Biomechanical Paradigm of Carotid Plaque Disruption and Imaging Biomarkers: Basic Science to Clinical Trials

Dedicated to advancing research in stroke care, the Translational Neurosurgery and Biotechnology Lab is conducting trailblazing research in multimodal carotid imaging to understand the formation of atherosclerotic plaque within vessels.

Three-panel multimodal carotid imaging

Scanning fiber endoscopy (SFE) and scanning electron microscopy (SEM) imaging of carotid plaques

Disruption of the inner surface of a vulnerable carotid plaque is considered to be the precipitating factor that culminates in the formation of clots that lead to stroke. The Translational Neurosurgery and Biotechnology Lab has been intensively working to better characterize the interplay of forces driving flow and tissue interactions, and the phenotypical hallmarks resulting from plaque disruption and healing. Based on extensive structural analysis and computational flow dynamic studies, we showed that carotid plaque disruption is a hemodynamically driven phenomenon triggered by fibrous cap weakening, delamination, and ulceration followed by penetration of blood and thrombosis. In this paradigm, intraplaque hemorrhage is of major importance and represents the smoking gun of the root-cause of a stroke.

Six slides of carotid plaques presented using multimodal imaging

Multimodal imaging of carotid plaques including micro-computed tomography (microCT), micro-MR, optical coherence tomography (OCT), SFE and SEM

To ensure that this new knowledge impacts patients' lives, the lab has leveraged cutting-edge preclinical imaging tools such as micro-CT, micro-MR and scanning electron micrography to better characterize unstable plaque phenotypes. In addition, we are pioneering the use of next-generation intravascular imaging platforms to visualize at unprecedented resolution these structural changes at the lumen-wall interface of vulnerable and disrupted plaque. In particular, the Translational Neurosurgery and Biotechnology Lab is conducting trailblazing research in multimodal carotid imaging including the use of laser scanning fiber endoscopy and OCT. Additionally, in collaboration with Mayo Clinic's Department of Radiology, our group has used and validated advanced MR sequences to noninvasively detect carotid intraplaque hemorrhage in patients with stroke and is pushing forward the first clinical trial to implement this approach.

This translational work is fueled by national and international collaborations including the Carotid Registry of Imaging and Pathology (CRIP), which was started and is run by the Translational Neurosurgery and Biotechnology Lab. This multicenter collaborative biobank receives carotid endarterectomy specimens from several major academic U.S.-based institutions and conducts pioneering translational research in carotid artery disease and vascular biology.

To translate these new disease insights and technological advancements into evidence-based medicine, the lab is working with National Institutes of Health (NIH) to launch the SYmptomatic Non-stenotic Carotids with High-Risk imaging biOmarkers (SYNCHRO) trial. This is a StrokeNet National Institute of Neurological Disorders (NINDS)-supported trial that challenges the dogma of carotid stenosis by using modern biomarkers of plaque vulnerability to risk-stratify people with strokes. This multicenter, hypothesis-driven imaging biomarker study will evaluate the rate of recurrent stroke in 600 patients with symptomatic nonstenotic carotid (SyNC) managed with intensive medical therapy. Successful completion of this Phase II trial, followed by a Phase III including randomization to a surgical arm, will lead to a paradigm shift in the management of carotid artery disease to prevent strokes, disability and death. This trial aims to provide the largely needed Level 1 evidence that aligns the clinical management of people with carotid artery disease with contemporary understanding of plaque disruption and thromboembolization.

Related publications

Savastano LE, Seibel E. Scanning fiber angioscopy: A multimodal intravascular imaging platform for carotid atherosclerosis. Neurosurgery. 2017; doi:10.1093/neuros/nyx322.

Savastano LE, Zhou Q, Smith A, Vega K, Murga-Zamalloa C, Gordon D, McHugh J, Zhao L, Wang M, Pandey A, Thompson BG, Zu J, Zhang J, Chen, YE, Seibel, EJ, Wang TD. Multimodal laser-based angioscopy for structural, chemical and biological imaging of atherosclerosis. Nature Biomedical Engineering. 2017; doi:10.1038/s41551-016-0023.

Savastano LE, Chaudhary N, Murga-Zamalloa C, Wang M, Wang T., Thompson BG. Diagnostic and interventional optical angioscopy in ex vivo carotid arteries. Operative Neurosurgery. 2017; doi:10.1093/ons/opw002.

Larson A, Nasr DM, Rizvi A, Alzuabi M, Seyedsaadat SM, Lanzino G, Huston J, Lehman VT, Savastano LE, Brinjikji W. Embolic stroke of undetermined source: The association with carotid intraplaque hemorrhage. JACC: Cardiovascular Imaging. 2021; doi:10.1016/j.jcmg.2020.08.007.

Larson A, Brinjikji W, Savastano LE, Huston J, Benson JC. Carotid intraplaque hemorrhage is associated with cardiovascular risk factors. Cerebrovascular Diseases. 2020; doi:10.1159/000508733.

Larson A, Nardi V, Lanzino G, Brinjikji W, Scharf E, Savastano LE. Symptomatic mild carotid artery stenosis. Contemporary Neurosurgery. 2020; doi:10.1097/01.CNE.0000723688.52449.d5.