REVAMP-PH: REpurposing Valsartan May Protect against Pulmonary Hypertension

REVAMP-PH：重新利用缬沙坦可以预防肺动脉高压

• 批准号: 10642368
• 负责人: Peter J Leary
• 金额: $ 76.18万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10642368
• 关键词: Activities of Daily Living; Address; Adult; Angiotensin II; Angiotensin II Receptor; Angiotensin Receptor; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Apoptosis; Area; Biochemical Markers; Cardiac; Cardiac Myocytes; Caring; Clinical; Development; Diameter; Diastole; Disease; Diuretics; Dose; Etiology; Evaluation; Failure; Fibrosis; Frequencies; Goals; Heart; Heart failure; Individual; Interstitial Lung Diseases; Left; Lung; Measures; Morbidity - disease rate; Muscle Cells; Natural History; New York; Outcome; Participant; Pathogenesis; Pathway interactions; Patient Outcomes Assessments; Patients; Pharmaceutical Preparations; Phase; Placebos; Progressive Disease; Pulmonary Emphysema; Pulmonary Hypertension; Pulmonary Vascular Resistance; Randomized; Randomized, Controlled Trials; Right Ventricular Function; Role; Safety; Signal Transduction; Societies; Stress; Testing; United States National Institutes of Health; Vasodilator Agents; Ventricular; Veterans; Walking; Work; clinical efficacy; cohort; coronary fibrosis; cost; effective therapy; efficacy evaluation; exercise capacity; health related quality of life; improved; innovation; instrument; mortality; novel; novel strategies; primary endpoint; pro-brain natriuretic peptide (1-76); pulmonary arterial hypertension; pulmonary vascular remodeling; randomized placebo controlled trial; receptor; right ventricular failure; routine therapy; secondary endpoint; success; targeted treatment; therapeutic target; tool; valsartan

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.

项目摘要 尽管在降低肺部的药物开发方面取得了重大进展 肺动脉高压（PAH）中的血管耐药性，没有已知的疗法 在PAH患者的右心室后负荷没有变化的情况下，使正确的心脏受益。正确的 心力衰竭是PAH患者发病率和死亡率的关键驱动力，但也使A复杂化 其他常见疾病的范围，例如肺气肿，间质性肺部疾病和左心衰竭。 我们正在采用一种针对PAH和右患者血管紧张素受体的新型方法 心脏衰竭。先前的动物研究表明血管紧张素信号传导可能有助于心肌 纤维化，在PAH和肺血管重塑的发病机理中也可能很重要。 血管紧张素受体阻滞剂在左心衰竭中已很好地确定，不仅其受益 左心后负荷改善的结果。我们的工作显示出大幅较低的全因 使用血管紧张素转化酶抑制剂或 血管紧张素受体阻滞剂。这些机械和观察结果提出了强大的可能性 血管紧张素受体阻断可能是对正确心力衰竭的有效治疗方法。 血管紧张素受体阻滞是一个吸引人的治疗靶标，与当前NIH很好地排列 重新利用现有，廉价和耐受性良好的药物的优先事项，以在其他 疾病状态。 PAH的药物特别昂贵。如果血管紧张素辅助治疗 受体阻滞剂有效，这将使PAH患者和社会一般会受益。 我们提出了第2阶段，单中心，随机的安慰剂对照试验（血管紧张素 PAH成人的受体阻滞剂）。该研究将评估24-的安全性和临床功效 瓦尔萨坦的周课程。主要终点是在24周内六分钟步行路程变化。 次要终点包括右心功能，右心化学标记的差异 失败（NT-ProBNP），纽约心脏协会功能阶级，与健康相关的生活质量（作为 通过疾病特定的重点-10仪器评估）以及常规的频率 在试验期间，PAH患者的疗法升级。