Mechanisms of Right Ventricular Dysfunction in Scleroderma-associated PAH

项目摘要 系统性硬化症(SSC)是一种异质性疾病，其特征是 内皮，以及成纤维细胞和免疫系统的失调。与SSC关联 肺动脉高压(SSC-PAH)，一种常见且经常被低估的并发症 SSC是一种毁灭性的综合征，通过右室(RV)统一导致死亡 失败了。在之前的资金支持期间，我们表现出固有的右室心肌压低。 用金标准RV压力-体积(PV)比较SSC-PAH与特发性PAH的功能 分析，并进一步揭示了体内功能障碍与深刻的 SSC-PAH皮肤心肌细胞(取自右室活检)的肌节功能障碍 反映为峰值钙激活张力和钙升高的显著下降 敏感度。这些新的发现，结合初步分析显示， RV肌钙蛋白I(TnI)磷酸化和肌球蛋白结合蛋白C(MyBP-C)降解 心肌，支持肌节功能障碍是RV的主要机制的假说 SSC-PAH出现故障，可能提前消亡。我们还应用了非侵入性RV成像， 包括斑点跟踪超声心动图，以评估右室局部功能，以及心脏 磁共振(CMR)评估右室重构、纤维化和心肌灌注 表明这些参数中的一些可以预测存活率。我们的总体假设是 局部微灌流和纤维化受损，导致收缩功能改变，有1) RV适应不良和SSC-PAH存活率下降的核心病理生物学过程； 可非侵入性检测；3)仅对RV靶向治疗有效。在目标1中，我们 将评估RV休息功能、生理储备和RV的治疗反应性- PV分析与右心的SSC-PAH患者的肺动脉相互作用 导尿术。在目标2中，我们将得出房车性能的最佳非侵入性度量 对治疗作出反应，并预测临床恶化和存活的时间。在《目标3》中我们将测试 无论是结合PAH治疗还是RV肌节增敏剂的最佳实践，都可以改善Pre 治疗SSC-PAH患者分离的右室肌丝的肌节功能障碍。

Project Summary Systemic sclerosis (SSc), is a heterogeneous disorder characterized by dysfunction of the endothelium, and dysregulation of fibroblasts and the immune system. SSc-associated pulmonary arterial hypertension (SSc-PAH), a common and often underdiagnosed complication of SSc, is a devastating syndrome leading uniformly to death through right ventricular (RV) failure. In the previous funding period, we demonstrated depressed intrinsic RV myocardial function in SSc-PAH compared to idiopathic PAH using gold standard RV pressure-volume (PV) analysis, and further revealed that in vivo dysfunction significantly correlates with profound sarcomeric dysfunction in SSc-PAH skinned cardiomyocytes (obtained from RV biopsies) as reflected by a marked decline in peak calcium-activated tension and enhanced calcium sensitivity. These novel findings, combined with preliminary analyses showing decreased troponin-I (TnI) phosphorylation and myosin binding protein-C (MyBP-C) degradation in RV myocardium, support the hypothesis that sarcomere dysfunction is a primary mechanism for RV failure, and likely early demise, in SSc-PAH. We also applied non-invasive RV imaging, including speckle-tracking echocardiography to assess RV regional function, and cardiac magnetic resonance (CMR) to assess RV remodeling, fibrosis, and myocardial perfusion to show that some of these parameters may predict survival. Our overall hypothesis is that impaired regional microperfusion and fibrosis, resulting in altered contractile function, are 1) pathobiologic processes at the core of RV maladaptation and decreased SSc-PAH survival; 2) can be detected non-invasively; and 3) can only respond to RV-targeted therapy. In Aim 1 we will assess treatment responsiveness of the RV rest function, physiologic reserve, and RV- Pulmonary arterial interaction in SSc-PAH patients by means of PV analysis and right heart catheterization. In Aim 2 we will derive optimal non-invasive measures of RV performance that respond to therapy and predict time to clinical worsening and survival. And in Aim 3 we will test whether best practice combination PAH therapy, or RV sarcomere sensitizers, improve pre- treatment sarcomere dysfunction in RV myofilaments isolated from SSc-PAH patients.