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Combination of Shear Stress and Molecular Imaging of Inflammation to Predict High-Risk Atherosclerotic Plaque

Final Report Summary - SMILE (Combination of Shear Stress and Molecular Imaging of Inflammation to Predict High-Risk Atherosclerotic Plaque)

One of the most important public health and medical issues confronting society in the Western world is the development and progression of atherosclerosis. The catastrophic clinical coronary manifestations of acute myocardial infarction and cardiac death typically arise suddenly without warning. Local hemodynamic factors, which we can now identify and measure in vivo, are responsible for the progression of atherosclerosis and precipitation of acute clinical events. Our pioneering group has been using invasive and non-invasive cardiovascular imaging, as well as sophisticated computational analyses, to assess in vivo the hemodynamic factors in the vascular beds. These sophisticated analyses will enable clinicians around the world to identify the specific sites where atherosclerosis will progress and cause an adverse clinical event, and tailor a specific therapeutic strategy to this high-risk area. The ultimate implications from the results of these studies for world health will be enormous. The sophisticated methodologies that we use are quite unique and there are very few centers in the world with experience in this kind of work.

Specific Aim 1: Experimental study to test the hypothesis that low ESS combined with the severity of inflammation can detect high-risk plaques. Using serial molecular magnetic resonance imaging and high-resolution computed tomography angiography we identified accelerated plaque progression and inflammation in aortic subsegments with low ESS. Our approach uniquely combined individual flow dynamic analysis with non-invasive molecular MR and CT imaging techniques for the identification and prediction of high-risk atherosclerotic lesions. The combination of local ESS, which is the stimulus for ongoing inflammation with the severity of inflammation has a great potential for the early identification of high-risk plaque upon which we can intervene preemptively to alter its natural history and stabilize it. This multimodal concept could enable the non-invasive monitoring of vulnerable plaques during therapeutic or invasive interventions, which may add further improvement for personalized preventive medicine and early identification of patients with subclinical high-risk lesions. Since the diameter of the rabbit aortas is comparable to that of human coronary arteries, our findings gain a high potential for clinical translation.

Specific Aim 2: Pilot clinical study to test the hypothesis that low ESS and inflammation can predict high-risk plaques. We utilized advanced high-resolution intracoronary imaging with 3D OCT to assess the local hemodynamic and remodeling patterns across the entire spectrum of atherosclerotic plaques in a single point in time. The study showed that low ESS and expansive remodeling are closely associated with high-risk plaque. The current study underscores the feasibility and incremental prognostic value of assessing the ESS, remodeling and plaque features simultaneously towards the identification of those plaques that will evolve to rupture and precipitate a coronary event. This study may set the foundation for larger prospective studies to investigate the fascinating hypothesis that low ESS, expansive remodeling and high-risk features (i.e. fibrous cap, inflammation, lipid pool) can help identify the truly highest-risk plaques and screen out plaques that are not in the highest-risk category. Early, accurate identification of lesions, which are likely to progress to high-risk plaques may allow pre-emptive interventional management (prophylactic stenting) and local targeted drug delivery, either with stents or catheters, to stabilize these plaques and avert adverse outcomes.

Collectively, in this project we utilized a sophisticated animal and clinical setting to demonstrate for the first time that combination of the magnitude of local ESS with the extent of local inflammation could potentially allow the detection of high-risk plaques (Figures 1 and 2). These findings provide important pathophysiological and clinical insights into the pathophysiology of atherosclerosis which are anticipated to will help cardiologists to identify the specific constellation of high-risk features that characterize the truly highest-risk plaques, and screen out plaques that are not in the highest-risk category. Early, accurate identification of lesions which are likely to progress to high-risk plaques may allow pre-emptive interventional management (prophylactic stenting) and local targeted drug delivery, either with stents or catheters, to stabilize these plaques and avert adverse outcomes. Also, improvement in the catheterization laboratory decision-making would decrease the high-risk of recurrence that now follows percutaneous coronary interventions. Considering the ongoing, intense interest in the diagnosis and management of high-risk plaques, the anticipated advances by the present study are expected to boost leading cardiovascular research.

With regard to the social impact of our study, timely identification and treatment of high-risk plaques at earlier stages of their natural course would decrease myocardial infarction and sudden death rates. In the long term the costly complications of atherosclerotic disease would be prevented, thus actually lowering healthcare costs while decreasing morbidity and mortality resulting from coronary artery disease. An enormous payback for society is anticipated if these tasks are achieved.