HeartShare: Next-Generation Phenomics to Define Heart Failure Subtypes and Treatment Targets - Clinical Centers

项目摘要 心力衰竭（HF）是影响超过500万美国成年人的关键公共卫生问题， 巨大的临床、社会和经济负担。超过一半的HF患者具有保留射血功能的HF 分数（HFpEF）。此外，HFpEF是高度异质性的，不同的病理机制有助于 与疾病的几个不同亚组的症状和不良结果有关。虽然有几个大型 已经进行了随机试验，没有发现任何药物治疗可以改善 HFpEF患者的症状或临床结局。我们的团队和其他人已经确定了这本小说 对HFpEF患者进行深度表型分型的方法可以鉴定出HFpEF患者的亚组， 有可能从靶向治疗中获益。 当前提案的总体目标是建立一个大型的深度表型患者队列 HF，重点关注HFpEF患者。我们建议建立一个1000名患者的队列， Penn临床中心：700例HFpEF患者，200例HFrEF患者（包括100例中等范围患者） LV EF，40-50%）和100例非HF高血压患者（合适的对照人群，因为大多数患者 HFpEF患者有高血压病史）。我们将综合全面的临床数据， 社会经济数据（特别是与健康的社会决定因素有关的数据）、以患者为中心的数据（如 生活质量和功能状态）、结构和机械心脏和心外表型（包括 实验室表征和创新的流动数据收集方法）和多组学方法。 表型数据将得到当代生物信息学方法的补充，以提高我们的 了解人类HFpEF。 我们的表型分析方案将提供与其他研究进行横断面比较的机会。 组内聚类方法的应用，以及建立一个全面的 特征性大型前瞻性队列，对严格裁定的HFpEF患者进行前瞻性随访， 硬成果。在这些患者中，我们将评估详细的心脏和心外表型，电子健康， 记录数据、患者报告的结果、对运动的有氧适应以及血浆和尿液蛋白质组学 代谢组学和微RNA我们还将评估关键的门诊表型，包括创新的 家庭血压监测方法，身体活动，睡眠时间和质量，以及重要的社会 健康的决定因素。将前瞻性裁定心力衰竭结局，包括心力衰竭相关 住院、死亡、心肌梗塞和中风。我们的分析方法将包括基于假设的 研究以及公正的发现方法，将利用当代生物信息学工具，但将 由指导委员会成员、其他临床试验机构的研究者团队进行专家解释 中心和整个科学界。

PROJECT SUMMARY Heart failure (HF) is a critical public health issue that affects over 5 million US adults and imposes an enormous clinical, social, and economic burden. Over half of individuals with HF have HF with preserved ejection fraction (HFpEF). Furthermore, HFpEF is highly heterogeneous, and different pathologic mechanisms contribute to symptoms and poor outcomes in several different subgroups of the disease. Although several largescale randomized trials have been performed, no pharmacological therapies have been identified that improve symptoms or clinical outcomes in patients with HFpEF. Our group and others have identified that novel approaches to deeply phenotyping patients with HFpEF can identify subgroups of patients with HFpEF that are likely to benefit from targeted therapy. The overarching goal of the current proposal is to establish a large cohort of deeply phenotyped patients with HF with a focus on patients with HFpEF. We propose establishing a cohort of 1000 patients across all 4 Penn clinical centers: 700 patients with HFpEF, 200 patients with HFrEF (including 100 patients with mid-range LV EF, 40-50%) and 100 non-HF patients with hypertension (a suitable control population, given that most patients with HFpEF have a history of hypertension). We will incorporate comprehensive clinical data, socioeconomic data (particularly as they relate to social determinants of health), patient-centered data (such as quality of life and functional status), structural and mechanistic cardiac and extracardiac phenotypes (including in-lab characterization and innovative ambulatory approaches to data collection) and multi-omics approaches. The phenotypic data will be complemented by contemporary bioinformatic approaches to enhance our understanding of human HFpEF. Our phenotyping protocol will provide the opportunity for cross-sectional comparisons against other groups above, application of within-group clustering approaches, as well as establishing a comprehensively characterized large prospective cohort of patients with strictly adjudicated HFpEF for prospective follow-up of hard outcomes. In these patients, we will assess detailed cardiac and extracardiac phenotypes, electronic health record data, patient-reported outcomes, aerobic adaptations to exercise, and plasma and urinary proteomics and metabolomics and micro RNAs. We will also assess key ambulatory phenotypes including innovative approaches to home blood pressure monitoring, physical activity, sleep duration and quality, and important social determinants of health. Heart failure outcomes will be prospectively adjudicated, including heart-failure related hospitalization, death, myocardial infarction and stroke. Our analytic approach will include hypothesis-based research as well as unbiased discovery approaches that will leverage contemporary bioinformatics tools but will be subject to expert interpretation by members of the Steering Committee, investigator teams at the other Clinical Centers, and scientific community at large.