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

Introduction: Vascular spasm following bypass grafting is a lethal complication of various revascularization surgeries. Cerebral revascularization surgery is the standard treatment modality for ischemic disease that require vessel sacrifice. Cerebrovascular graft transplantation surgeries carry a 5-10% risk of vasospasm, which can lead to lethal neurological sequelae. The current literature does not support any single spasm prevention agent and lacks universal protocols. Here we report a superior clinical outcome associated with botox clinical application and provide studies on the potential mechanism of action of BoNT/A to reduce vasospasm.

Methods: We queried a database of bypass surgery patients undergoing cerebral revascularization surgery by one surgeon at our facility between 2014 and 2020 to obtain patient characteristics and clinical outcomes. Patients were studied for angiographic vasospasm, clinical vasospasm, recurrent stroke, mortality, and functional outcomes. Next, we used paired vascular graft tissue for ex vivo BoNT/A studies to assess for spasmolytic downstream effectors; by immunohistology for cleaved SNAP25 (cSNAP25); western blotting, cSNAP25, pMLC, pMYPT, and ROCK1/2. Liquid chromatography-mass spectrometry (LC-MS) was used to measure levels of catecholamines.

Results: We found that BoNT/A graft treatment in current low dose is associated with significant 1) reduction in clinical vasospasm (13.3%, p< 0.05), 2) increase in arterial cleaved SNAP25 levels, and 3) significantly reduced levels of pMLC, pMYPT, as well as 4) significantly reduced levels of catecholamines. In addition, our clinical data analysis showed no safety concerns between BoNT/A and control group. The two groups were comparable in terms of 30-day all-cause stroke rate, 30-day all-cause mortality, post-operative graft patency, and improvement in mRS from baseline to final follow-up.

Conclusion : We investigated the potential spasmolytic value of Botox in improving clinical outcomes and studied the associations between treatment and changes in downstream protein levels and catecholamine that explains mitigation of clinical vasospasm, leading to vascular relaxation is through pleotropic vasodilatory pathways.