Project Summary Although there has been substantial progress in the development of medications to lower pulmonary vascular resistance in pulmonary arterial hypertension (PAH), there are no therapies that are known to benefit the right heart in the absence of changes in right ventricular afterload in patients with PAH. Right heart failure is the key driver for morbidity and mortality in patients with PAH, but also complicates a range of other common diseases such as emphysema, interstitial lung disease, and left heart failure. We are pursuing a novel approach that targets angiotensin receptors in patients with PAH and right heart failure. Previous animal studies suggest angiotensin signaling may contribute to myocardial fibrosis and could also be important in the pathogenesis of PAH and pulmonary vascular remodeling. Angiotensin receptor blockers are well established in left heart failure where their benefit is not merely a result of improvement in left heart afterload. Our work has shown a substantially lower all-cause mortality in veterans with pulmonary hypertension who use angiotensin converting enzyme inhibitors or angiotensin receptor blockers. These mechanistic and observational results raise the strong possibility that angiotensin receptor blockade might be an effective treatment for right heart failure. Angiotensin receptor blockade is an appealing therapeutic target that is well aligned with current NIH priorities of repurposing existing, inexpensive, and well-tolerated medications for novel use in other disease states. Medications for PAH are particularly expensive. If adjunctive therapy with an angiotensin receptor blockers are efficacious, this would benefit PAH patients and society at-large. We propose a Phase 2, single-center, randomized placebo-controlled trial of valsartan (an angiotensin receptor blocker) in adults with PAH. The study will evaluate the safety and clinical efficacy of a 24- week course of valsartan. The primary endpoint is change in six-minute walk distance at 24 weeks. Secondary endpoints include differences in right ventricular function, biochemical markers of right heart failure (NT-proBNP), New York Heart Association Functional Class, health related quality of life (as assessed by the disease specific emPHasis-10 instrument), and the frequency with which routine therapies for patients with PAH are escalated during the trial.