Shear Stress and Endothelial Pathophysiology in Intracranial Atherosclerosis

University Of California Los Angeles, Los Angeles CA

Investigators

Linked publications & trials

Abstract

PROJECT SUMMARY/ABSTRACT The overall goal of this proposed renewal is to establish that the focal region of low shear stress (0-4 dyne/cm2) immediately downstream or in the post-stenotic segment of intracranial atherosclerotic disease (ICAD) is a marker of atherogenesis and recurrent stroke, providing a therapeutic target for anti-inflammatory or anti- thrombotic interventions. Our central hypothesis is that post-stenotic low shear stress associated with atherogenic endothelial pathophysiology provides a rational basis for precision medicine of ICAD. Our prior data on low shear stress in the MCA in SAMMPRIS confirms the potential influential role of shear stress associated with endothelial pathophysiology recognized in systemic atherosclerosis yet extended to the cerebral circulation for the first time. Our three expanded independent specific aims leverage an ongoing, invaluable collaboration and the unmatched quality of the SAMMPRIS imaging archive. The Neurovascular Imaging Research Core at UCLA will conduct the prospective experiments to validate focal low shear stress measured on CTA CFD of ICAD across all arteries in SAMMPRIS with detailed anatomical flow models created from the same source images [SA-1]. This aim enables us to use our validated flow models to directly observe flow vortices and adjacent low shear stress in all ICAD arterial sites [SA-1]. These validated flow models serve as a scaffold for endothelium, where the cell morphology, expression of VCAM-1 and platelet aggregation can be studied in all ICAD locations [SA-2]. The clinical relevance of post-stenotic low shear stress (0-4 dyne/cm2) in these arterial lesions will be corroborated by imaging adjudication of stroke in the downstream territory after initial treatment in SAMMPRIS [SA-3]. Associations of this clearly defined potential therapeutic target of post-stenotic low shear stress will be examined with respect to all arterial sites and treatment methods in SAMMPRIS [SA-3]. All image post-processing, CTA and DSA CFD, 3D printing, and biological assays of endothelial pathophysiology will be conducted at UCLA, where we have pioneered this workflow. The ongoing multidisciplinary enthusiasm of SAMMPRIS trial leadership is an important element of this new approach to ICAD that employs our collaborative work and publications of these landmark trials and their detailed imaging and clinical analyses. Our extensive prior work reflecting collaborative multidisciplinary expertise on a novel imaging and biological framework, coupled with intensive experience linking the SAMMPRIS imaging and clinical datasets, provide a logical extension of knowledge on atherogenic low shear stress into the cerebral circulation.