Novel Biomarkers of Right Ventricular Dysfunction in Pulmonary Arterial Hypertension

项目摘要/摘要 肺动脉高压(PAH)是一种复杂的肺血管疾病，导致 右室(RV)进行性适应性和非适应性形态和功能改变， 最终导致RV衰竭，这是PAH生存的唯一最关键的负面决定因素。房车评估 已经通过血流动力学和无创成像技术得到了很好的证实，包括右心 插管和压力-容积环(PV-Loop)技术，以及心脏磁共振(CMR)， 分别进行了分析。临床上需要用以下方法识别可靠的、非侵入性的和经济有效的生物标记物 机制意义，可以评估右室功能，重塑，并指导治疗干预。在……里面 临床前研究，我们小组已经证明了血管抑制因子和血管生成因子之间的失衡 是疾病进展和随后的RV功能障碍的关键。我们已经证明了血管抑制肽 内皮抑素(Endostatin，ES)是胶原18a1(Col18a1)的裂解产物，在PAH中升高，并与 死亡率上升。此外，ES诱导血栓反应蛋白1(TSP1)释放，并伴随有害的下游 血流动力学和形态上的RV结果。在这方面，这项提案的全球目标是确定 COL18a1/Es/TSP1通路中的血管抑制分子是相互关联的可靠生物标志物 PAH和RV功能与重塑为了检验我们的假设，我们将使用来自两组定义明确的 一群人。这个项目有三个新颖的目标。首先，确定ES和TSP1血浆之间的联系 PAH和RV功能障碍和病理性RV重构的水平，我们将检测Es和TSP1在 我的赞助人领导的一项完整的NIH/NHLBI研究显示，患有和不患有PAH的患者的血浆。房车 通过测量收缩末期弹性比(EES)，从多拍PV环获得函数 有效动脉弹性(EA)作为RV-PA偶联的替代指标。房车改建将使用以下工具进行评估 CMR测量右室质量和VMI(室壁质量指数：RV/LV质量之比)。第二，对房车的定义 COL18a1和TSP1在PAH中的表达及其与RV功能障碍和重构的关系 用免疫组织化学方法评价人心脏中Col18a1和TSP1表达的右室空间定位 从PAH患者的尸检中获得；以及RV中COL18a1和TSP1mRNA表达的相关性 我的赞助商收集的心内膜心肌活检样本，右室功能和重塑如上所述。 第三，明确帕金森病患者ES和TSP1血浆水平对治疗的反应及其与 为了改善右室功能障碍和重塑，我们将检测血浆中ES和TSP1的水平 参加由我的赞助商领导的第二项NIH/NHLB未来家长研究的参与者。vbl.使用 配对分析，我们将确定治疗前后ES和TSP1水平的变化以及他们 与右室功能及重构的相关性。这些目标的成功实现将支持专家系统的使用 和TSP1作为新的、无创的、可靠的生物标志物，可以追踪PAH的RV功能和重塑。

Project Summary/Abstract Pulmonary arterial hypertension (PAH) is a complex disorder of the pulmonary vasculature resulting in progressive adaptive and maladaptive morphological and functional changes in the right ventricle (RV), ultimately leading to RV failure, the single most crucial negative determinant of survival in PAH. RV evaluation has been well established using hemodynamic and noninvasive imaging techniques, including right heart catheterization and pressure-volume loops (PV-loops) technology, and cardiac magnetic resonance (CMR), respectively. There is a clinical need to identify reliable, noninvasive, and cost-effective biomarkers with mechanistic significance, that can assess RV function, remodeling, and guide therapeutic interventions. In preclinical studies, our group has demonstrated that an imbalance between angiostatic and angiogenic factors is critical for disease progression and subsequent RV dysfunction. We have shown that the angiostatic peptide endostatin (ES), a cleaved product from Collagen 18a1 (Col18a1), is elevated in PAH and associated with increased mortality. Furthermore, ES induces thrombospondin 1 (TSP1) release with deleterious downstream hemodynamic and morphologic RV outcomes. In this context, this proposal's global objective is to identify the angiostatic molecules within the Col18a1/ES/TSP1 pathway as reliable biomarkers of the association between PAH and RV function and remodeling. To test our hypothesis, we will use data from two sets of well-defined cohorts. This project has three novel aims. First, to define associations between ES and TSP1 plasma levels in PAH and RV dysfunction and pathologic RV remodeling, we will measure ES and TSP1 levels in the plasma of patients with and without PAH from a completed NIH/NHLBI study led by my sponsor. RV function will be derived from multi-beat-PV loops with measurement of the ratio of end-systolic elastance (Ees) and effective arterial elastance (Ea), as a surrogate of RV-PA coupling. RV remodeling will be assessed using RV mass and VMI (Ventricular Mass Index: ratio between RV and LV mass) by CMR. Second, to define RV Col18a1 and TSP1 expression in PAH and the association with RV dysfunction and remodeling, we will asses the spatial RV localization of Col18a1 and TSP1 expression, by immunohistochemistry, in human hearts obtained from autopsies of PAH patients; and the correlation of Col18a1 and TSP1 mRNA expression, from RV endomyocardial biopsy samples collected by my sponsor, with RV function and remodeling as decribed above. Third, to define response to therapy in ES and TSP1 plasma levels in PAH and their correlation with improvement in RV dysfunction and remodeling, we will assay ES and TSP1 levels from plasma of participants who are being enrolled in a second prospective NIH/NHLB parent study led by my sponsor. Using a matched paired analysis, we will identify changes in ES and TSP1 levels pre and post-therapy and their correlation with RV function and remodeling. Successful completion of these aims will support the use of ES and TSP1 as novel, noninvasive, and reliable biomarkers that can track RV function and remodeling in PAH.