This K08 application focuses on the thrombosis which occurs as a common and severe complication in chronic heart failure (CHF), a major source of morbidity and mortality in the U.S. Recent evidence has linked CHF with a hypercoagulable state as demonstrated by elevated indices of thrombin and tissue factor (TF) activation. Both thrombin and TF play a critical role in the formation of clot and thrombotic complications on the endothelial surface, however, their role in thrombosis in CHF is currently unclear. The Principal Investigator has proposed a comprehensive five-year research program that will focus on the procoagulant and anticoagulant molecules on the endocardium in the prothrombotic state of chronic heart failure (CHF). This proposal builds upon exciting preliminary data generated in our laboratory which has led to a working hypothesis that the biophysical and inflammatory conditions in CHF lead to a loss of thromboresistance in the failing heart. We will examine whether the condition of heart failure alters endocardia! anticoagulant-procoagulant homeostasis such that these changes are associated with increased thrombogenicity. Specific Aim #1 will provide careful in vivo analysis of anticoagulant and procoagulant molecules on the endocardium and the functional consequences of altered anticoagulantprocoagulant homeostasis. Specific Aim #2 will examine in vitro underlying molecular mechanisms of altered homeostasis determined in inflammatory- and mechanically-stressed murine endocardium. Finally, Specific Aim #3 will explore in vivo strategies to restore homeostasis on the endocardium using adenoviral gene delivery and exogenous activated protein C. In summary, our studies will elucidate the critical role of the endocardium in maintaining anticoagulant-procoagulant homeostasis and how CHF alters this balance. This research project will synthesize experiments already familiar to the Principal Investigator and his sponsor's laboratory as well as new experiments and skills that are vital to the Pi's development as a physician scientist. These results may lead to a shift in our current understanding of thrombosis in CHF and potentially lead to strategies which would directly impact patients with CHF at risk for thrombosis. Chronic heart failure is an extremely common disease in the United States with over 5 million cases. Thromboembolic disease is a significant problem in patients with CHF. Elucidating the mechanisms underlying the procoagulant nature of CHF could greatly reduce the associated morbidity and mortality. (End of Abstract)