Contributions of pulmonary arterial and venous remodeling to HFpEF in the elderly

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 左心室射血分数(HFpEF)，目前尚无有效的治疗方法。肺动脉高压 (PH)是临床上公认的肺血管功能障碍(PVD)的最常见表现，是 发生心力衰竭，高达83%的HFpEF患者存在，其中它预示着病情恶化 结果。因此，PVD是HFpEF的一个有吸引力的治疗靶点，但其病理生理机制复杂 左房压力升高、肺实质损伤和固有因素的不同贡献 肺血管功能障碍。在HFpEF中理解PVD的一个关键障碍是缺乏知识 关于血流动力学异常背后的肺血管解剖改变。这个 调查团队率先开发和验证了先进的图像处理管道，以 胸部CT平扫对肺静脉和动脉重构的定量研究 扫描。在NHLBI资助的COPDgene研究中，他们发表的和来自吸烟者的初步数据表明， 肺血管重塑与右室功能障碍和功能减退有关，且更多 经常在HF中观察到。他们现在建议将这些发现扩展到以社区为基础的老年人队列中 成人明确肺血管重构在HFpEF发生发展中的作用。这项建议是 中心假说是促炎和促纤维化通路的激活促进了肺 血管重塑，部分通过伴随的左心功能不全和肺实质损伤，导致 PH，RV功能障碍，最终是心衰。该项目将利用最近完成的胸部CT(用于CAC)和 第7次研究访问1579名社区动脉粥样硬化风险(ARIC)研究参与者的超声心动图 (2018年2月-2019年11月；年龄~81±4岁)。新的基于CT的肺血管重塑和重建方法 实质损伤(纤维性、肺气肿)，以及先进的3D和基于应变的RV回声测量 功能将被执行。这些数据将与临床评估、结果监测、 基于适体的蛋白质组学和基因组学，帮助确定预防进行性PVD的最相关靶点 在非常年长的人身上。具体目标包括：(1)确定左心功能不全和肺功能不全的程度 实质损伤促进高龄老年人肺静脉和动脉重构；(2)测定 肺血管重构在多大程度上预测RV功能障碍、功能容量降低和 事件HFpEF；以及(3)识别预测肺血管重构的蛋白质和蛋白质网络。 复制将在COPD基因和Framingham心脏研究以及孟德尔随机分析中发生 将识别潜在因果关联的子集。量化肺血管重塑将 识别病理生理上不同形态的PVD亚型，使更准确地应用 现有的治疗方法，而相关分子通路的发现可能为新的治疗靶点提供信息。

Heart failure (HF) disproportionately affects the elderly who predominantly develop HF with preserved left ventricular (LV) ejection fraction (HFpEF), for which no efficacious therapies exist. Pulmonary hypertension (PH) – the most clinically recognized expression of pulmonary vascular dysfunction (PVD) – is a risk factor for incident HF and is present in upto 83% of patients with prevalent HFpEF, among whom it portends worse outcomes. PVD is therefore an attractive therapeutic target in HFpEF, but its pathophysiology is complex with variable contributions from elevated left atrial pressure, pulmonary parenchymal injury, and intrinsic pulmonary vascular dysfunction. A critical barrier to understanding PVD in HFpEF is a lack of knowledge regarding the anatomic alterations in the pulmonary vasculature underlying abnormal hemodynamics. The investigative team has pioneered development and validation of advanced image processing pipelines to quantify pulmonary venous and arterial remodeling on non-contrast chest computerized tomography (CT) scans. Their published and preliminary data from smokers in the NHLBI-funded COPDGene study show that pulmonary vascular remodeling associates with RV dysfunction and worse functional capacity, and is more frequently observed in HF. They now propose to extend these findings to a community-based cohort of older adults to define the role of pulmonary vascular remodeling in the development of HFpEF. This proposal’s central hypothesis is that activation of pro-inflammatory and pro-fibrotic pathways promotes pulmonary vascular remodeling, partially via concomitant LV dysfunction and pulmonary parenchymal injury, leading to PH, RV dysfunction, and ultimately HF. This project will leverage recently completed chest CT (for CAC) and echocardiography in 1,579 Atherosclerosis Risk in Communities (ARIC) study participants at the 7th study visit (2/2018-11/2019; age ~81±4 yrs). Novel CT-based measures of pulmonary vascular remodeling and parenchymal injury (fibrotic, emphysematous), and advanced 3D and strain-based echo measures of RV function will be performed. These data will be integrated with clinical assessments, outcomes surveillance, aptamer-based proteomics, and genomics to help define the most relevant targets to prevent progressive PVD in the very elderly. Specific aims include: (1) Define the extent to which LV dysfunction and pulmonary parenchymal injury promote pulmonary venous and arterial remodeling in the very elderly; (2) Determine the extent to which pulmonary vascular remodeling predicts RV dysfunction, reduced functional capacity, and incident HFpEF; and (3) Identify proteins and protein networks that predict pulmonary vascular remodeling. Replication will occur in COPDGene and the Framingham Heart Study, and Mendelian randomization analyses will identify the subset of potentially causal associations. Quantifying pulmonary vascular remodeling will identify pathophysiologically distinct morphologic PVD sub-phenotypes enabling more precise application of existing therapies, while discovery of associated molecular pathways may inform novel therapeutic targets.