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，这些老年人主要发展HF， 心室（LV）射血分数（HFpEF），对于其不存在有效的疗法。肺动脉高压 (PH)- 肺血管功能障碍（PVD）的最临床公认的表达-是肺血管功能障碍的风险因素。 在高达83%的HFpEF患者中存在，在这些患者中，它预示着更严重的 结果。因此，PVD是HFpEF中有吸引力的治疗靶点，但其病理生理学复杂， 左心房压力升高、肺实质损伤和内源性 肺血管功能障碍理解HFpEF中PVD的一个关键障碍是缺乏知识 关于肺血管系统的解剖学改变导致血液动力学异常。的 研究团队率先开发和验证了先进的图像处理管道， 在非造影胸部计算机断层扫描（CT）上量化肺静脉和动脉重塑 扫描。他们在NHLBI资助的COPDGene研究中发表的吸烟者的初步数据显示， 肺血管重构与右室功能障碍和功能下降有关， 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， 成年人，以确定肺血管重塑在HFpEF发展中的作用。这个提议 中心假设是促炎和促纤维化途径的激活促进肺纤维化。 血管重塑，部分通过伴随的LV功能障碍和肺实质损伤，导致 PH，RV功能障碍，最终HF。本项目将利用最近完成的胸部CT（CAC）， 第7次研究访视时，1，579名社区动脉粥样硬化风险（ARIC）研究参与者的超声心动图 （2/2018-11/2019;年龄约81±4岁）。基于CT的肺血管重构新指标 实质损伤（纤维化、肺气肿）和RV的高级3D和应变超声测量 功能将被执行。这些数据将与临床评估、结局监测、 基于适体的蛋白质组学和基因组学，以帮助确定最相关的目标，以防止进行性PVD 在老年人中。具体目标包括：（1）定义LV功能障碍和肺功能障碍的程度 肺实质损伤促进老年人肺静脉和肺动脉重构;（2）确定肺静脉和肺动脉重构的程度。 肺血管重构预测RV功能障碍、功能能力降低的程度，以及 偶发HFpEF;和（3）鉴定预测肺血管重构的蛋白质和蛋白质网络。 复制将发生在COPD基因和心脏研究，孟德尔随机化分析 将识别潜在因果关联的子集。定量肺血管重构将 鉴定病理生理学上不同形态学PVD亚表型， 现有的治疗方法，而发现相关的分子途径可能会告知新的治疗靶点。

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.