Experimental aortic aneurysm severity and growth depend on topical elastase concentration and lysyl oxidase inhibition

Abdominal aortic aneurysm (AAA) formation and expansion is highly complex and multifactorial, and the improvement of animal models is an important step to enhance our understanding of AAA pathophysiology. In this study, we explore our ability to influence aneurysm growth in a topical elastase plus β-Aminopropionitrile (BAPN) mouse model by varying elastase concentration and by altering the cross-linking capability of the tissue. To do so, we assess both chronic and acute effects of elastase concentration using volumetric ultrasound. Our results suggest that the applied elastase concentration affects initial elastin degradation, as well as long-term vessel expansion. Additionally, we assessed the effects of BAPN by (1) removing it to restore the cross-linking capability of tissue after aneurysm formation and (2) adding it to animals with stable aneurysms to interrupt cross-linking. These results demonstrate that, even after aneurysm formation, lysyl oxidase inhibition remains necessary for continued expansion. Removing BAPN reduces the aneurysm growth rate to near zero, resulting in a stable aneurysm. In contrast, adding BAPN causes a stable aneurysm to expand. Altogether, these results demonstrate the ability of elastase concentration and BAPN to modulate aneurysm growth rate and severity. The findings open several new areas of investigation in a murine model that mimics many aspects of human AAA.

Age and Sex Dependency of Thoracic Aortopathy in a Mouse Model of Marfan Syndrome

Thoracic aortic aneurysm is one of the manifestations of Marfan syndrome (MFS) that is known to affect men more severely than women. However, the incidence of MFS is similar between men and women. The aim of this study is to show that during pathological aortic dilation, sex-dependent severity of thoracic aortopathy in a mouse model of Marfan syndrome translates into sex-dependent alterations in cells and matrix of the ascending aorta, consequently affecting aortic biomechanics. Fibrillin1 C1041G/+ were used as a mouse model of MFS. Ultrasound measurements from 3-12 months showed increased aortic diameter in Marfan aorta with larger percent increase in diameter for males compared to females. Immunohistochemistry showed decreased contractile smooth muscle cells in Marfan aortic wall compared to healthy aorta, which was accompanied by decreased contractility measured by wire myography. Elastin autofluorescence, second harmonic generation microscopy of collagen fibers and passive biomechanical assessments using myography showed more severe damage to elastin fibers, increased medial fibrosis, and increased stiffness of the aortic wall in MFS males but not females. Male and female heterozygotes showed increased expression of Sca-1-positive adventitial progenitor cells vs. controls at young ages. In agreement with clinical data, Marfan mice demonstrate sex-dependent severity of thoracic aortopathy. It was also shown that aging exacerbates the disease state especially for males. Our findings suggest that female mice are protected from progression of aortic dilation at early ages, leading to a lag in aneurysm growth.

Computational fluid dynamics to access the future risk of ascending aortic aneurysms

Background A methodology to identify patients with ascending aortic aneurysm (AsAA) under high risk of aortic growth is not completely defined. Objective This research seeks to numerically characterize the blood flow and relate resulting stress distribution with AsAA growth. Methods Analytical, observational, single-center study in which a computational fluid dynamics (CFD) protocol was applied to aortic Computed Tomography Angiogram (CTA) images of patients with AsAA. Two (CTA) exams with at least one year of difference were obtained. From the CTA-gathered images, three-dimensional models were generated, and clinical data were registered. Study of velocity field and coherent structures (vortices) was performed aiming to relate them to aneurysm growth or non-growth, and thereafter to compare with the clinical data of these patients. Kolmogorov-Smirnov test was used to evaluate the normality distribution and for non-normal distribution, the non-parametric Wilcoxon signed-rank test was applied for comparisons of paired data of the aortic angles. Statistical significance was set at 5%. Results The incident jet in the aortic wall generated recirculation areas in the posterior region of the jet, inducing complex vortices formation, for the group that presented aneurysm growth, leading to an increase of the average pressure at the ascending aortic wall (Fig. 1), between exams. While for the group without aneurysm growth, the average pressure decreased. Conclusion This pilot study showed that CFD based upon CTA may in the near future be a tool to help identify flow patterns associated with AsAA remodeling process. FUNDunding Acknowledgement Type of funding sources: None. Figure 1. Axialvelocity. Iso-surface-without-growth Figure 2. Isosurface of Q-criterion. Without growth

Hemodynamic changes after intracranial aneurysm growth

OBJECTIVE For accurate risk assessment of unruptured intracranial aneurysms, it is important to understand the underlying mechanisms that lead to rupture. It is known that hemodynamic anomalies contribute to aneurysm growth and rupture, and that growing aneurysms carry higher rupture risks. However, it is unknown how growth affects hemodynamic characteristics. In this study, the authors assessed how hemodynamic characteristics change over the course of aneurysm growth. METHODS The authors included patients with observed aneurysm growth on longitudinal MRA in the period between 2012 and 2016. Patient-specific vascular models were created from baseline and follow-up images. Subsequently, intraaneurysmal hemodynamic characteristics were computed using computational fluid dynamics. The authors computed the normalized wall shear stress, oscillatory shear index, and low shear area to quantify hemodynamic characteristics. Differences between baseline and follow-up measurements were analyzed using paired t-tests. RESULTS Twenty-five patients with a total of 31 aneurysms were included. The aneurysm volume increased by a median (IQR) of 26 (9–39) mm3 after a mean follow-up period of 4 (range 0.4–10.9) years. The median wall shear stress decreased significantly after growth. Other hemodynamic parameters did not change significantly, although large individual changes with large variability were observed. CONCLUSIONS Hemodynamic characteristics change considerably after aneurysm growth. On average, wall shear stress values decrease after growth, but there is a large variability in hemodynamic changes between aneurysms.