The Evolution of Endocardial Thrombosis in Heart Failure

描述(由申请人提供)： K08的应用重点是血栓形成，这是慢性心力衰竭(CHF)的一种常见和严重的并发症，慢性心力衰竭是美国发病率和死亡率的主要来源。最近的证据表明，CHF与高凝状态有关，凝血酶和组织因子(TF)激活指数的升高证明了这一点。凝血酶和转铁蛋白在血管内皮细胞表面血栓形成和血栓并发症的形成中起重要作用，但它们在充血性心力衰竭血栓形成中的作用目前尚不清楚。首席调查员提出了一项全面的五年研究计划，重点是慢性心力衰竭(CHF)血栓前状态下心内膜上的促凝剂和抗凝血剂分子。这一建议建立在我们实验室产生的令人兴奋的初步数据的基础上，这些数据导致了一个工作假设，即CHF中的生物物理和炎症条件导致衰竭心脏的血栓抵抗丧失。我们将研究心力衰竭的状况是否会改变心内膜！抗凝剂-促凝剂的动态平衡，因此这些变化与血栓形成能力的增加有关。具体目标#1将提供对心内膜上抗凝剂和促凝剂分子的体内仔细分析，以及抗凝剂促凝血剂动态平衡改变的功能后果。具体目标#2将在体外研究炎症和机械应激小鼠心内膜中确定的动态平衡改变的潜在分子机制。最后，具体目标#3将探索在体策略，使用腺病毒基因传递和外源激活蛋白C来恢复心内膜的动态平衡。综上所述，我们的研究将阐明心内膜在维持抗凝-促凝剂动态平衡中的关键作用，以及CHF如何改变这种平衡。这项研究项目将综合首席调查员和他的赞助商实验室已经熟悉的实验，以及对PI作为内科科学家的发展至关重要的新实验和技能。这些结果可能会改变我们目前对CHF血栓形成的理解，并可能导致直接影响有血栓形成风险的CHF患者的策略。慢性心力衰竭在美国是一种非常常见的疾病，有超过500万例。血栓栓塞症是充血性心力衰竭患者的一个重要问题。阐明充血性心力衰竭促凝血特性的潜在机制可以大大降低相关的发病率和死亡率。 (摘要结束)

DESCRIPTION (provided by applicant): 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)