Botulinum Toxin Application for Treatment of Graft Vasospasm: A Reverse Translational Study

Vascular graft vasospasm is a lethal risk when using grafts for revascularization and reconstructive surgery. Revascularization is a treatment modality for ischemic diseases including Moyamoya disease that requires bypass surgery. Cerebrovascular graft transplantation carries a 5-10% risk of vasospasm, which can lead to devastating neurological sequelae. Here we report clinical outcomes associated with ex vivo botulinum toxin A (BoNT/A) treatment of arterial graft and provide reverse translational studies investigating the potential mechanisms of action of BoNT/A to reduce vasospasm. A retrospective review of the maintained database of patients undergoing surgery was performed for 63 patients. We used paired human vascular graft tissue for ex vivo BoNT/A studies to assess for spasmolytic downstream effectors; cleaved SNAP25, pMLC, pMYPT, ROCK1/2, and levels of catecholamines. We found that low-dose BoNT/A graft treatment is associated with 1) a reduction in clinical vasospasm (13.3%, p<0.05) without any identified safety concerns in patients, 2) an increase in arterial cleaved SNAP25, 3) reduced levels of pMLC and pMYPT, and 4) reduced levels of catecholamines. The mechanism of action leading to vascular relaxation is likely through pleiotropic vasodilatory pathways. The application of BoNT/A as a spasmolytic has potentially safe and broad applications across multiple surgical and scientific subspecialties.