Functional and Biological Phenotyping of Pediatric PH

儿科 PH 的功能和生物学表型

• 批准号: 8353346
• 负责人: ROBIN SHANDAS
• 金额: $ 44.79万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8353346
• 关键词: Adult; Biological; Biological Markers; Biology; Biomechanics; Biomedical Engineering; Blood Vessels; Cardiac; Cessation of life; Child; Childhood; Clinical; Clinical Research; Clinical assessments; Collection; Complex; Coupled; Coupling; Disease; Distal; Energy Transfer; Etiology; Evaluation; Extracellular Matrix Proteins; Failure; Fingerprint; Health; Heart; Heart failure; Heterogeneity; Human; Image; Institution; Knowledge; Lead; Low Cardiac Output; Lung; Measures; Mechanics; Methods; Metric; MicroRNAs; Morbidity - disease rate; Outcome; Pathway interactions; Patients; Phenotype; Population; Published Comment; Pulmonary Hypertension; Pulmonary Vascular Resistance; Pulmonary vessels; Pump; Relative (related person); Right Ventricular Function; Right ventricular structure; Right-On; Role; Series; Supportive care; System; Techniques; Testing; Therapeutic; Vascular remodeling; Ventricular; Work; bench to bedside; electric impedance; hemodynamics; improved; interdisciplinary approach; interest; mortality; novel; novel marker; pressure; pulmonary arterial hypertension

DESCRIPTION (provided by applicant): Pulmonary hypertension in children is a critical determinant of morbidity and mortality in various pediatric diseases. Despite advances in therapies, long-term outcome in many settings remain poor. Although reasons for this are multi-factorial, one critical component is the relative lack of disease-defining knowledge regarding the functional impact of the disease on the right heart and coupled pulmonary vasculature. In fact, clinically, pulmonary arterial hypertension continues to be evaluated predominantly as a distal vascular phenomenon, and only limited recognition is given to the fact that the pulmonary arterial system (PA) is intimately coupled with right ventricular function in health and disease. Functionally speaking, RV-PA coupling is driven by the principles of hydrodynamic and mechanical energy transfer and is thus not markedly dependent on the biological heterogeneity of the pediatric PH population. Over the last 7 years, our group using a reverse "bedside-to-bench" approach have developed novel markers of RV afterload using vascular input impedance principles, and have shown on studies of over 250 pediatric subjects with pulmonary hypertension that PVR does not represent the sole metric of RV afterload, that PA stiffness increases dramatically in pediatric pulmonary hypertension patients and consequently loads the RV to a proportionally greater level, and that inclusion of impedance and PA stiffness measures improves prediction of 1-year outcomes. These clinical studies generated a series of mechanistic studies to understand how the upstream pulmonary vessels stiffen, which have led to novel and interesting hypotheses regarding the role of extracellular matrix proteins in upstream vascular remodeling, mechanisms of healthy versus maladaptive remodeling, and differences in the developing versus the fully developed RV-PA system. These are currently being tested by our group and others through parallel efforts. In this project, we intend to "complete the RV-PA axis picture" by extending our clinical studies on evaluating RV afterload to include pump function from global and local viewpoints and thereby develop and test clinically usable methods to functionally phenotype the pediatric PH patient. In parallel and since biological maladaptation of the RV may precede discernable functional maladaptation, we will biologically phenotype these patients using an established circulating marker of cardiac failure (BNP and NTproBNP) and emerging circulating biomarkers of cardiac failure (micro RNAs). Together these studies will test our hypotheses that RV decompensation in pediatric PH is significantly correlated to deteriorating RV-PA coupling, and that comprehensive functional and biological phenotyping of the RV-PA axis in pediatric PH provides significantly greater prediction of 1- and 2-year clinical outcomes. Through the coordinated, multidisciplinary approach proposed here, which involves experts in bioengineering, imaging, pediatric heart failure, pediatric pulmonary hypertension, and micro RNAs, we should: 1) gain greater understanding of precisely how the human, pediatric RV compensates or decompensates under hypertensive load; 2) generate novel yet clinically usable techniques for the routine evaluation of the RV-PA function; 3) identity the combination of functional and biological phenotypes that best predict outcomes in this complex disease population; and 4) advance our understanding of the functional relationship between RV-PA coupling and RV health. As in prior work, we believe methods, questions and results generated from this study should help guide mechanistic studies to elucidate specific pathways of RV and RV-PA decompensation. PUBLIC HEALTH RELEVANCE: Pulmonary arterial hypertension (PAH) is a fatal disease in children and adults in which progressive increases in load on the right ventricle (RV) ultimately lead to heart failure and death. Current clinical assessment of the disease involves invasive collection of pulmonary vascular resistance (PVR), which is believed to represent RV load, and thus a primary determinant of heart failure. Studies at our institution and others have already shown pulmonary vascular input impedance better characterizes RV load, and in turn, better predicts PAH outcome. We believe that combining impedance with new mechanical and biological measures of RV function will further improve our understanding of the pulmonary system, and in turn further improve prediction of PAH outcomes.

描述（由申请人提供）：儿童肺动脉高压是各种儿科疾病发病率和死亡率的关键决定因素。尽管治疗方法取得了进步，但许多情况下的长期结果仍然不佳。尽管其原因是多因素的，但一个关键因素是相对缺乏关于该疾病对右心和相关肺血管系统功能影响的疾病定义知识。事实上，在临床上，肺动脉高压仍然主要被评估为远端血管现象，并且对肺动脉系统（PA）与健康和疾病中的右心室功能密切相关的事实仅给予有限的认识。从功能上讲，RV-PA 耦合是由流体动力和机械能量转移原理驱动的，因此并不明显依赖于儿科 PH 人群的生物异质性。在过去的 7 年里，我们的团队使用反向“床边到工作台”方法，利用血管输入阻抗原理开发了新的 RV 后负荷标志物，并对 250 多名患有肺动脉高压的儿科受试者进行的研究表明，PVR 并不代表 RV 后负荷的唯一指标，PA 硬度在儿科肺动脉高压患者中急剧增加，因此 RV 负荷成比例地更大 水平，并且纳入阻抗和 PA 刚度测量可以改善对 1 年结果的预测。这些临床研究产生了一系列机制研究，以了解上游肺血管如何变硬，从而产生了关于细胞外基质蛋白在上游血管重塑中的作用、健康与适应不良重塑的机制以及发育中与完全发育的 RV-PA 系统之间的差异等新颖而有趣的假设。我们的团队和其他人目前正在通过并行努力对这些进行测试。在这个项目中，我们打算通过扩展评估 RV 后负荷的临床研究来“完成 RV-PA 轴图”，包括从整体和局部角度考虑泵功能，从而开发和测试临床可用的方法来对儿科 PH 患者进行功能表型分析。与此同时，由于右心室的生物适应不良可能先于可辨别的功能适应不良，我们将使用已建立的心力衰竭循环标志物（BNP 和 NTproBNP）和新出现的心力衰竭循环生物标志物（微小 RNA）对这些患者进行生物学表型。这些研究将共同​​检验我们的假设，即儿科 PH 中的 RV 代偿失调与 RV-PA 耦合恶化显着相关，并且儿科 PH 中 RV-PA 轴的全面功能和生物表型分析可以显着更好地预测 1 年和 2 年临床结果。通过这里提出的协调的、多学科的方法，其中涉及生物工程、影像学、小儿心力衰竭、小儿肺动脉高压和微小RNA方面的专家，我们应该：1）更好地了解人类、小儿右心室在高血压负荷下如何补偿或失代偿； 2) 产生新颖且临床可用的技术来常规评估 RV-PA 功能； 3) 确定最能预测这一复杂疾病群体结果的功能和生物学表型组合； 4) 加深我们对 RV-PA 耦合与 RV 健康之间功能关系的理解。与之前的工作一样，我们相信本研究产生的方法、问题和结果应有助于指导机制研究，以阐明 RV 和 RV-PA 失代偿的具体途径。 公共卫生相关性：肺动脉高压 (PAH) 是儿童和成人的一种致命疾病，右心室 (RV) 负荷逐渐增加，最终导致心力衰竭和死亡。目前对该疾病的临床评估涉及肺血管阻力（PVR）的侵入性收集，这被认为代表右心室负荷，因此是心力衰竭的主要决定因素。我们机构和其他机构的研究已经表明，肺血管输入阻抗可以更好地表征 RV 负荷，进而更好地预测 PAH 结局。我们相信，将阻抗与 RV 功能的新机械和生物测量相结合将进一步提高我们对肺系统的了解，进而进一步改善对 PAH 结果的预测。