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，其特征在于神经系统的功能障碍。 内皮，以及成纤维细胞和免疫系统的失调。SSC相关 肺动脉高压（SSc-PAH），一种常见且常被低估的并发症 SSc是一种毁灭性的综合征，通过右心室（RV）导致死亡 失败在上一个资助期，我们证明了固有RV心肌抑制 使用金标准RV压力-容积（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（从RV活检获得）中的肌节功能障碍， 反映在峰值钙激活张力显着下降和钙增强 灵敏度这些新的发现，结合初步分析显示， RV中肌钙蛋白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的主要机制的假设 在SSc-PAH中失败和可能的早期死亡。我们还应用了非侵入性RV成像， 包括斑点追踪超声心动图，以评估RV区域功能， 磁共振（CMR）评估RV重塑、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 受损的局部微灌注和纤维化，导致收缩功能改变，1） RV适应不良和SSc-PAH存活率降低的核心病理生物学过程; 2） 可以非侵入性地检测;和3）只能响应RV靶向治疗。在目标1中， 将评估RV静息功能、生理储备和RV- 通过PV分析和右心分析SSc-PAH患者的肺动脉相互作用 漂浮导管在目标2中，我们将得出RV性能的最佳非侵入性测量， 对治疗有反应并预测临床恶化和生存的时间。在目标3中，我们将测试 无论是最佳实践的PAH联合治疗，还是RV肌节增敏剂， 治疗从SSc-PAH患者分离的RV肌丝中的肌节功能障碍。

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.