Comprehensive Clinical Assessment of Pediatric PHT

描述（由申请人提供）：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。该K24项目提出了研究和培训工作的独特组合，以推进PH的临床评价，同时培训临床研究人员对基础物理学和血液动力学的基本理解以及将这些原理准确应用于新型临床诊断。

DESCRIPTION (provided by applicant): Pulmonary hypertension is a critical determinant of morbidity and mortality in various pediatric diseases. Despite advances in therapies, long-term outcomes 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. This K24 project proposes a unique combination of research studies and training efforts to advance clinical evaluation of PH while training clinical research fellows with both sold fundamental understanding of underlying physics and hemodynamics and accurate application of such principles to novel clinical diagnostics.