24]), antiplatelet or anticoagulant drugs (SMD, 0.93 [95% CI, 0.63–1.22]), and renin-angiotensin system inhibitors (SMD, 1.45 [95% CI, 0.58–2.33]) reduced AAA diameter. Interventions initiated soon after model induction commenced were more likely to reduce AAA diameter (R 2 , 16%; P =0.007). Funnel plots suggested possible publication bias. Most studies did not report blinding or sample size calculations, and the risk of bias was considered medium or high in 20 (57%) of the 35 studies. Conclusions: There is low-quality evidence that a range of drugs are effective in limiting AAA progression when administered early after AAA induction in mouse models. Some of these drugs, such as antiplatelet and renin-angiotensin system inhibitors, have been reported to be ineffective in clinical trials.

scholarly journals A preclinical ultrasound method for the assessment of vascular disease progression in murine models

Ultrasound ◽  
2018 ◽  
Vol 27 (2) ◽  
pp. 85-93
Author(s):  
Justyna Janus ◽  
Baris Kanber ◽  
Wadhah Mahbuba ◽  
Charlotte Beynon ◽  
Kumar V Ramnarine ◽  
...  
Keyword(s):  
Image Processing ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Vascular Disease ◽  
Mouse Models ◽  
Murine Models ◽  
Analysis Method ◽  
Manual Analysis ◽  
Abdominal Aortic ◽  
Automatic Image Processing

Introduction The efficacy of preclinical ultrasound at providing a quantitative assessment of mouse models of vascular disease is relatively unknown. In this study, preclinical ultrasound was used in combination with a semi-automatic image processing method to track arterial distension alterations in mouse models of abdominal aortic aneurysm and atherosclerosis. Methods Longitudinal B-mode ultrasound images of the abdominal aorta were acquired using a preclinical ultrasound scanner. Arterial distension was assessed using a semi-automatic image processing algorithm to track vessel wall motion over the cardiac cycle. A standard, manual analysis method was applied for comparison. Results Mean arterial distension was significantly lower in abdominal aortic aneurysm mice between day 0 and day 7 post-onset of disease (p < 0.01) and between day 0 and day 14 (p < 0.001), while no difference was observed in sham control mice. Manual analysis detected a significant decrease (p < 0.05) between day 0 and day 14 only. Atherosclerotic mice showed alterations in arterial distension relating to genetic modification and diet. Arterial distension was significantly lower (p < 0.05) in Ldlr−/− (++/−−) mice fed high-fat western diet when compared with both wild type (++/++) mice and Ldlr−/− (++/−−) mice fed chow diet. The manual method did not detect a significant difference between these groups. Conclusions Arterial distension can be used as an early marker for the detection of arterial disease in murine models. The semi-automatic analysis method provided increased sensitivity to differences between experimental groups when compared to the manual analysis method.

scholarly journals Markers of inflammation in men with small abdominal aortic aneurysm

2010 ◽  
Vol 52 (1) ◽  
pp. 145-151 ◽  
Author(s):  
Duncan J. Parry ◽  
Hamad S. Al-Barjas ◽  
Louise Chappell ◽  
S. Tawqeer Rashid ◽  
Robert A.S. Ariëns ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Markers Of Inflammation ◽  
Abdominal Aortic

Anemia is Associated With Mortality Following Endovascular Repair of Abdominal Aortic Aneurysm

2012 ◽  
Vol 46 (3) ◽  
pp. 223-228 ◽  
Author(s):  
Athanasios Saratzis ◽  
Nikolaos Melas ◽  
James P. Hunter ◽  
Hannah Dixon ◽  
Peter Nightingale ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Endovascular Repair ◽  
Inflammatory Markers ◽  
Cox Regression ◽  
Reactive Protein ◽  
Markers Of Inflammation ◽  
Kaplan Meier ◽  
Abdominal Aortic ◽  
The Impact

Aim: The aim of this study was to compare midterm mortality between anemic and nonanemic patients undergoing endovascular repair of abdominal aortic aneurysm and to assess a correlation with markers of inflammation. Methods: Anemia was defined as hemoglobin <13 (men) and <12 g/dL (women). The impact of anemia and inflammatory markers on mortality was assessed using Kaplan-Meier curves and Cox regression. Results: A total of 224 patients (12 females [5.36%]; age: 69.73 ± 8.72 years) were included; 102 (45.53%) were anemic. Median follow-up was 17 months (interquartile range: 7-25 months). Nine patients died (1.79%; 8 anemic vs 1 nonanemic). Survival was lower for patients with anemia (log-rank, P = .01). White blood cell count and C-reactive protein (CRP) differed significantly ( P < .001 and P = .01). Anemia and CRP were associated with decreased survival (Cox regression, P = .01, hazard ratio [HR]: 0.35, 95% confidence interval: 0.14-0.84 and P = .002, HR: 1.18, 95% CI: 1.06-1.31). Conclusion: Patients with anemia had decreased survival over the midterm; inflammatory markers were higher among this group.

scholarly journals Effects of Atherosclerotic Plaque on the Enlargement of an Experimental Model of Abdominal Aortic Aneurysm in Rabbits

2004 ◽  
Vol 28 (1) ◽  
pp. 71-78 ◽  
Author(s):  
H Kobayashi ◽  
M Matsushita ◽  
K Oda ◽  
N Nishikimi ◽  
T Sakurai ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Experimental Model ◽  
Atherosclerotic Plaque ◽  
Abdominal Aortic

Abstract P340: Associations between Subclinical Carotid Atherosclerosis and Future Risk of Abdominal Aortic Aneurysm: the Atherosclerosis Risk in Community (ARIC) Study

Circulation ◽  
2014 ◽  
Vol 129 (suppl_1) ◽  
Author(s):  
Lu Yao ◽  
Alvaro Alonso ◽  
Pamela Lutsey ◽  
Susan Cheng ◽  
Aaron Folsom ◽  
...  
Keyword(s):  
Risk Factors ◽  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Atherosclerotic Plaque ◽  
Carotid Atherosclerosis ◽  
Density Lipoprotein ◽  
Carotid Atherosclerotic Plaque ◽  
Carotid Ultrasound ◽  
Abdominal Aortic ◽  
Future Risk

Background: Abdominal aortic aneurysm (AAA) is a potentially lethal vasculopathy that shares multiple risk factors with conventional atherosclerotic disease, including advanced age, male sex, hypertension, and smoking. However, it is still debated whether subclinical atherosclerosis is an independent risk factor for AAA. Hypothesis: Subclinical carotid atherosclerosis is positively associated with future risk of AAA, independent of shared cardiovascular risk factors. Methods: We included 15,363 ARIC participants (74% whites) who had measures of carotid ultrasound at baseline (1987-89) at 45-64 years of age. Carotid intima-media thickness (cIMT) was measured bilaterally in the common carotid artery, carotid bifurcation, and internal carotid artery. Mean cIMT was estimated by combining the averages of cIMT measures at the 6 carotid sites. The presence of atherosclerotic plaque at any of the 6 segments was defined based on wall thickness ≥1.5 mm, or the presence of luminal encroachment or irregular intimal surface, or characteristics of arterial wall structural heterogeneity. Clinical AAAs were ascertained through hospital discharge diagnoses and death certificates through 2010. We used Cox proportional hazard models to examine the association between baseline carotid ultrasound measures and subsequent occurrence of clinical AAA. Results: In the total study sample (age 54±6 years, 45% men), the median (25 th to 75 th percentiles) cIMT at baseline was 0.71 (0.62 to 0.82) mm. Over an average of 21 years of follow up, a total of 392 clinical AAAs (74% male and 85% Whites) were ascertained. After adjustment for age, sex and race, participants in the highest quartile of baseline cIMT had 2.25 times higher risk of AAA (95% CI: 1.81, 2.79) compared to those in the lower 75 percentile. The presence of carotid atherosclerotic plaque at baseline was associated with 1.77 times increased risk of AAA (95% CI: 1.44, 2.17) after adjustment for age, sex and race. The associations for cIMT and atherosclerotic plaque remained significant after additional adjustment for baseline height, pack-years of smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and hypertension: HR=1.66 (95% CI: 1.32, 2.08) for cIMT quartile 4 vs lower 75 percentile and 1.34 (95% CI: 1.08, 1.66) for presence of carotid atherosclerotic plaque. Further exclusion of participants with history of coronary heart disease or stroke at baseline slightly attenuated but did not abolish the associations of cIMT and atherosclerotic plaque with AAA (p<0.05 after the exclusions). Conclusion: Our study findings suggest that subclinical carotid atherosclerosis in middle-age is independently associated with future risk of clinical AAA.

scholarly journals Thrombospondin-1 (TSP1) Contributes to the Development of Vascular Inflammation by Regulating Monocytic Cell Motility in Mouse Models of Abdominal Aortic Aneurysm

2015 ◽  
Vol 117 (2) ◽  
pp. 129-141 ◽  
Author(s):  
Zhenjie Liu ◽  
Stephanie Morgan ◽  
Jun Ren ◽  
Qiwei Wang ◽  
Douglas S. Annis ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Cell Motility ◽  
Mouse Models ◽  
Vascular Inflammation ◽  
Monocytic Cell ◽  
Abdominal Aortic ◽  
Thrombospondin 1

scholarly journals The Impact of Abdominal Aortic Aneurysm on Cardiovascular Diseases

2021 ◽  
Vol 62 (6) ◽  
pp. 1235-1240
Author(s):  
Kyung Jai Ko ◽  
Ju Hwan Yoo ◽  
Hyung Jin Cho ◽  
Mi Hyeong Kim ◽  
Kang Woong Jun ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Cardiovascular Diseases ◽  
Aortic Aneurysm ◽  
Abdominal Aortic ◽  
The Impact
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