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Neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of abdominal aortic aneurysms (AAAs). This study has addressed the notion that NET components might serve as AAA biomarkers or novel targets of AAA therapy. Thus, parameters of neutrophil activation and NET formation were measured in plasma. Their diagnostic marker value was explored in 41 AAA patients and 38 healthy controls. The NET parameter citrullinated histone H3 (citH3) was then validated in 63 AAA patients and 63 controls matched for cardiovascular disease. The prognostic marker potential was investigated in 54 observation periods of AAA growth over 6 months. NETs were further assessed in conditioned medium and sections of aortic tissue. CitH3 was found to be increased in blood (median 362 vs 304 ng/mL, P = 0.004) and aortic tissue (50 vs 1.5 ng/mg, P < 0.001) of AAA patients compared to healthy controls and accumulated in the intraluminal thrombus (629 ng/mg). The diagnostic potential of citH3 ranged at 0.705 area under the ROC curve (AUROC) and was validated with the independent sample set. Furthermore, plasma citH3 predicted AAA growth over the next 6 months (AUROC: 0.707, P = 0.015) and dropped significantly after surgical aneurysm repair. In an angiotensin II -based mouse model of experimental AAA, an inhibitor of histone citrullination was applied to

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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.