Pathophysiology and Treatment of Pulmonary Hypertension

慢性肺动脉高压（CPH）是一种毁灭性的疾病-其进展是无情的，最终导致右心衰竭（RHF）和大多数患者死亡。不幸的是，我们的知识的病理生理学后遗症，预示着心脏衰竭与CPH仍然严重不足，以指导病人护理这一日益重要的疾病过程。 此外，常见的内科和外科治疗方案的作用机制仍然未知，个体患者对治疗的反应是不可预测的。使用动物中CPH的标准实验模型，将使用两种新技术创建和研究RHF：1.右心房（RA）容量钳夹，和2.）反馈回路控制肺动脉（PA）闭塞。 RA容量钳制技术将首次允许分离RA功能的机制，包括其对心输出量的贡献和在CPH中的代偿作用。 此外，反馈回路控制的PA闭塞将允许区分间接血管舒张效应与流行治疗方案对右心力学的直接心肌效应。 一系列实验将评估普通药物治疗和新的、尚未证实的手术治疗对右心功能和整体心脏性能的影响。拟议的研究将针对以下具体目标：（1）定义导致RHF的CPH病理生理后遗症; 2.）确定后负荷减少、舒张期舒张和顺应性的变化以及常见但知之甚少的医学治疗剂的收缩抑制之间的平衡;以及3.）确定分级房间隔造口术对不同程度CPH受试者右心功能和总心输出量的生理后果。 该项目的长期目标是了解这种致残性疾病的生理后遗症，指导适当的药物和手术治疗，并开发新的治疗策略，以改善CPH患者的预后。

Chronic pulmonary hypertension (CPH) is a devastating disease - its progression is relentless, culminating in right heart failure (RHF) and death in the majority of patients. Unfortunately, our knowledge of the pathophysiologic sequelae that portend cardiac failure with CPH remains grossly inadequate to direct patient care for this increasingly important disease process. Furthermore, the mechanisms of action of common medical and surgical treatment options remain unknown, and the individual patient's response to therapy is unpredictable. Using a standard experimental model of CPH in animals, RHF will be created and studied with two novel techniques: 1.) Right atrial (RA) volume clamping, and 2.) Feedback-loop controlled pulmonary artery (PA) occlusion. The RA volume-clamping technique will permit, for the first time, isolation of the mechanics of RA function, including its contribution to cardiac output and compensatory role in CPH. In addition, feedback-loop controlled PA occlusion will permit differentiation of the indirect vasodilatory effects from the direct myocardial effects of popular therapeutic regimens on right heart mechanics. A series of experiments will assess the impact of common medical therapies and new, as of yet unproven, surgical therapies on right heart function and global cardiac performance. The proposed studies will address the following specific aims: l.) Define the pathophysiologic sequelae of CPH that produce RHF; 2.) Determine the balance between afterload reduction, changes in diastolic relaxation and compliance, and contractile inhibition with common, but poorly understood medical therapeutic agents; and 3.) Determine the physiologic consequences of graded atrial septostomy on right heart function and total cardiac output in subjects with varying degrees of CPH. The long-range goals of this project are to understand the physiologic sequelae of this crippling disease, guide appropriate medical and surgical therapy, and develop, new treatment strategies that will improve outcome for patients with CPH.