Mechanisms of Right Ventricular Dysfunction in Scleroderma-associated PAH

硬皮病相关 PAH 右心室功能障碍的机制

• 批准号: 10687859
• 负责人: Paul M. Hassoun
• 金额: $ 24.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-15 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687859
• 关键词: Aftercare; Bicycling; Biopsy; Blood Vessels; Calcium; Cardiac; Cardiac Catheterization Procedures; Cardiac Myocytes; Cardiac Output; Cardiovascular system; Cessation of life; Clinical; Collagen; Combined Modality Therapy; Complication; Connective Tissue Diseases; Coupling; Depressed mood; Diagnosis; Disease; Distal; Echocardiography; Exercise; Fibroblasts; Fibrosis; Functional disorder; Funding; Future; Gadolinium; Heart; Image; Immune; Immune system; Impairment; In Vitro; Lung; Magnetic Resonance; Measures; Medical; Microfilaments; Modernization; Molecular; Molecular Analysis; Myocardial; Myocardial perfusion; Myocardium; Non-Invasive Detection; Outcome; Pathway interactions; Patients; Performance; Perfusion; Phosphorylation; Physiologic intraventricular pressure; Physiological; Process; Production; Prognosis; Property; Proteins; Proteomics; Reporting; Rest; Right Ventricular Dysfunction; Right Ventricular Function; Right ventricular structure; Sarcomeres; Scleroderma; Skin; Stress; Supination; Syndrome; Systemic Scleroderma; Testing; Therapeutic; Time; Troponin I; Ventricular; adverse outcome; clinical application; disease prognosis; efficacy testing; endothelial dysfunction; hemodynamics; improved; in vivo; indexing; myosin-binding protein C; non-invasive imaging; novel; precision medicine; pressure; primary pulmonary hypertension; prospective; prospective test; pulmonary arterial hypertension; right ventricular failure; right ventricular remodeling; survival prediction; targeted treatment; treatment response; treatment strategy

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.

项目概要 系统性硬化症（SSc）是一种异质性疾病，其特征是神经系统功能障碍 内皮细胞、成纤维细胞和免疫系统失调。 SSc相关 肺动脉高压（SSc-PAH）是一种常见且经常被诊断不足的并发症 SSc 是一种破坏性综合征，均通过右心室 (RV) 导致死亡 失败。在之前的资助期间，我们证明了内源性 RV 心肌抑制 使用金标准 RV 压力-容积 (PV) 与特发性 PAH 相比，SSc-PAH 中的功能 分析，并进一步揭示体内功能障碍与深刻的相关性 SSc-PAH 皮心肌细胞（从 RV 活检获得）中的肌节功能障碍为 反映在峰值钙激活张力显着下降和钙增强 敏感性。这些新颖的发现与初步分析相结合，显示减少 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 SSc-PAH 患者失败，并可能早期死亡。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右心室区域功能和心脏功能 磁共振 (CMR) 评估 RV 重塑、纤维化和心肌灌注 表明其中一些参数可以预测生存。我们的总体假设是 局部微灌注受损和纤维化，导致收缩功能改变，是 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； 3) 只能对 RV 靶向治疗有反应。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 通过 PV 分析和右心分析 SSc-PAH 患者的肺动脉相互作用 导管插入术。在目标 2 中，我们将推导 RV 性能的最佳非侵入性测量， 对治疗的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 无论是最佳实践组合 PAH 治疗，还是 RV 肌节敏化剂，都可以改善预 治疗从 SSc-PAH 患者中分离出的 RV 肌丝的肌节功能障碍。

项目成果

Passive Leg Raise: A Leg Up in the Diagnosis of Heart Failure With Preserved Ejection Fraction?

被动抬腿：在射血分数保留的心力衰竭诊断中的抬腿方法？

• 发表时间: 2022-04
• 作者: Cubero Salazar, Ilton M;Hsu, Steven
• 通讯作者: Hsu, Steven

Characteristics and Predictors of Late Right Heart Failure After Left Ventricular Assist Device Implantation.

左心室辅助装置植入后晚期右心衰竭的特征和预测因素。

• 发表时间: 2023-03-01
• 作者: Alkhunaizi, Fatimah A;Azih, Nnamdi I;Read, Jacob M;Goldberg, Rachel L;Gulati, Arune A;Scheel 3rd, Paul J;Muslem, Rahatullah;Gilotra, Nisha A;Sharma, Kavita;Kilic, Ahmet;Houston, Brian A;Tedford, Ryan J;Hsu, Steven
• 通讯作者: Hsu, Steven

Updating clinical endpoint definitions.

更新临床终点定义。

• 发表时间: 2013-01
• 影响因子: 2.6
• 作者: Hassoun, Paul M;Nikkho, Sylvia;Rosenzweig, Erika B;Moreschi, Gail;Lawrence, John;Teeter, John;Meier, Christian;Ghofrani, Ardeshir H;Minai, Omar;Rinaldi, Paula;Michelakis, Evangelos;Oudiz, Ronald J
• 通讯作者: Oudiz, Ronald J

Systemic sclerosis-associated pulmonary arterial hypertension.

系统性硬化症相关的肺动脉高压。

• 发表时间: 2013-10
• 影响因子: 9.6
• 作者: Chaisson, Neal F;Hassoun, Paul M
• 通讯作者: Hassoun, Paul M

Updating clinical endpoints in pulmonary arterial hypertension: when challenges are welcome.

更新肺动脉高压的临床终点：迎接挑战。

• 发表时间: 2013-09
• 影响因子: 2.6
• 作者: Hassoun, Paul M;Nikkho, Sylvia;Oudiz, Ronald J
• 通讯作者: Oudiz, Ronald J