Abstract Background: Cardiovascular disease (CVD) is the leading cause of death in the United States. It is estimated that 83.6 million Americans presently have at least one form of CVD and by 2030, 40.5% of the population will have some form of CVD, an increase of about 10% compared to 2010. Atherosclerosis, the main cause of CVD, is a systemic, pathologic condition characterized by several structural changes of the arteries. Increased arterial stiffness results primarily from increased collagen deposition and elastin fragmentation in the medial layer of the arterial wall and is recognized as an independent risk factor for adverse vascular events. Modifications of arterial structure lead to changes in arterial elasticity and viscosity, which have recently been found to predate clinical manifestations of occlusive atherosclerotic disease. Moreover, these changes tend to be widespread and are not limited to a single arterial bed and, as a consequence, contribute to target organ damage. These alterations in the artery are the culmination of known and unknown vascular risk factors that promote formation and progression of atherosclerotic lesions and may also increase the propensity for atherosclerotic plaque rupture. Our Goal is to develop a new class of arterial biomarkers based on the viscoelastic and nonlinear material properties of the vessel wall. These biomarkers could be used in the future for early assessment of subclinical abnormalities in the carotid artery by providing a widely available technology to detect ?presymptomatic? vascular disease to refine both CVD risk stratification and follow up for subsequent interventions. We will use acoustic radiation force (ARF) to generate propagating waves with high frequency bandwidth in the arterial wall. The wave motion will be analyzed with numerical dispersion methods, which we call arterial dispersion ultrasound vibrometry (ADUV). We use these ADUV wave propagation methods to quantitatively and noninvasively characterize the viscoelastic moduli of the in vivo artery. The resulting methods will be applicable to a wide range of patients, because they can be implemented on many clinical ultrasound instruments installed throughout the world. Method: We utilize acoustic radiation force (ARF) to produce propagating waves with wide bandwidth (frequency range) in the wall of the arteries and then measure the propagation motion with ultrafast ultrasound imaging. These measurements are made with high temporal resolution (<20 milliseconds). From the wave motion, we calculate the viscoelastic moduli of the arterial wall throughout the cardiac cycle to evaluate viscoelastic properties of the artery at different blood pressures to quantify the nonlinear behavior of the arterial wall. Specifically, we use the wave velocity dispersion (variation of velocity with frequency) and attenuation properties of the wave modes generated using the ARF to estimate the viscoelastic properties of the arterial wall. To this end, we will continue to advance our modeling work with experts in numerical waveguide and finite element modeling and inversion to develop accurate and efficient algorithms that convert the measured dispersion and attenuation curves from ARF excitation to blood pressure-dependent viscoelastic moduli of the arterial wall to improve our understanding of wave propagation in the arterial wall. Models developed in this project will be used for fast inversions to solve for the material properties of the artery. The proposed ADUV method has high spatial (1-3 cm) resolution allowing local measurements to be made. Localized measurement of the viscoelastic and nonlinear material properties of the artery will provide new ultrasound-based biomarkers for assessment of cardiovascular health. We will validate these new biomarkers with clinical laboratory measurements in healthy subjects, patients with confirmed atherosclerotic cardiovascular disease, and patients who have risk factors for cardiovascular disease. Approach: To achieve these important goals, we will conduct a research program with the following Specific Aims: 1) Develop a suite of increasingly complex computational models of carotid arteries for computing dispersion and attenuation of guided waves generated using acoustic radiation force. 2) Develop inversion algorithms to robustly estimate arterial wall mechanical properties. 3) Validate the arterial dispersion ultrasound vibrometry measurements with clinical laboratory measurements in healthy human subjects, patients with confirmed atherosclerotic cardiovascular disease, and patients with cardiovascular risk factors.