Mechanisms of Right Ventricular Dysfunction in PAH

PAH 右心室功能障碍的机制

• 批准号: 8353603
• 负责人: Paul M. Hassoun
• 金额: $ 70.37万
• 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 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353603
• 关键词: Activities of Daily Living; Angiogenesis Modulating Agents; Bicycling; Biological Assay; Biological Markers; Biopsy; Blood Vessels; Calcium; Cardiac; Cardiac Catheterization Procedures; Cardiomyopathies; Cause of Death; Cessation of life; Chemosensitization; Classification; Clinical; Collagen; Connective Tissue Diseases; Coupling; Cytokine Activation; Data; Defect; Disease; Disease Marker; Distal; Endostatins; Endothelium; Evolution; Exercise; Failure; Fibroblasts; Frequencies; Functional disorder; Future; Gene Expression Profile; Genes; Heart; Human; Image; Immune; Immunity; Integrins; Knowledge; Lead; Leg; Link; Lung; Magnetic Resonance Imaging; Measures; Messenger RNA; MicroRNAs; Microfilaments; Migration Inhibitory Factor; Molecular; Muscle Cells; Myocardial; Myocardial perfusion; Myocardial tissue; Organ; Pathway interactions; Patients; Performance; Perfusion; Physiological; Physiology; Production; Prognostic Factor; Property; Proteomics; Protocols documentation; Pulmonary Hypertension; Pulmonary artery structure; Rest; Right Ventricular Dysfunction; Right Ventricular Function; Right ventricular structure; Right-On; Risk; Risk Factors; Role; Sarcomeres; Sensitivity and Specificity; Serum; Signal Transduction; Skin; Stress; Structure; Systemic Scleroderma; Testing; Time; Tissues; Transforming Growth Factor beta; Transforming Growth Factors; Vascular Diseases; Ventricular; Ventricular Remodeling; angiogenesis; base; cardiovascular imaging; disorder risk; electric impedance; hemodynamics; high risk; imaging modality; improved; indexing; insight; novel; outcome forecast; phenylpyruvate tautomerase; pressure; pulmonary arterial hypertension; therapeutic target; treatment strategy

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. PUBLIC HEALTH RELEVANCE: This application will: 1) establish standard clinical imaging and hemodynamic biomarkers of RV function in PAH; 2) identify the cause of RV dysfunction and role in SSc-PAH survival; and 3) unravel pathogenic mechanisms underlying altered myocardial contractile function in PAH that can serve as future therapeutic targets for RV 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，并且可能由未知（特发性，IPAH）原因以及系统性硬化症（SSc）等疾病引起，系统性硬化症是一种以以下特征为特征的疾病：内皮细胞和成纤维细胞失调以及免疫力改变。右心室 (RV) 衰竭 是 PAH 死亡的主要原因，在 SSc 相关 PAH (SSc-PAH) 中尤为突出，同时在所有 PAH 中也很重要。尽管采用现代疗法，SSc-PAH 的中位生存期仅为 3 年，远低于 IPAH。我们最近发现了新的血流动力学和非侵入性基于图像的预测生存的危险因素，并在新的初步数据中揭示了 SSc-PAH 中右心室心肌收缩力的异常。我们认为，SSc-PAH 与 IPAH 相比，生存率较差是由于与肺动脉 (PA) 负荷无关的内在右心室功能障碍，部分原因是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测量，以揭示疾病演变和风险的新机制和标志物。这三个具体目标将 1) 基于心脏磁共振成像得出 RV 性能的最佳非侵入性测量，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来评估储备 RV 功能； 3) 获得 RV 活检，以测试原发性肌节功能障碍对 PAH（任一形式）中 RV 收缩力降低的作用，确定与转化生长因子-β 级联和血管生成调节剂相关的细胞因子激活途径，并评估相关血清生物标志物的潜力反映 RV 疾病。这将为 RV 功能提供急需的见解 用于评估 RV 功能障碍的新型生物标志物（功能性和信号传导）可用于临床。我们还将首次对 PAH 中人类心肌组织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，并产生重要的新见解，为未来旨在改善 PAH 中 RV 功能的治疗铺平道路。 公共健康相关性：该应用程序将： 1) 建立 PAH 中 RV 功能的标准临床影像和血流动力学生物标志物； 2) 确定 RV 功能障碍的原因以及在 SSc-PAH 存活中的作用； 3) 揭示 PAH 心肌收缩功能改变的致病机制，可作为 PAH 右心室功能障碍的未来治疗靶点。