Mechanisms of Right Ventricular Dysfunction in PAH

描述（由申请人提供）：肺动脉高压（PAH）由远端肺血管的严重重塑引起，并且可以由未知（特发性，IPAH）原因以及系统性硬化症（SSc）等疾病发展而来，SSc是一种以内皮和成纤维细胞失调和免疫改变为特征的疾病。右心室（RV）衰竭 PAH的主要死亡原因，在SSc相关PAH（SSc-PAH）中尤为突出，而在所有PAH中均很重要。尽管有现代治疗，SSc-PAH的中位生存期仅为3年，远低于IPAH。我们最近确定了新的血流动力学和非侵入性基于图像的风险因素预测生存，并在新的初步数据中，揭示了SSc-PAH的RV心肌收缩力异常。我们认为，SSc-PAH与IPAH相比生存率更差是由于独立于肺动脉（PA）负荷的固有RV功能障碍，这部分是由于肌节功能障碍和微血管疾病。我们将填补关于SSc-PAH和IPAH中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志物。三个特定目标将：1）基于心脏磁共振成像得出RV性能的最佳无创测量，以预测IPAH和SSc-PAH的生存率; 2）通过有创压力-容量和右心导管插入术确定RV功能和PA相互作用，使用频率起搏和腿部运动评估储备RV功能;和3）获得RV活检，以测试原发性肌节功能障碍在PAH中降低RV收缩力的作用（任一形式），鉴定与转化生长因子-β级联和血管生成调节剂相关的细胞因子活化途径，并评估相关血清生物标志物反映RV疾病的潜力。这将为RV功能提供急需的见解， 新的生物标志物（功能和信号），以评估RV功能障碍，可用于临床。我们还将首次对PAH患者的人体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结合起来，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.