Pathophysiology and Treatment of Pulmonary Hypertension

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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.