Functional and Biological Phenotyping of Pediatric PH

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，但在许多情况下的长期结果仍然很差。虽然其原因是多因素的，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系统的功能影响的疾病定义知识。事实上，临床上，肺动脉高压仍然主要作为远端血管现象进行评估，并且仅有限地认识到肺动脉系统（PA）与健康和疾病中的右心室功能密切相关的事实。从功能上讲，RV-PA偶联由流体动力学和机械能转移原理驱动，因此不明显依赖于儿科PH人群的生物异质性。在过去7年中，我们的研究小组使用反向"床旁到工作台"方法，利用血管输入阻抗原理开发了RV后负荷的新标记物，并在超过250例肺动脉高压儿科受试者的研究中表明，PVR并不代表RV后负荷的唯一指标，在小儿肺动脉高压患者中PA刚度显著增加，因此RV负荷成比例地更高，包括阻抗和PA刚度测量改善了1年结果的预测。这些临床研究产生了一系列的机制研究，以了解上游肺血管是如何扩张的，这导致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展中与完全发展的RV-PA系统的差异的新的和有趣的假设。目前，我们小组和其他人正在通过平行努力对这些方法进行测试。在本项目中，我们打算通过扩展我们关于评价RV后负荷的临床研究，以从全局和局部角度纳入泵功能，从而开发和测试临床可用的方法，以功能性表型儿科PH患者，从而"完成RV-PA轴图"。同时，由于RV的生物学适应不良可能先于可辨别的功能性适应不良，我们将使用已确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。这些研究将共同验证我们的假设，即小儿PH中的RV失代偿与RV-PA偶联恶化显著相关，并且小儿PH中RV-PA轴的综合功能和生物学表型可显著提高1年和2年临床结局的预测。通过这里提出的协调的多学科方法，包括生物工程、成像、小儿心力衰竭、小儿肺动脉高压和microRNA方面的专家，我们应该：1）更好地了解人类、小儿RV在高血压负荷下是如何代偿或失代偿的; 2）产生新的但临床上可用的技术，用于常规评价RV-PA功能; 3）确定功能和生物表型的组合，最好地预测这种复杂疾病人群的结果;和4）推进我们对RV-PA偶联和RV健康之间的功能关系的理解。与之前的工作一样，我们认为本研究产生的方法、问题和结果应有助于指导机制研究，以阐明RV和RV-PA失代偿的特定途径。 公共卫生相关性：肺动脉高压（PAH）是儿童和成人的一种致死性疾病，其中右心室（RV）负荷的进行性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，认为PVR代表RV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。我们认为，将阻抗与RV功能的新的机械和生物学指标相结合，将进一步提高我们对肺系统的理解，进而进一步提高PAH结局的预测。

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.