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BACKGROUND: To delineate the effects of integrin αv signaling in Marfan syndrome (MFS) and examine the potential efficacy of integrin αv blockade as a therapeutic strategy for MFS aneurysms. METHODS: Induced pluripotent stem cells were differentiated into aortic smooth muscle cells (SMCs) of the second heart field (SHF) and neural crest lineages, enabling in vitro modeling of thoracic aortic aneurysm in MFS. Fbn1 C1039G/+ MFS mice treated with integrin αv antagonist (GLPG0187) confirmed the pathological role of integrin αv on aneurysm formation. RESULTS: Induced pluripotent stem cell–derived MFS SHF SMCs overexpress integrin αv relative to MFS neural crest and healthy control SHF cells. Furthermore, downstream targets of integrin αv (FAK [focal adhesion kinase]/Akt Thr308 /mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment GLPG0187 reduced p-FAK/p-Akt Thr308 /mTORC1 activity in MFS SHF back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS neural crest and control SMCs, which was then inhibited by GLPG0187 treatment. In the Fbn1 C1039G/+ MFS mouse model, integrin αv, p-Akt Thr308 , and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6–14 weeks) resulted in reduced aneurysm growth, elastin fragmentation, and normalization of the FAK/Akt Thr308 /mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. CONCLUSIONS: The integrin αv-FAK-Akt Thr308 signaling pathway is activated in induced pluripotent stem cell SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-Akt Thr308 signaling in Fbn1 C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

Objectives: The susceptibility-vessel-sign (SVS) allows thrombus visualization, length estimation and composition, and it may impact reperfusion during mechanical thrombectomy (MT). SVS can also describe thrombus shape in the occluded artery: in the straight M1-segment (S-shaped), or in an angulated/traversing a bifurcation segment (A-shaped). We determined whether SVS clot shape influenced reperfusion and outcomes after MT for proximal middle-cerebral-artery (M1) occlusions.Methods: Between May 2015 and March 2018, consecutive patients who underwent MT at one comprehensive stroke center and who had a baseline MRI with a T2* sequence were included. Clinical, procedural and radiographic data, including clot shape on SVS [angulated/bifurcation (A-SVS) vs. straight (S-SVS)] and length were assessed. Primary outcome was successful reperfusion (TICI 2b-3). Secondary outcome were MT complication rates, MT reperfusion time, and clinical outcome at 90-days. Predictors of outcome were assessed with univariate and multivariate analyses.Results: A total of 62 patients were included. 56% (35/62) had an A-SVS. Clots were significantly longer in the A-SVS group (19 mm vs. 8 mm p = 0.0002). Groups were otherwise well-matched with regard to baseline characteristics. There was a significantly lower rate of successful reperfusion in the A-SVS cohort (83%) compared to the S-SVS cohort (96%) in multivariable analysis [OR 0.04 (95% CI, 0.002–0.58), p = 0.02]. There was no significant difference in long term clinical outcome between groups.Conclusion: Clot shape as determined on T2* imaging, in patients presenting with M1 occlusion appears to be a predictor of successful reperfusion after MT. Angulated and bifurcating clots are associated with poorer rates of successful reperfusion.

Objectives: Baseline-core-infarct volume is a critical factor in patient selection and outcome in acute ischemic stroke (AIS) before mechanical thrombectomy (MT). We determined whether oxygen extraction efficiency and arterial collaterals, two different physiologic components of the cerebral ischemic cascade, interacted to modulate baseline-core-infarct volume in patients with AIS-LVO undergoing MT triage.Methods: Between January 2015 and March 2018, consecutive patients with an AIS and M1 occlusion considered for MT with a baseline MRI and perfusion-imaging were included. Variables such as baseline-core-infarct volume [mL], arterial collaterals (HIR: TMax > 10 s volume/TMax > 6 s), high oxygen extraction (HOE, presence of the brush-sign on T2*) were assessed. A linear-regression was used to test the interaction of HOE and HIR with baseline-core-infarct volume, after including potential confounding variables.Results: We included 103 patients. Median age was 70 (58–78), and 63% were female. Median baseline-core-infarct volume was 32 ml (IQR 8–74.5). Seventy six patients (74%) had HOE. In a multivariate analysis both favorable HIR collaterals (p = 0.02) and HOE (p = 0.038) were associated with lower baseline-core-infarct volume. However, HOE significantly interacted with HIR (p = 0.01) to predict baseline-core-infarct volume, favorable collaterals (low HIR) with HOE was associated with small baseline-core-infarct whereas patients with poor collaterals (high HIR) and HOE had large baseline-core-infarct.Conclusion: While HOE under effective collateral blood-flow has the lowest baseline-core-infarct volume of all patients, the protective effect of HOE reverses under poor collateral blood-flow and may be a maladaptive response to ischemic stroke as measured by core infarctions in AIS-LVO patients undergoing MT triage.