Proteomic Profiling of Precise Exercise Pathophenotypes Across the HFpEF Spectrum

项目总结/摘要 射血分数保留的心力衰竭（HF）（HFpEF）占HF的约50%，但检测方法有限。 预防和治疗。目前检测/治疗HFpEF的方法依赖于在 休息，在HFpEF中心的多器官系统中缺失储备能力受损， 通过锻炼。在第一个R 01阶段，我们在2011年进行了3117次心肺运动试验（CPOTT）。 心脏功能研究（FHS），量化心肺功能，个人运动反应， 代谢组学特征。我们定义了运动的“正常”代谢反应，并报告了新的测量方法， 健康受损和HF风险。引人注目的是，在4名无症状的社区居住FHS参与者中， 在我们的研究中，与血流动力学证实的HFpEF患者重叠的健康受损 临床转诊实验室。与HFpEF生理学相关的代谢也与运动反应相关， FHS。这些结果强调了临床HFpEF和早期HFpEF之间关键的分子和表型重叠。 它的发展阶段，提供了一个独特的机会，以确定HFpEF的起源和揭示新的目标 进行筛查/预防。蛋白质是潜在的可靶向生物标志物，其提供特定的生物标志物的读数。 与多个器官相关的途径，与遗传学直接相关，并且具有明确的过程， 试验开发。这种更新的假设是，与精确HFpEF相关的分子途径 在运动过程中捕获的表型将在HFpEF易感性发生之前很久就确定HFpEF易感性的机制。 常规临床检测。我们利用第一阶段开发的2个独特样本：（1）表型分析 在CPET期间进行血流动力学测量的HFpEF患者（MGH-ExS，N=500）和（2）FHS参与者， 静息/峰值运动时的CPET和血浆样本（N=1500）。我们将研究一个广泛的循环蛋白质组（>3000 静息/峰值运动时的蛋白质）与精确运动表型、计算机生物信息学和人类 遗传学在3个目标中指定运动反应的蛋白质组特征。在目标1中，我们确定了器官- HFpEF对运动的特异性反应（使用剩余蛋白质组）及其与亚临床表型的关系 是社区HFpEF易感性的核心。在目标2中，我们将量化循环蛋白质组的变化， 与急性运动，并评估如何运动引起的变化不同，在HFpEF的存在（MGH-ExS与。 FHS）和HFpEF风险因素。在目标3中，我们测量HFpEF表型的蛋白质组学特征的关联 在不同种族的一级预防队列中发生HF和心血管疾病（CVD）。我们也 在大型生物库中构建与HF/CVD相关的相关蛋白质（pQTLs）的遗传工具， 孟德尔随机化。该应用将与HFpEF相关的广泛途径的分析与 在第一次资助期间收集的独特、精确的运动表型，以解决 HFpEF和优先考虑新的目标，以更早，更精确的预防。该项目将提供一个独特的 科学界的资源，所有数据在完成后立即公开。

PROJECT SUMMARY/ABSTRACT Heart failure (HF) with preserved ejection fraction (HFpEF) represents ≈50% of HF, with limited methods for prevention and treatment. Current approaches to detect/treat HFpEF rely on cardiac phenotypes obtained at rest, missing reserve capacity impairments in multiple organ systems central to HFpEF that are uniquely revealed through exercise. In the first R01 period, we performed 3117 cardiopulmonary exercise tests (CPETs) in the Framingham Heart Study (FHS) to quantify cardiorespiratory fitness, individual exercise responses, and their metabolomic signatures. We defined a “normal” metabolic response to exercise and reported novel measures of impaired fitness and HF risk. Strikingly, ≈1 in 4 asymptomatic community-dwelling FHS participants displayed fitness impairment that overlapped with individuals with hemodynamically confirmed HFpEF studied in our clinical referral lab. Metabolites related to HFpEF physiology were also associated with exercise responses in FHS. These results underscore a critical molecular and phenotypic overlap between clinical HFpEF and the early stages of its development, providing a unique opportunity to define the origins of HFpEF and reveal new targets for its screening/prevention. Proteins are potentially targetable biomarkers that provide a readout of specific pathways relevant to multiple organs, have direct correlation with genetics, and have a well-defined process for assay development. The hypothesis of this renewal is that molecular pathways related to precise HFpEF phenotypes captured during exercise will specify mechanisms underlying HFpEF susceptibility long before its usual clinical detection. We leverage 2 unique samples developed in the first period: (1) deeply-phenotyped HFpEF patients with hemodynamic measures during CPET (MGH-ExS, N=500) and (2) FHS participants with CPET and plasma samples at rest/peak exercise (N=1500). We will study a broad circulating proteome (>3000 proteins at rest/peak exercise) in relation to precise exercise phenotypes, in silico bioinformatics, and human genetics to specify proteomic signatures of exercise response in 3 aims. In Aim 1, we identify pathways of organ- specific responses to exercise in HFpEF (using the rest proteome) and their relation to subclinical phenotypes central to HFpEF susceptibility in the community. In Aim 2, we will quantify changes in the circulating proteome with acute exercise and evaluate how exercise-induced changes differ in the presence of HFpEF (MGH-ExS vs. FHS) and HFpEF risk factors. In Aim 3, we measure association of proteomic signatures of HFpEF phenotypes with incident HF and cardiovascular disease (CVD) in racially diverse primary prevention cohorts. We also construct genetic instruments of implicated proteins (pQTLs) for association with HF/CVD in large biobanks using Mendelian randomization. This application unites profiling of broad pathways with relevance to HFpEF with unique, precise exercise phenotypes collected during the first grant period to resolve clinical heterogeneity in HFpEF and to prioritize novel targets for earlier and more precise prevention. This project will provide a unique resource for the scientific community, with all data made publicly available immediately upon completion.