Incidence, severity, mortality, and confounding factors for dissecting AAA detection in angiotensin II-infused mice: a meta-analysis

Patrick Segers, Nikolaos Stergiopulos, Bram Trachet
Oxford University Press, 2015
Journal paper

Abstract

Aims While angiotensin II-infused mice are the most popular model for preclinical aneurysm research, representative data on incidence, severity, and mortality of dissecting abdominal aortic aneurysms (AAAs) have never been established, and the influence of confounding factors is unknown. Methods and Results We performed a meta-analysis including 194 manuscripts representing 1679 saline-infused, 4729 non-treated angiotensin II-infused, and 4057 treated angiotensin II-infused mice. Incidence (60%) and mortality (20%) rates are reported overall as well as for grade I (22%), grade II (26%), grade III (29%), and grade IV (24%) aneurysms. Dissecting AAA incidence was significantly (P

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Ascending Aortic Aneurysm in Angiotensin II–Infused Mice: Formation, Progression, and the Role of Focal Dissections

Lydia Aslanidou, Alessandra Piersigilli, Patrick Segers, Jessica Sordet-Dessimoz, Nikolaos Stergiopulos, Bram Trachet

Objective To understand the anatomy and physiology of ascending aortic aneurysms in angiotensin II-infused ApoE(-/-) mice. Approach and Results We combined an extensive in vivo imaging protocol (high-frequency ultrasound and contrast-enhanced microcomputed tomography at baseline and after 3, 10, 18, and 28 days of angiotensin II infusion) with synchrotron-based ultrahigh resolution ex vivo imaging (phase contrast X-ray tomographic microscopy) in n=47 angiotensin II-infused mice and 6 controls. Aortic regurgitation increased significantly over time, as did the luminal volume of the ascending aorta. In the samples that were scanned ex vivo, we observed one or several focal dissections, with the largest located in the outer convex aspect of the ascending aorta. The volume of the dissections moderately correlated to the volume of the aneurysm as measured in vivo (r(2)=0.46). After 3 days of angiotensin II infusion, we found an interlaminar hematoma in 7/12 animals, which could be linked to an intimal tear. There was also a significant increase in single laminar ruptures, which may have facilitated a progressive enlargement of the focal dissections over time. At later time points, the hematoma was resorbed and the medial and adventitial thickness increased. Fatal transmural dissection occurred in 8/47 mice at an early stage of the disease, before adventita remodeling. Conclusions We visualized and quantified the dissections that lead to ascending aortic aneurysms in angiotensin II-infused mice and provided unique insight into the temporal evolution of these lesions.

2016

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation

Peter Modregger, Alessandra Piersigilli, Patrick Segers, Jessica Sordet-Dessimoz, Nikolaos Stergiopulos, Bram Trachet

Aims In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. Methods and results We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. Conclusion Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.

Oxford University Press2015

In a number of cardiovascular diseases, the paucity of longitudinal human data hinders our understanding of disease evolution and forestalls the discovery of new therapeutic strategies. We therefore heavily rely on animal models to elucidate the mechanisms that govern disease development. Nonetheless, the reference mouse arterial physiology and hemodynamics of its systemic circulation have yet to be described. But preclinical research is not limited to healthy mice; it helps decode the elusive etiology of potentially deadly pathologies such as aortic aneurysms and dissections. A key question is: Why are these pathologies so location-specific? In humans, abdominal aortic aneurysms affect the infrarenal aorta and aortic dissections form in the thoracic aorta. Inversely, in the most commonly used mouse model of this field, aortic dissections preferentially form in the suprarenal abdominal aorta but reasons for such localization remain unknown in humans and mice. In Chapter 1 we aimed to fill the knowledge gap of mouse hemodynamics, by translating an existing 1D model of the human arterial circulation to the healthy mouse. The model combines a broad range of literature data with a detailed description of the murine vasculature. Model predictions of pressure and flow were validated against pressure, velocity and diameter measurements from a large independent dataset of mice. This versatile tool can be used to simulate pathology and facilitate the implementation of the 3R's principle in research practice. Our next steps aimed to unravel the origins of site-specific aortic dissections in the mouse model of Angiotensin II infusion. Initially, we imaged the inceptive stage of disease to understand what happens in the suprarenal mouse aorta. Then, we explored why both from a biomechanical and a mechanobiological standpoint. In Chapter 2, we use high-resolution synchrotron imaging to characterize the early morphology of the suprarenal aorta in mice infused with Angiotensin II, prior to overt dissecting events. We found that the primary damage of the wallâs microstructure preferentially occurs around two major side branches of the aorta. After evidence of this direct involvement of side branches in disease onset, we investigated the underlying reasons from two distinct perspectives. In the synchrotron-based computational study of Chapter 3, we hypothesized that biomechanical forces expose branching sites to early vascular injury. We used an in-house framework which enables a. computational structural mechanics of the aortic wall using mouse-specific geometries, and b. mouse-specific validation to indicate whether high mechanical strain spatially coincides with microstructural defects. Branch-related hotspots of strain co-localized with early damaged microstructure, thus pointing towards a mechanically-driven mechanism that nucleates around the aortic branches. In Chapter 4 we explored from a mechanobiological perspective if the suprarenal aorta's vascular function changes prior to dissection. We found a regional variation: both the contractile and the endothelial function were severely compromised in the suprarenal aortaâs dissection-prone segment, but only mildly so in its dissection-protected segments. Surprisingly, vascular function was largely preserved in the adjacent side branches, creating a local discontinuity in the profile of contractile capacity between the (diseased) aorta and the (non-diseased) branches.

EPFL2019

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation

Peter Modregger, Alessandra Piersigilli, Patrick Segers, Jessica Sordet-Dessimoz, Nikolaos Stergiopulos, Bram Trachet

Oxford University Press2015

EPFL2019