The Pulmonary Hypertension- Multi-Dimensional Omics to Characterize Right Heart Adaptation (PH-MOCHA) study

项目摘要 尽管降低肺血管病变的药物开发取得了实质性进展， 肺动脉高压（PAH）的阻力，没有已知的治疗方法可以受益 右心室后负荷无变化时的右心。右心衰竭是关键 PAH患者发病率和死亡率的驱动因素，但也使一系列其他常见的 肺气肿和左心衰等疾病。 我们目前正在招募参与者参加NHLBI申办的2期单中心随机 法莫替丁（一种H2受体拮抗剂）作为一种新的治疗成人哮喘的安慰剂对照试验 呸。这项研究评估了法莫替丁24周疗程稳定右心的能力 失败研究终点包括6分钟步行距离、右心室功能和扩张， 右心衰竭的生化标志物（nt-pro-BNP），纽约心脏协会功能分级， 和健康相关的生活质量，如通过疾病特异性emPHasis-10工具评估的。 该应用程序的主要目标是利用我们正在进行的临床试验中的样本进行 一个多组学和系统生物学的方法来阐明这个独特的队列的生物学， 心衰目前的建议旨在更好地了解调节的生物影响。 组胺信号传导，定义了可能患有右心衰竭的个体的多组学特征， 对H2受体拮抗剂作出反应，并发现区分个体的激活途径， 右心功能稳定的患者与右心衰竭恶化的患者相比。我们以前的工作 强烈暗示了组胺信号在右心衰竭中的重要作用， 产生了令人兴奋的初步数据，表明基于组学的表征可以在临床上识别 PAH患者的相关表型。 目前的提案与NHLBI战略愿景保持一致，优先考虑更深入的 了解心脏，肺和血液疾病的生物学，通过多学科的整合， 组学数据和离散的临床表型。这一目标在当前的提案中尤为重要 考虑到右心衰竭在一系列不同疾病中的负担以及缺乏有效的 促进右心适应而不是衰竭的药物。我们的目标是提高我们 对右心衰竭中组胺信号传导的理解有望在短期至中期临床上 考虑到针对这一途径的耐受性良好、廉价的药物数量，

Project Summary Despite 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. 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 and left heart failure. We are currently enrolling participants in an NHLBI sponsored, Phase 2, single-center, randomized placebo controlled trial of famotidine (an H2 receptor antagonist) as a novel therapeutic for adults with PAH. The study is evaluating the ability of a 24-week course of famotidine to stabilize right heart failure. Study end-points include six-minute walk distance, right ventricular function and dilation, biochemical markers of right heart failure (nt-pro-BNP), New York Heart Association Functional Class, and health related quality of life as assessed by the disease specific emPHasis-10 instrument. The primary goal of this application is to leverage samples from our ongoing clinical trial to undertake a multi-omics and systems biology approach to elucidate the biology of this unique cohort with right heart failure. The current proposal is designed to better understand the biologic impact of modulating histaminic signaling, define the multi-omics profiles of individuals with right heart failure who are likely to respond to H2 receptor antagonists, and to discover activated pathways distinguishing individuals with stable right heart function from those with worsening right heart failure. Our previous work strongly implicates an important role for histaminic signaling in right heart failure and we have generated exciting preliminary data showing that omics-based characterization can identify clinically relevant phenotypes in patients with PAH. The current proposal is well aligned with the NHLBI strategic vision to prioritize a deeper understanding of biology in diseases of the heart, lung, and blood through the integration of multi- omics data and discrete clinical phenotypes. This goal is particularly important in the current proposal given the burden of right heart failure across a range of distinct diseases and the lack of effective medications that promote right heart adaptation over failure. The proximate goal of enhancing our understanding of histaminic signaling in right heart failure promises short to intermediate-term clinical deliverables given the number of well-tolerated, inexpensive medications targeting this pathway.