REVAMP-PH: REpurposing Valsartan May Protect against Pulmonary Hypertension

项目摘要 尽管在降低肺动脉压的药物开发方面取得了实质性进展， 肺动脉高压（PAH）的血管阻力，目前还没有已知的治疗方法， 在PAH患者的右心室后负荷无变化的情况下，对右心有益。权 心力衰竭是PAH患者发病率和死亡率的主要驱动因素，但也使 一系列其他常见疾病，如肺气肿、间质性肺病和左心力衰竭。 我们正在寻求一种靶向PAH患者血管紧张素受体的新方法， 心衰以前的动物研究表明血管紧张素信号可能有助于心肌 肺纤维化，并且在PAH和肺血管重塑的发病机制中也可能是重要的。 血管紧张素受体阻滞剂在左心衰竭中已得到很好的应用，其益处不仅仅是 这是左心室后负荷改善的结果。我们的研究表明， 使用血管紧张素转换酶抑制剂或 血管紧张素受体阻断剂。这些机制和观测结果提出了强烈的可能性 血管紧张素受体阻滞剂可能是治疗右心衰竭的有效方法。 血管紧张素受体阻滞剂是一个有吸引力的治疗靶点，与目前的NIH 优先考虑将现有的、廉价的和耐受性良好的药物重新用于其他疾病的新用途， 疾病状态。治疗PAH的药物特别昂贵。如果使用血管紧张素 受体阻滞剂是有效的，这将使PAH患者和整个社会受益。 我们提出了一个2期，单中心，随机安慰剂对照试验缬沙坦（一种血管紧张素 受体阻滞剂）。该研究将评估24- 一周的疗程。主要终点是24周时6分钟步行距离的变化。 次要终点包括右心功能、右心生化标志物的差异 心力衰竭（NT-proBNP）、纽约心脏协会功能分级、健康相关生活质量（作为 通过疾病特异性emPHasis-10仪器评估），以及常规 PAH患者的治疗在试验期间递增。

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.