Comprehensive Clinical Assessment of Pediatric PHT

描述(由申请人提供)：在各种儿科疾病中，肺动脉高压是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，但许多环境中的长期结果仍然很差。虽然原因是多方面的，但一个关键因素是相对缺乏关于疾病对右心和对肺血管的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一种远端血管现象，而对这样一个事实的认识有限，即在健康和疾病中，肺动脉系统(PA)与右心功能密切相关。从功能上讲，RV-PA偶联是由流体动力学和机械能量转移原理驱动的，因此不明显依赖于儿科PH群体的生物异质性。在过去的7年中，我们团队采用反向“床边到工作台”的方法，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名患有肺动脉高压的儿科受试者的研究中表明，PVR不代表RV后负荷的唯一指标，在儿科肺动脉高压患者中，PA硬度显著增加，从而使RV负荷达到比例更大的水平，并且包括阻抗和PA硬度测量提高了对1年预后的预测。这些临床研究产生了一系列机制研究，以了解上游肺血管是如何硬化的，这些研究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RV-PA系统发育与充分发育的差异等新颖而有趣的假说。目前，我们小组和其他人正在通过平行努力对这些措施进行测试。这个K24项目提出了一种独特的研究和培训工作的组合，以促进对PH的临床评估，同时培训具有基本物理和血流动力学基础知识并将这些原则准确应用于新的临床诊断的临床研究人员。

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.