Four Surgical Modifications to the Classic Elastase Perfusion Aneurysm Model Enable Haemodynamic Alterations and Extended Elastase Perfusion

Busch, Albert; Chernogubova, Ekaterina; Jin, Hong; Meurer, Felix; Eckstein, Hans‐Henning; Kim, Mia; Maegdefessel, Lars

doi:10.1016/j.ejvs.2018.03.018

Cited by 31 publications

(33 citation statements)

References 34 publications

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“…Additionally, ultrasound imaging showed a reduction in arterial velocity and a 61% increase in volume/length from days 0 to 56, as well as a rapid reduction in circumferential cyclic strain, providing quantitative evidence of decreased pulsatility due to changes in arterial material properties. These results are consistent with previous works that show that a low concentration of PPE results in elastin degradation and collagen turnover, both of which result in hemodynamic and morphological changes in the vessel [16,26]. Lastly, a decrease in iliac circumferential cyclic strain distal to the suture placement provided evidence that the partial iliac artery ligation increased peripheral vessel stiffness.…”

Section: Discussionsupporting

confidence: 92%

Effects of Iliac Stenosis on Abdominal Aortic Aneurysm Formation in Mice and Humans

et al. 2019

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Reduced lower-limb blood flow has been shown to lead to asymmetrical abdominal aortic aneurysms (AAAs) but the mechanism of action is not fully understood. Therefore, small animal ultrasound (Vevo2100, FUJIFILM VisualSonics) was used to longitudinally study mice that underwent standard porcine pancreatic elastase (PPE) infusion (n = 5), and PPE infusion with modified 20% iliac artery stenosis in the left (n = 4) and right (n = 5) iliac arteries. Human AAA computed tomography images were obtained from patients with normal (n = 9) or stenosed left (n = 2), right (n = 1), and bilateral (n = 1) iliac arteries. We observed rapid early growth and rightward expansion (8/9 mice) in the modified PPE groups (p < 0.05), leading to slightly larger and asymmetric AAAs compared to the standard PPE group. Further examination showed a significant increase in TGFβ1 (p < 0.05) and cellular infiltration (p < 0.05) in the modified PPE group versus standard PPE mice. Congruent, yet variable, observations were made in human AAA patients with reduced iliac outflow compared to those with normal iliac outflow. Our results suggest that arterial stenosis at the time of aneurysm induction leads to faster AAA growth with aneurysm asymmetry and increased vascular inflammation after 8 weeks, indicating that moderate iliac stenosis may have upstream effects on AAA progression.

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Section: Discussionsupporting

confidence: 92%

Effects of Iliac Stenosis on Abdominal Aortic Aneurysm Formation in Mice and Humans

et al. 2019

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“…In a murine model, researchers impaired aortic outflow by stenosing one iliac artery and showed increased AAA diameter. 27 Interestingly, in their murine model they observed aneurysms to bulge towards the contralateral side instead of the disturbed side, as found in lower limb amputees and our cases with iliac artery aneurysms. 13…”

Section: Flow Disturbance In the Common Iliac Artery Leads To Aortic supporting

confidence: 70%

Morphology and Hemodynamics in Isolated Common Iliac Artery Aneurysms Impacts Proximal Aortic Remodeling

Parker

Powell

Kelsey

et al. 2019

ATVB

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Objective Isolated common iliac artery aneurysms (CIAA) are rare. Their prognosis and influence on aortoiliac blood flow and remodeling are unclear. We evaluated the hypotheses that morphology at and distal to the aortic bifurcation, together with the associated hemodynamic changes, influence both the natural history of CIAA and proximal aortic remodeling. Approach and Results 25 isolated CIAAs (15 intact, 10 ruptured), in 23 patients were reconstructed and analyzed with computational fluid dynamics: all showed abnormal flow. Then we studied a series of 24 hypothetical aortoiliac geometries in silico with varying abdominal aortic deflection and aortic bifurcation angles: key findings were assessed in an independent validation cohort of 162 patients. Wall shear stress in isolated unilateral CIAAs was lower than the contralateral CIA, 0.38±0.33 Pa versus 0.61±0.24 Pa, inversely associated with CIAA diameter (p<0.001) and morphology (high shear stress in variants distal to a sharp kink). Rupture usually occurred in regions of elevated low and oscillatory shear (LOS) with a wide aortic bifurcation angle. Abdominal aortas deflected towards the CIAA for most unilateral isolated CIAAs (14/21). In silico, wider bifurcation angles created high focal regions of LOS in the CIA. The associations of unilateral CIAA with aortic deflection and CIA diameter with bifurcation angle were confirmed in the validation cohort. Conclusions Decreasing wall shear stress is strongly associated with CIAA progression (larger aneurysms and rupture), whilst abnormal blood flow in the CIAA appears to promote proximal aortic remodeling, with adaptive lateral deflection of the abdominal aorta towards the aneurysmal side.

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“…(11) Treatment started 7 days after aneurysm induction when a small AAA had already developed upon PPE instillation. (7) Lenvatinib completely halted aneurysm growth over the following 3 weeks until sacrifice (fold increase of dilation in Figure 1A, absolute values in Suppl.…”

Section: Lenvatinib Halts Aneurysm Growth In Murine Aaa and Induces Myh11 Expressionmentioning

confidence: 94%

“…(6) However, small animal models remain limited in their ability to mimic human disease, and thus making it impossible to test local and site-specific delivery of therapeutics directly into the aortic wall. (7) To date, several treatment strategies using established drugs with other indications were successfully tested in rodent AAA models (e.g., doxycycline or sartans). Some have even entered small scale clinical trials, however, failed to limit aneurysm growth and rupture risk in patients.…”

Section: Introductionmentioning

confidence: 99%

Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility

Busch¹,

Pauli²,

Winski³

et al. 2021

JCI Insight

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Rationale: To evaluate the repurposing of lenvatinib, a multi tyrosine kinase inhibitor, in limiting experimental abdominal aortic aneurysm (AAA) growth.Objective: AAA is a disease with high morbidity and mortality, especially in case of rupture. No pharmacologic treatment is currently available. Novel therapeutic strategies are targeting vascular smooth muscle cells (VSMC) and angiogenesis.Repurposing of clinically available drugs has proven its benefit to extend treatment strategies and may be suited to halt aortic dilatation.Findings: Porcine pancreatic elastase (PPE) was used to induce murine AAAs.Systemic and local lenvatinib forms of treatment were evaluated, and RNA profiling identified myosin heavy chain 11 (Myh11) as the most deregulated transcript. Daily oral treatment significantly reduced aneurysm formation in two independent mouse models. In addition, a novel large animal aneurysm model in hypercholesterolemic low-density lipoprotein receptor knockout (LDLR -/-) Yucatan minipigs was applied to endovascularly deliver lenvatinib via drug-eluting balloons (DEB). Here, a single local endovascular delivery blocked AAA progression successfully compared to a DEBdelivered control treatment when reaching 28 days post aneurysm induction.Reduced VSMC proliferation and a restored contractile phenotype were observed in animal tissues (murine and porcine), as well as AAA patient-derived cells. Apart from increasing MYH11 levels, lenvatinib reduced downstream ERK signaling. Conclusion:Lenvatinib is a promising new therapy to limit aortic aneurysm expansion upon local endovascular delivery. The tyrosine kinase inhibitor was able to positively affect pathways of key relevance to human AAA disease. The novel endovascular local delivery using DEBs offers new treatment strategies for additional therapies capable of slowing down aneurysm expansion.

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Four Surgical Modifications to the Classic Elastase Perfusion Aneurysm Model Enable Haemodynamic Alterations and Extended Elastase Perfusion

Abstract: The alteration of the classic PPE aneurysm by outflow modulation and further elastase perfusion to the juxtarenal and aortoiliac segment modifies morphology and diameter, and thus increases the translational value in future research.

Cited by 31 publications

References 34 publications

Effects of Iliac Stenosis on Abdominal Aortic Aneurysm Formation in Mice and Humans

Effects of Iliac Stenosis on Abdominal Aortic Aneurysm Formation in Mice and Humans

Morphology and Hemodynamics in Isolated Common Iliac Artery Aneurysms Impacts Proximal Aortic Remodeling

Lenvatinib halts aortic aneurysm growth by restoring smooth muscle cell contractility

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