Mechanisms of Right Ventricular Dysfunction in PAH

描述(由申请人提供)：肺动脉高压(PAH)是由远端肺血管的严重重塑引起的，可由不明原因(特发性，IPAH)以及系统性硬化症(SSC)等疾病发展，SSC是一种以内皮和成纤维细胞调节失调为特征的疾病，以及免疫功能改变。右室(RV)衰竭， 多环芳烃的主要死亡原因在与多环芳烃相关的多环芳烃(SSC-PAH)中尤为突出，但在所有多环芳烃中都很重要。尽管进行了现代治疗，SSc-PAH的中位生存期只有3年，远远差于IPAH。我们最近发现了新的血流动力学和基于影像的非侵入性危险因素来预测生存，并在新的初步数据中揭示了SSc-PAH患者右室心肌收缩功能的异常。我们认为SSC-PAH与IPAH相比存活率更差的原因是固有的RV功能障碍，而不是肺动脉(PA)负荷，这部分是由于肌节功能障碍和微血管疾病。我们将填补SSC-PAH和IPAH中有关RV-PA疾病的主要知识空白，并测试PAH中RV功能的新的侵入性和非侵入性临床指标，以揭示疾病演变和风险的新机制和标记物。这三个具体目标将1)基于心脏磁共振成像得出最佳的无创右室功能指标，以预测IPAH和SSC-PAH的存活；2)通过有创压力-容量和右心插管确定RV功能和PA相互作用，使用心率起搏和腿部运动来评估储备RV功能；以及3)获取RV活组织检查，以测试原发性肌节功能障碍对PAH(无论是哪种形式)RV收缩能力降低的作用，确定与转化生长因子-β级联反应和血管生成调节因子有关的细胞因子激活途径，以及评估相关血清生物标志物反映RV疾病的可能性。这将提供对房车功能和 新的生物标志物(功能和信号)可用于评估RV功能障碍，可用于临床。我们还将首次对PAH患者心肌组织中的分子通路进行肌丝分析和评估，将其与完整的器官生理学相结合，并产生关键的新见解，为未来旨在改善PAH患者RV功能的治疗铺平道路。

DESCRIPTION (provided by applicant): Pulmonary arterial hypertension (PAH) results from severe remodeling of the distal lung vessels, and can develop from unknown (idiopathic, IPAH) causes as well as diseases such as systemic sclerosis (SSc), a disorder characterized by endothelial and fibroblast dysregulation, and altered immunity. Right ventricular (RV) failure, the major cause of death with PAH, is particularly prominent in SSc-associated PAH (SSc-PAH) while important in all PAH. Despite modern therapy, SSc-PAH has a median survival of only 3 years, far worse than IPAH. We recently identified novel hemodynamic and non-invasive image-based risk factors predictive of survival and, in new preliminary data, reveal abnormal RV myocardial contractility in SSc-PAH. We propose that worse survival in SSc-PAH versus IPAH results from intrinsic RV dysfunction independent of pulmonary arterial (PA) loading, which is due in part to sarcomeric dysfunction and micro-vascular disease. We will fill major knowledge gaps regarding RV-PA disease in SSc-PAH and IPAH, and test new invasive and non- invasive clinical measures of RV function in PAH to reveal novel mechanisms and markers of disease evolution and risk. The three Specific Aims will 1) derive optimal non-invasive measures of RV performance based on cardiac magnetic resonance imaging to predict survival in both IPAH and SSc-PAH; 2) determine RV function and PA interaction by invasive pressure-volume and right heart catheterization, using rate pacing and leg-exercise to assess reserve RV function; and 3) obtain RV biopsies to test the role of primary sarcomere dysfunction to reduced RV contractility in PAH (either form), identify cytokine activation pathways linked to transforming growth factor-beta cascades and angiogenesis modulators, and assess the potential for associated serum biomarkers to reflect RV disease. This will provide critically needed insights into RV function and novel biomarkers (functional and signaling) to assess RV dysfunction, which can be used clinically. We will also provide the first myofilament analysis and assessment of molecular pathways in human myocardial tissue in PAH, coupling this to intact organ physiology, and yielding critical new insights that can pave the way to future therapies aimed at improving RV function in PAH.