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 Outcomes of planned and unplanned (rescue) double arterial cannulation (DAC) in surgery for acute type A aortic dissection were investigated retrospectively. METHODS The study involved 805 patients who were divided into 4 groups according to the cannulation strategy: single cannulation of the femoral artery (n = 338), axillary artery (n = 256), left ventricular apex (n = 52) or ascending aorta (n = 5) (total, n = 57), and DAC (n = 154). Patients who underwent DAC were divided between planned (n = 132) and rescue (n = 22) usage. Characteristics and outcomes were compared between groups. Both unmatched and propensity score-matched analyses were performed. RESULTS Shock (39%, 19%, 33% and 14%, in the femoral artery, axillary artery, left ventricular apex/ascending aorta and DAC, respectively) and leg malperfusion (5%, 16%, 16% and 26%, respectively) differed significantly (P < 0.001), but in-hospital mortality did not (9%, 8%, 18% and 7%, respectively; P = 0.096). The 5-year survival rates were 79.4%, 79.7%, 78.6% and 82.2%, respectively. Propensity score-matched analysis showed no statistically significant differences in in-hospital mortality rates (10%, 12%, 14% and 9%, respectively; P = 0.78) and 5-year survival rates (78.4%, 72.3%, 82.3% and 78.0%, respectively). The leading vessel combination and indications for planned and rescue DAC were the femoral and axillary arteries (98%) and true lumen narrowing and/or leg malperfusion (34%), and the axillary followed by femoral (77%) artery and low cardiopulmonary bypass flow (36%). In-hospital mortality in the planned and rescue DAC groups was 7% and 9%, respectively. CONCLUSIONS DAC seems effective for both prevention and management of intraoperative malperfusion.

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