PROJECT SUMMARY Aortic dissection (AD) is a devastating cardiovascular disease known for its rapid propagation and high morbidity and mortality. Diagnosis of the initial presentation of AD is a challenge because the symptoms are similar to those of many other health problems. In the absence of intervention, AD results in a mortality rate of up to 90%, with most of these deaths occurring within 48 hours of the onset of AD. AD is among the top 20 causes of death in the US, with 20-40% of patients die even before reaching hospital. There is a clear problem in our ability to manage AD patients in their crucial initial stage of development and to develop strategies for a timely treatment. AD usually initiates at a focal region that shows disrupted microarchitecture and compromised mechanical properties. Once dissected, the mechanical behavior of the separated aortic wall tissues become greatly affected, suggesting that layering discontinuity may play a role in triggering AD. Considering these distinct mechanical processes, we expect that understanding the evolvement of the focal and layering abnormalities may provide useful insights into the development of early diagnostic and intervention. The goal of this proposed research is to advance our understanding of the important role of local tissue mechanical properties and microstructures of the arterial wall in in the initiation and progression of AD. Large elastic arteries consist of concentric layers of elastic lamellae with inhomogeneously distributed elastic and collagen extracellular matrix (ECM) fibers. Our recent studies revealed several previously unrecognized findings, which provide strong evidence that ECM inhomogeneity is physiologically important. The overarching hypothesis of this proposed research is that the evolvement of inhomogeneity in local mechanical properties and ECM microstructure, both along and across the arterial wall, are triggering factors of AD. We will test this hypothesis using state-of-the-art quantitative ECM imaging, noninvasive local mechanical property mapping, discrete-finite element modelling, and tissue testing and validation with three aims: Specific Aim 1: To establish mappings of local ECM structure and mechanical properties of human thoracic aorta with sub-millimeter resolution. Specific Aim 2: To investigate the depth- and region-dependence of aortic layer delamination. Specific Aim 3: To create a computational model that incorporates ECM structural inhomogeneity and local wall mechanical properties to predict the propensity of AD. The knowledge we gain from this research is expected to provide insights into biomechanical markers useful for the diagnosis and treatment of AD. The new biomechanical markers considering local structural and mechanical inhomogeneities will identify the origin and propensity of AD with direct clinical impact on the developments of new early diagnostics and interventions.