scholarly journals Targeting the Extracellular Matrix in Abdominal Aortic Aneurysms Using Molecular Imaging Insights

2021 ◽  
Vol 22 (5) ◽  
pp. 2685
Author(s):  
Lisa Adams ◽  
Julia Brangsch ◽  
Bernd Hamm ◽  
Marcus R. Makowski ◽  
Sarah Keller
Keyword(s):  
Extracellular Matrix ◽  
Molecular Imaging ◽  
Molecular Targets ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Type I ◽  
Target Tissue ◽  
Pharmacologic Treatment ◽  
Abdominal Aortic

This review outlines recent preclinical and clinical advances in molecular imaging of abdominal aortic aneurysms (AAA) with a focus on molecular magnetic resonance imaging (MRI) of the extracellular matrix (ECM). In addition, developments in pharmacologic treatment of AAA targeting the ECM will be discussed and results from animal studies will be contrasted with clinical trials. Abdominal aortic aneurysm (AAA) is an often fatal disease without non-invasive pharmacologic treatment options. The ECM, with collagen type I and elastin as major components, is the key structural component of the aortic wall and is recognized as a target tissue for both initiation and the progression of AAA. Molecular imaging allows in vivo measurement and characterization of biological processes at the cellular and molecular level and sets forth to visualize molecular abnormalities at an early stage of disease, facilitating novel diagnostic and therapeutic pathways. By providing surrogate criteria for the in vivo evaluation of the effects of pharmacological therapies, molecular imaging techniques targeting the ECM can facilitate pharmacological drug development. In addition, molecular targets can also be used in theranostic approaches that have the potential for timely diagnosis and concurrent medical therapy. Recent successes in preclinical studies suggest future opportunities for clinical translation. However, further clinical studies are needed to validate the most promising molecular targets for human application.

Abstract 107: Depletion of Plasmacytoid Dendritic Cells Inhibits Experimental Abdominal Aortic Aneurysms

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Baohui Xu ◽  
Haojun Xuan ◽  
Naoki Fujimura ◽  
Sara A Michie ◽  
Ronald L Dalman
Keyword(s):  
Dendritic Cells ◽  
Inflammatory Diseases ◽  
Myeloid Cells ◽  
Abdominal Aortic Aneurysms ◽  
Plasmacytoid Dendritic Cells ◽  
Aortic Aneurysms ◽  
Major Type ◽  
Abdominal Aortic

Introduction: Abdominal aortic aneurysms (AAA) manifest histologic features consistent with other chronic inflammatory diseases. Infiltrating mural myeloid cells (e.g. macrophages) are already recognized as important contributors to aneurysm pathogenesis, however, the role of plasmacytoid dendritic cells (pDC), major type 1 interferon-producing myeloid cells involving in autoimmune diseases and atherosclerosis, has not been previously investigated in this context. Methods and Results: AAAs were created in 12 week old male C57BL/6J mice by transient intra-aortic infusion of porcine pancreatic elastase (PPE). AAA development and progression were assessed via serial ultrasound determination of aortic diameter in vivo , and histology at sacrifice. The fraction of circulating leukocytes identified as pDCs was significantly increased immediately following PPE infusion (aneurysm initiation). Treatment with mPDCA-1 mAb (400 μg i.p. q.o.d.), beginning one day prior to PPE infusion, depleted more than 90% of bone marrow, spleen and peripheral blood pDCs (data not shown) and suppressed subsequent aneurysm development and progression compared to that noted in PPE-infused mice treated with control mAb. mPDCA-1 treatment promoted aortic medial elastin and smooth muscle preservation, while limiting mural macrophage accumulation and neocapillary formation. Conclusion: These findings suggest a role for plasmacytoid dendritic cells in promoting the initiation and progression of experimental abdominal aortic aneurysms.

Method for Incorporating Three-Dimensional Residual Stresses Into Patient-Specific Simulations of Arteries

2013 ◽  
Author(s):  
David M. Pierce ◽  
Thomas E. Fastl ◽  
Hannah Weisbecker ◽  
Gerhard A. Holzapfel ◽  
Borja Rodriguez-Vila ◽  
...  
Keyword(s):  
Medical Imaging ◽  
Three Dimensional ◽  
Constitutive Models ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Patient Specific ◽  
Abdominal Aortic ◽  
Model Geometry ◽  
Reconstructed Model

Through progress in medical imaging, image analysis and finite element (FE) meshing tools it is now possible to extract patient-specific geometries from medical images of, e.g., abdominal aortic aneurysms (AAAs), and thus to study clinically relevant problems via FE simulations. Medical imaging is most often performed in vivo, and hence the reconstructed model geometry in the problem of interest will represent the in vivo state, e.g., the AAA at physiological blood pressure. However, classical continuum mechanics and FE methods assume that constitutive models and the corresponding simulations start from an unloaded, stress-free reference condition.

A Review of the In Vivo and In Vitro Biomechanical Behavior and Performance of Postoperative Abdominal Aortic Aneurysms and Implanted Stent-Grafts

2008 ◽  
Vol 15 (4) ◽  
pp. 468-484 ◽  
Author(s):  
Timothy J. Corbett ◽  
Anthony Callanan ◽  
Liam G. Morris ◽  
Barry J. Doyle ◽  
Pierce A. Grace ◽  
...  
Keyword(s):  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Stent Grafts ◽  
Biomechanical Behavior ◽  
Abdominal Aortic ◽  
And Performance

Abstract 496: Extracellular Matrix Secretion by Vascular Smooth Muscle Cells: Role of MiR-195 and MiR-29b

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Anna Zampetaki ◽  
Xiaoke Yin ◽  
Ursula Mayr ◽  
Renata Gomes ◽  
Sarah Langley ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Muscle Cells ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Vascular Smcs

Rationale: Extracellular matrix (ECM) remodeling is a key function of vascular smooth muscle cells (SMCs). MicroRNAs (miRNAs), in particular the miR-29 family and miR-195, have been implicated in the control of ECM secretion. Objective: To perform a proteomics comparison of miRNA effects on ECM production by vascular SMCs. Methods and Results: Murine SMCs were transfected with miRNA mimics and antimiRs of miR-29b and miR-195, and their conditioned medium was analyzed by mass spectrometry. Both miRNAs targeted a cadre of ECM proteins, including proteoglycans, collagens, proteases, elastin and proteins associated with elastic microfibrils, albeit miR-29 showed a stronger effect. The proteomics findings were subsequently validated at the transcription level using quantitative polymerase chain reaction. Similar to miR-29, in vivo inhibition of miR-195 by intraperitoneal injection of cholesterol bound antagomiRs led to significant alterations of elastin expression in murine aortas. Since elastin degradation is a key event in aortic aneurysm formation, we investigated miR-195 expression in patients. In human aortic aneurysmal tissue, miR-195 expression was reduced compared to non-aneurysmal tissue. In plasma, a comparison between male patients with abdominal aortic aneurysms and controls matched for diabetes and hypertension returned a panel of five highly correlated miRNAs: miR-195, miR-125b, miR-148a, miR-20a and miR-340 showed significant inverse associations with the presence of abdominal aortic aneurysms and aortic diameter, with miR-195 dominating in terms of association strength. Conclusions: Using proteomic analysis, we compared the effect of miR-29 and miR-195 on ECM secretion by vascular SMCs and identified novel miRNA targets. Findings in patients support an important role for miR-195 in vascular remodeling as evidenced by reduced miR-195 expression in human aneurysmal tissue and an inverse correlation between plasma miR-195 levels and aortic diameter.

In vivo demonstration of focal fibrinolytic activity in abdominal aortic aneurysms

1993 ◽  
Vol 7 (6) ◽  
pp. 675-679 ◽  
Author(s):  
Niels Tromholt ◽  
Svend Juul Jørgensen ◽  
Birger Hesse ◽  
Mogens Sandbjerg Hansen
Keyword(s):  
Fibrinolytic Activity ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Abdominal Aortic

Pulsatile Flow in Fusiform Models of Abdominal Aortic Aneurysms: Flow Fields, Velocity Patterns and Flow-Induced Wall Stresses

2004 ◽  
Vol 126 (4) ◽  
pp. 438-446 ◽  
Author(s):  
Robert A. Peattie ◽  
Tiffany J. Riehle ◽  
Edward I. Bluth
Keyword(s):  
Shear Stress ◽  
Pulsatile Flow ◽  
Maximum Shear Stress ◽  
Wall Stress ◽  
Abdominal Aortic Aneurysms ◽  
Flow Fields ◽  
Aortic Aneurysms ◽  
Abdominal Aortic ◽  
Risk Of Rupture

As one important step in the investigation of the mechanical factors that lead to rupture of abdominal aortic aneurysms, flow fields and flow-induced wall stress distributions have been investigated in model aneurysms under pulsatile flow conditions simulating the in vivo aorta at rest. Vortex pattern emergence and evolution were evaluated, and conditions for flow stability were delineated. Systolic flow was found to be forward-directed throughout the bulge in all the models, regardless of size. Vortices appeared in the bulge initially during deceleration from systole, then expanded during the retrograde flow phase. The complexity of the vortex field depended strongly on bulge diameter. In every model, the maximum shear stress occurred at peak systole at the distal bulge end, with the greatest shear stress developing in a model corresponding to a 4.3 cm AAA in vivo. Although the smallest models exhibited stable flow throughout the cycle, flow in the larger models became increasingly unstable as bulge size increased, with strong amplification of instability in the distal half of the bulge. These data suggest that larger aneurysms in vivo may be subject to more frequent and intense turbulence than smaller aneurysms. Concomitantly, increased turbulence may contribute significantly to wall stress magnitude and thereby to risk of rupture.

Morphometry and Classification in Abdominal Aortic Aneurysms: Patient Selection for Endovascular and Open Surgery

1997 ◽  
Vol 4 (1) ◽  
pp. 39-44 ◽  
Author(s):  
Hardy Schumacher ◽  
Hans H. Eckstein ◽  
Friedrich Kallinowski ◽  
Jens Rainer Allenberg
Keyword(s):  
Patient Selection ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Type I ◽  
Infrarenal Aorta ◽  
Iliac Arteries ◽  
Proximal Neck ◽  
Aorta Aneurysm ◽  
Abdominal Aortic ◽  
Selection For

Purpose: To evaluate the anatomic morphology of abdominal aortic aneurysms (AAAs) and compose a classification system to facilitate patient selection for endovascular graft (EVG) repair. Methods: Data on 242 consecutive AAA patients evaluated on a nonemergent basis in a 3.5-year period to July 1996 were prospectively entered into a registry. Patients were examined using sequential intravenous spiral computed tomographic angiography and intraarterial digital subtraction angiography. The data collected and analyzed included: diameters of the supra- and infrarenal aorta, aneurysm, aortoiliac bifurcation, and iliac arteries; lengths of the proximal neck, distal cuff, and aneurysm; degrees of iliac artery tortuosity; and occlusion of the visceral, renal, or iliac arteries. Results: The 242 aneurysms could be easily grouped into three distinctive categories related to the extent of the aneurysmal disease. Type I AAAs (11.2%) had nondilated, thrombus-free infrarenal (15 mm) necks and distal (10 mm) cuffs appropriate for EVG anchoring. In type II and its subgroups (72.3%), a sufficient proximal neck was present, but the aneurysm extended into the iliac arteries; 56% of these were eligible for a bifurcated endograft. In type III (16.5%), a sufficient proximal neck was missing, independent of distal involvement. In all, 51.7% were good EVG candidates based on AAA morphology. Taking into consideration relevant concomitant vascular diseases, proximal iliac kinking, and iliac, renal, or visceral occlusive disease, only 30.2% of the population were potential candidates for an efficient and secure EVG repair using the devices currently available. Conclusions: In contrast to classical open repair, detailed preoperative measurements are recommended for EVG planning. The use of liberal EVG indications may lead to a higher incidence of complications, whereas restrictive morphology-based selection criteria may offer excellent results.

scholarly journals Inhibition of macrophage histone demethylase JMJD3 protects against abdominal aortic aneurysms

2021 ◽  
Vol 218 (6) ◽  
Author(s):  
Frank M. Davis ◽  
Lam C. Tsoi ◽  
William J. Melvin ◽  
Aaron denDekker ◽  
Rachael Wasikowski ◽  
...  
Keyword(s):  
Aortic Rupture ◽  
Critical Role ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Pharmacologic Therapy ◽  
Gene Promoters ◽  
Macrophage Phenotype ◽  
Inflammatory Gene ◽  
Abdominal Aortic

Abdominal aortic aneurysms (AAAs) are a life-threatening disease for which there is a lack of effective therapy preventing aortic rupture. During AAA formation, pathological vascular remodeling is driven by macrophage infiltration, and the mechanisms regulating macrophage-mediated inflammation remain undefined. Recent evidence suggests that an epigenetic enzyme, JMJD3, plays a critical role in establishing macrophage phenotype. Using single-cell RNA sequencing of human AAA tissues, we identified increased JMJD3 in aortic monocyte/macrophages resulting in up-regulation of an inflammatory immune response. Mechanistically, we report that interferon-β regulates Jmjd3 expression via JAK/STAT and that JMJD3 induces NF-κB–mediated inflammatory gene transcription in infiltrating aortic macrophages. In vivo targeted inhibition of JMJD3 with myeloid-specific genetic depletion (JMJD3f/fLyz2Cre+) or pharmacological inhibition in the elastase or angiotensin II–induced AAA model preserved the repressive H3K27me3 on inflammatory gene promoters and markedly reduced AAA expansion and attenuated macrophage-mediated inflammation. Together, our findings suggest that cell-specific pharmacologic therapy targeting JMJD3 may be an effective intervention for AAA expansion.

The Development of Physiological Compliant Abdominal Aortic Aneurysm Models for In Vitro Flow Studies

2009 ◽  
Author(s):  
Timothy J. Corbett ◽  
Barry J. Doyle ◽  
Anthony Callanan ◽  
Tim M. McGloughlin
Keyword(s):  
Abdominal Aortic Aneurysm ◽  
Aortic Aneurysm ◽  
Material Properties ◽  
Abdominal Aortic Aneurysms ◽  
Aortic Aneurysms ◽  
Flow Loop ◽  
The Past ◽  
Abdominal Aortic

A vast amount of experimental research has been undertaken in the past decade to investigate different aspects of preoperative and postoperative abdominal aortic aneurysms (AAAs). Much of this research has been based on the use of mock arteries in an in vitro flow loop to mimic the behaviour of the abdominal aorta in vivo [1]. These models should be reproducible, have consistent material properties, consistent thickness and be physiological in behaviour.

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