Proteomic signatures to identifypathways underlying the progression toheart failure

心力衰竭(HF)对老年人的影响不成比例，老年人主要发生心力衰竭并保留左心衰 心室射血分数(HFpEF)。神经激素阻断尚未被证明对HFpEF有效，而且没有 目前存在疾病特异性治疗方法。迫切需要有针对性的新途径，以及 基础/翻译数据表明，全身炎症是一个潜在的未开发的治疗靶点， 尽管人类数据是有限的。本应用程序的目标是定义炎症的贡献 心功能不全和显性心衰发生的途径和新的致病途径 老年人。中心假设是特定的炎症和神经激素途径将 不同的预测进行性左心功能不全和晚年发生的心衰表型(HFpEF与HFrEF)， 详细的纵向蛋白质组和表型数据将允许发现新的生物 心衰的途径和预后风险标记物。基于适体的蛋白质组学提供了精确的定量 4,931个循环蛋白和史无前例的炎症性和非炎性 小路。采用严格的流行病学方法，我们将结合大规模蛋白质组学和详细的 心血管纵向表型(回声、脉搏波速度)和前瞻性心力衰竭的判定 主要针对以下具体目标的社区动脉粥样硬化风险(ARIC)队列：1) 识别单个循环蛋白质和蛋白质网络，预测发生心力衰竭和心力衰竭的表型 (HFpEF Vs HFrEF)；2)确定与食管瘤纵向恶化相关的蛋白质和蛋白质网络 左室舒张和收缩功能；3)确定候选蛋白质和蛋白质网络最有可能 利用基因组数据研究进行性左心功能不全和心力衰竭的介体。建议中的 研究将阐明炎症--与神经激素--通路在心力衰竭中的作用 开发和发现晚年心力衰竭的新介体。这些贡献将是重大的，因为 通过确定几种现有药物靶向的通路的重要性，我们的发现可以迅速 转化为预防心力衰竭的新干预措施--降低心力衰竭相关发病率的重要步骤 和死亡率。本研究方案的根本性创新之处在于：(1)聚焦大范围流通 了解HFpEF病理生物学的蛋白质组学，同时评估炎症， 神经激素，以及在HFpEF高危人群中预防心力衰竭发生的新途径；(2)整合 蛋白质组和基因组数据，以确定候选蛋白质和途径，这些蛋白质和途径是心力衰竭的危险媒介 反对危险标记物；以及(3)评估肥厚和舒张期以外的新的HFpEF前驱因素 功能障碍，包括左心室张力受损、肺血管功能障碍和右室功能障碍。这个项目 有望为促进HFpEF的生物途径提供一个原创性的、完整的理解， 为未来HFpEF病理生物学的机械性和转化性研究提供一个概念性框架。

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular ejection fraction (HFpEF). Neurohormonal blockade has not proven efficacious for HFpEF, and no disease-specific therapy currently exists. There is an urgent need for novel targetable pathways, and basic/translational data implicate systemic inflammation as a potential unexploited therapeutic target, although human data is limited. The objective of this application is to define the contributions of inflammatory pathways to, and identify novel causal pathways for, the development of cardiac dysfunction and overt HF in the elderly. The central hypothesis is that specific inflammatory and neurohormonal pathways will differentially predict progressive LV dysfunction and incident HF phenotype (HFpEF vs HFrEF) in late life, and that detailed longitudinal proteomic and phenotypic data will allow for discovery of novel biologic pathways and prognostic risk markers for HF. Aptamer-based proteomics provide precise quantification of 4,931 circulating proteins and unprecedented profiling of relevant inflammatory and non-inflammatory pathways. Employing rigorous epidemiologic approaches, we will combine large-scale proteomics with detailed longitudinal cardiovascular phenotyping (echo, pulse wave velocity) and prospective HF adjudication in the largely biracial Atherosclerosis Risk in Communities (ARIC) cohort to address the following specific aims: 1) To identify individual circulating proteins and protein networks that predict incident HF and HF phenotype (HFpEF vs HFrEF); 2) To determine proteins and protein networks associated with longitudinal worsening of LV diastolic and systolic function; 3) To identify candidate proteins and protein networks most likely to be mediators of progressive LV dysfunction and HF using genomic data. The contributions of the proposed research will be to clarify the role of inflammatory – relative to neurohormonal – pathways for HF development and to discover novel mediators of HF in late life. These contributions will be significant because by determining the importance of pathways targeted by several existing agents, our findings could rapidly translate into novel preventative interventions for HF – an essential step to decrease HF-associated morbidity and mortality. This research proposal is fundamentally innovative in: (1) focusing on large-scale circulating proteomics to understand HFpEF pathobiology, with simultaneous assessment of inflammatory, neurohormonal, and novel pathways in a cohort at risk for HFpEF to prevent HF development; (2) integrating proteomic and genomic data to identify candidate proteins and pathways that are HF risk mediators as opposed to risk markers; and (3) assessing novel antecedents to HFpEF beyond hypertrophy and diastolic dysfunction, including impaired LV strain, pulmonary vascular dysfunction, and RV dysfunction. This project is expected to provide an original, integrated understanding of the biologic pathways promoting HFpEF, providing a conceptual framework for future mechanistic and translational studies of HFpEF pathobiology.