Pulmonary Hypertension in Left Heart Disease

项目概要/摘要 左心疾病 (LHD) 导致肺动脉高压（PH-LHD，又名 2 类 PH）、右心室 (RV) 失败，并增加死亡率和发病率。肺血管生物学研究进展 第 1 组 PH 的肺动脉 (PA) 循环和相关动物模型已带来有效的治疗 对于第 1 组 PH。 PH-LHD 中第 1 组 PH 疗法的试验显示出高度可变（有利、中性或 有害）影响。我们认为两个关键的知识差距导致了治疗反应的可变性 并阻碍治疗 PH-LHD 的进展：(1) 缺乏机械信息血流动力学 定义性质（血管收缩与重塑）和位置（PA 与肺静脉）的分类系统 (PV)) LHD 中的肺血管疾病，以及 (2) 缺乏对血管特异性的了解（PV 与 PA） 介导 PH-LHD 肺血管疾病的生物途径。该提案的目的是 弥补这些知识差距并实现 PH-LHD 的治疗创新。基于广泛的初步 在人类和实验 (Exp) PH-LHD 的研究中，我们的中心假设是 PH-LHD 是一种表型 多样化的实体，其最终的治疗方法将由独特的血流动力学表型和 血管特异性（PA 与 PV）病理生理学扰动。在人类和 Exp PH-LHD 中，我们将使用新颖的 根据肺血管阻力（PVR）对 PH-LHD 表型进行血流动力学评估， 血管反应性和 PVR 的纵向分布（目标 1）。研究结果将在人类 PH-LHD 中得到验证 评估有氧能力、右心室储备功能和肺运动的表型组特异性差异 拥堵。 Exp PH-LHD 中的发现将通过定义 PA 和 PV 重塑（定量 组织形态计量学）。我们的广泛假设是 PVR 升高的主要机制和位置 PH-LHD 具有临床意义和解剖学基础。在人类和 Exp PH-LHD 中，我们将 （目标 2）使用基于组织化学、蛋白质组学和转录组学的技术和生物信息学分析来定义 PH-LHD 表型组的血管特异性机制。这些研究将结合 Aim 1 血流动力学 血管特异性血管生物学的表型分析方法。在目标 3 中，我们将确定治疗药物是否基于 根据我们对人类和 Exp 的组学研究，PH-LHD 将改善 PV 或 PA 重塑并延缓进展 早期或晚期 PH-LHD 表型组中的 PH 值。这项工作的研究成果将是一个新的 PH-LHD 的血流动力学分类与特定的病理生理学和治疗目标相关，从而使 PH-LHD 的个体化医学方法。

PROJECT SUMMARY / ABSTRACT Left heart disease (LHD) leads to pulmonary hypertension (PH-LHD, aka Group 2 PH), right ventricular (RV) failure, and increased mortality and morbidity. Advances in pulmonary vascular biology gleaned from study of the pulmonary arterial (PA) circulation in Group 1 PH and relevant animal models have led to effective therapies for Group 1 PH. Trials of Group 1 PH therapies in PH-LHD have shown highly variable (favorable, neutral or harmful) effects. We propose that two critical knowledge gaps contribute to variability in therapeutic response and impede progress in treating PH-LHD: (1) the lack of a mechanistically informative hemodynamic classification system defining the nature (vasoconstriction vs remodeling) and location (PA vs pulmonary venous (PV)) of pulmonary vascular disease in LHD, and (2) lack of understanding of vessel specific (PV vs PA) biological pathways mediating pulmonary vascular disease in PH-LHD. The objective of this proposal is to address these knowledge gaps and enable therapeutic innovation in PH-LHD. Based on extensive preliminary studies in human and experimental (Exp) PH-LHD, our central hypothesis is that PH-LHD is a phenotypically diverse entity whose ultimate therapeutic approach will be defined by unique hemodynamic phenogroups and vessel specific (PA vs PV) pathophysiological perturbations. In human and Exp PH-LHD, we will use novel hemodynamic assessments to phenotype PH-LHD according to pulmonary vascular resistance (PVR), vasoreactivity, and the longitudinal distribution of PVR (Aim 1). Findings will be validated in human PH-LHD by assessing phenogroup-specific differences in aerobic capacity, RV reserve function and exertional lung congestion. Findings in Exp PH-LHD will be validated by defining PA and PV remodeling (quantitative histomorphometry). Our broad hypothesis is that both the primary mechanism and location of the elevated PVR in PH-LHD have clinical implications and anatomical underpinnings. In human and Exp PH-LHD, we will then (Aim 2) use histochemical, proteomic, and transcriptomic based techniques and bioinformatic analyses to define vessel specific mechanisms across PH-LHD phenogroups. These studies will couple the Aim 1 hemodynamic phenotyping approach to vessel specific vascular biology. In Aim 3, we will determine if therapeutic agents based on our omics studies in human and Exp PH-LHD will ameliorate PV or PA remodeling and delay the progression of PH in Early or Late Exp PH-LHD phenogroups. The research outcome from this work will be a new hemodynamic classification of PH-LHD linked to specific pathophysiology and therapeutic targets, thus enabling individualized medicine approaches to PH-LHD.