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

项目摘要 尽管在降低肺血管的药物开发方面取得了实质性进展 在肺动脉高压(PAH)中存在阻力，目前还没有已知的有益于 右心在无右室后负荷变化。右心衰竭是关键 PAH患者的发病率和死亡率的驱动因素，但也使一系列其他常见的 肺气肿和左心衰竭等疾病。 我们目前正在招募NHLBI赞助的参与者，第二阶段，单中心，随机 安慰剂对照试验法莫替丁(一种H2受体拮抗剂)作为一种新的治疗成人糖尿病的方法 啊哈。该研究正在评估为期24周的法莫替丁稳定右心的能力。 失败了。研究的终点包括六分钟步行距离、右室功能和扩张， 右心衰竭生化标志物(NT-PRO-BNP)，纽约心脏协会功能分级， 以及由疾病特定强调-10量表评估的与健康相关的生活质量。 这个应用程序的主要目标是利用我们正在进行的临床试验的样本来进行 一种多组学和系统生物学的方法来阐明这一独特的队列的生物学 心力衰竭。目前的建议是为了更好地理解生物调节的影响。 组胺信号，定义右心衰竭患者的多组学特征，这些患者很可能 对H2受体拮抗剂的反应，并发现区分个体的激活通路 右心衰竭者右心功能稳定。我们之前的工作 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，表明基于组学的特征可以在临床上识别 PAH患者的相关表型。 目前的提案与NHLBI的战略愿景很好地结合在一起，以确定更深层次的 通过多学科的整合了解心、肺和血液疾病的生物学 组学数据和离散的临床表型。这一目标在目前的提案中尤为重要 考虑到右心衰竭对一系列不同疾病的负担，以及缺乏有效的 促进右心适应而不是衰竭的药物。近期目标是加强我们的 了解组胺信号在右心衰竭中的短期和中期临床意义 考虑到针对这一途径的耐受性良好的廉价药物的数量，可交付的药物。

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.