PROJECT SUMMARY For patients with advanced cardiovascular disease, implanted cardiac devices can significantly improve their survival and quality of life. While lifesaving, cardiac devices carry the added risk of developing a cardiac device infection (CDI), in which case the device has to be surgically removed. In many cases, patients with a CDI present with vague symptoms and undergo a number of inconclusive tests, resulting in a delay in their diagnosis. If left undiagnosed or untreated the mortality from a CDI is high. If identified early, CDIs can be treated swiftly, thereby reducing infection-related complications. Currently there are no reliable methods for early prevention or identification of CDI. Rapid and accurate CDI diagnosis is critical in cardiac device recipients who have a Staphylococcus aureus bloodstream infection, as the risk of CDI approaches 50%. Building on the candidate's published work, this research will use the singular resource of the Bloodstream Infection Biorepository to define the vascular biomarker signature associated with an individual's risk for a S. aureus-CDI. Second, the biological basis for why some, but not all patients, develop a CDI will be identified through the application of a novel in vitro model system of bacteremia, created by the candidate in collaboration with Biomedical Engineering. This project will: 1) define the biomarker signature associated with S. aureus-CDI, 2) determine how changes in vascular mechanics affect infection risk, and 3) apply a novel tissue engineered blood vessel system to identify critical endothelial-bacterial-device interactions that impact CDI risk. Results from this project will serve as a basis for follow-up R01 proposals, which will prospectively evaluate adjunctive CDI biomarker signatures among other etiologies of bloodstream infection and determine if a patient's endothelial phenotype is an independent risk factor for CDI. This project has direct relevance to the NHLBI's strategic goals and objectives of identifying phenotypic, biomarker, and molecular characteristics predictive of outcome, that when applied in clinical studies, can predict differential response to therapy in individuals. This project will also support the candidate's transition to an independent research career. This project will provide expertise and advanced skillsets in tissue engineering, vascular biology, and clinical research, all of which are necessary for the candidate's long-term career goal of identifying key factors that impact susceptibility to CDIs and developing effective therapeutic strategies for their prevention and treatment. The primary mentor for this award is Dr. Vance Fowler, an internationally recognized clinician-scientist in S. aureus bacteremia who has extensive experience as a mentor of junior faculty researchers. A complementary and diverse group of mentors will provide guidance in tissue engineering (Dr. Truskey) and vascular biology (Dr. Kontos). The candidate will use...