Functional and Biological Phenotyping of Pediatric PH

儿科 PH 的功能和生物学表型

• 批准号: 8850551
• 负责人: ROBIN SHANDAS
• 金额: $ 0.35万
• 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/8850551
• 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.

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。尽管在治疗方面取得了进展，但在许多情况下，长期结果仍然很差。虽然造成这种情况的原因是多因素的，但一个关键因素是相对缺乏关于疾病对右心和耦合肺血管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价为一种远端血管现象，只有有限的认识到肺动脉系统（PA）在健康和疾病中与右心室功能密切相关。从功能上讲，RV-PA耦合是由流体动力学和机械能传递原理驱动的，因此不明显依赖于儿科PH人群的生物学异质性。在过去的7年里，我们的研究小组使用反向的“从床到台”的方法，利用血管输入阻抗原理开发了RV后负荷的新标志物，并在250多名儿科肺动脉高压患者的研究中表明，PVR并不是RV后负荷的唯一指标，儿科肺动脉高压患者的PA刚度显著增加，因此RV负荷比例更高。阻抗和PA刚度测量的纳入改善了1年预后的预测。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，这导致了关于细胞外基质蛋白在上游血管重构中的作用，健康与不适应重构的机制，以及发育中与完全发育的RV-PA系统的差异的新颖和有趣的假设。目前，我们的小组和其他人正在通过类似的努力对这些方法进行测试。在这个项目中，我们打算通过扩展我们评估RV后负荷的临床研究，从整体和局部的角度来包括泵功能，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，从而“完成RV- pa轴图像”。同时，由于RV的生物适应不良可能先于可识别的功能适应不良，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rna）对这些患者进行生物学表型分析。总之，这些研究将验证我们的假设，即儿童PH中RV失代偿与RV- pa耦合恶化显著相关，并且儿科PH中RV- pa轴的综合功能和生物学表型可以显著预测1年和2年的临床结果。通过本文提出的多学科协作方法，包括生物工程、影像学、小儿心力衰竭、小儿肺动脉高压和微rna等方面的专家，我们应该：1)更准确地了解人类、儿童RV在高血压负荷下是如何代偿或失代偿的；2)为常规评估RV-PA功能提供新颖且临床可用的技术；3)识别功能表型和生物学表型的组合，最能预测这种复杂疾病人群的预后；4)进一步了解RV- pa耦合与RV健康之间的功能关系。与之前的工作一样，我们相信本研究的方法、问题和结果将有助于指导机制研究，以阐明RV和RV- pa失代偿的具体途径。