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，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。这个K24项目提出了一个独特的研究和培训的结合，以推进PH的临床评估，同时培训临床研究人员，使他们对潜在的物理和血液动力学有基本的了解，并能准确地将这些原理应用于新的临床诊断。

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.