In this application, we seek to develop a transcutaneous ultrasound-induced thermal strain imaging (US-TSI) probe and protocol for human use and evaluate the ability to quantify the lipid burden in carotid atherosclerotic plaques (AP) in patients undergoing carotid endarterectomy (CEA). Stroke affects millions in the U.S. each year. Although progress in the treatment has been made, the mortality rate remains high at ~8-12% within 30 days of a stroke. Surgical interventions such as CEA or stenting help to prevent stroke in a subset of patients who have significant carotid stenosis. However, only a small fraction of the patients with carotid stenosis develop symptoms of transient ischemic attack or stroke. Current screening tools are effective at estimating degree of stenosis and offer some general morphometric information but cannot accurately predict which lesions are at higher risk of causing symptoms. This leads to questions of which patients with significant carotid disease need to be treated and the uncertainty results in significant over-treatment of CEA or stenting, which often results in surgical complications like stroke and myocardial infarction. Post-mortem and ex vivo studies in the past as well as recent clinical trials strongly suggest that vulnerable carotid AP possess a lipid rich core (LRC). Noninvasive characterization of AP composition and morphology to identify rupture prone lesions would be an extremely powerful clinical tool. It offers the potential to reduce morbidity, mortality, and healthcare costs through early detection of AP with high-risk features. In the carotid alone, noninvasive AP characterization could help address 650,000+ ischemic strokes attributed to carotid AP in the U.S. annually while reducing the $30 billion for the treatment and long-term care following stroke as well as reducing the number of unnecessary carotid interventions. Transcutaneous US-TSI is a promising, noninvasive means of evaluating the lipids of carotid AP. Our previous cholesterol-fed rabbit study and pilot human subject study demonstrated that US-TSI identified and quantified percent lipid contents of AP. The current application for optimizing US-TSI for human use builds logically on this work, which supports a strong scientific premise. The central hypothesis in this project is that US-TSI can effectively quantify lipid contents of carotid AP in human subjects. Our long-term goal is to use US-TSI to create carotid triplex sonography (CTS) which will enhance the current gold standard, carotid duplex sonography (CDS), by allowing for detection of AP composition along with morphometric measures of stenosis. If successful, US-TSI will change clinical paradigm by improving patient selection for carotid interventions and the longitudinal follow up of patients with carotid disease. Furthermore, CTS will also provide a means of evaluating the treatment efficacy of newly developed drugs. Within the scope of this proposal the central hypothesis will be tested as follow: SA1: Develop a US-TSI probe and a protocol suitable for human application. SA2: Evaluate the US-TSI probe and the protocol in a clinically relevant large animal AP model. SA3: In situ evaluation of freehand US-TSI scan on human subjects.
Cardiovascular disease (CVD) is the leading cause of death in the US. Rupture of plaques in blood vessels is main cause of stroke and heart attack. Early and accurate identification of unstable plaque is critical for identifying patients at high-risk for timely and most effective treatments thus drastically reduced risk of stroke and heart attack. Current methods for identifying such high-risk plaques are either invasive or not reliable. The most common noninvasive clinical examination of the carotid artery is carotid duplex sonography (CDS). CDS is the basis for proceeding with surgical intervention such as carotid endarterectomy (CEA) that removes plaques from carotid. While CDS has proven to be robust and accurate in evaluating the plaque size, it cannot provide insight in determining the internal composition and distribution of plaques, especially the lipid core, which is known to be a true indicator of high-risk plaques. The lack of ability in CDS to detect high-risk plaques results in a large number of unnecessary surgeries, specifically CEA, requiring extensive annual follow up expenses in addition to risk of secondary heart attack or stroke from CEA surgery, yet still missing true high- risk patients for stroke with very high lifetime cost. We have developed a non-invasive alternate ultrasound technique, named US-induced thermal strain imaging (US-TSI) that detects lipid contents, which will overcome critical limitations with current CDS-based diagnosis of stroke risk described above. Due to its novel ability to non-invasively detect internal plaque composition, US-TSI can better identify patients with high risk for stroke and target them for best treatments prior to stroke. Following our successful in vivo feasibility that US-TSI image analysis compares well with gold standard histology through animal (rabbit plaque model) studies in past years, the critical experiment that needs to occur next is the first-in-human clinical use of US-TSI that we propose in this application. To proceed with human subject study, the device and algorithm that were used for the previous rabbit study will have to be rebuilt for a human subject, which will be first tested on a large animal (pig plaque model) model prior to human subject study. If successful, the findings and technology evaluated through this project will provide a strong motivation and form a core foundation for further extended clinical study toward translation into clinics.
