Functional and Biological Phenotyping of Pediatric PH

儿科 PH 的功能和生物学表型

基本信息

  • 批准号:
    8890190
  • 负责人:
  • 金额:
    $ 54.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-08-15 至 2016-06-30
  • 项目状态:
    已结题

项目摘要

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):儿童的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。在这个项目中,我们打算通过扩展我们的临床研究,从全局和局部的角度评估RV后负荷以包括泵功能,从而完成RV-PA轴的图像,从而开发和测试临床上可用的方法来对儿童PH患者进行功能表型分析。同时,由于RV的生物适应不良可能先于可辨别的功能适应不良,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(MicroRNAs)对这些患者进行生物学表型。总之,这些研究将检验我们的假设,即儿童PH患者的RV失代偿与RV-PA偶联的恶化显著相关,并且儿童PH患者RV-PA轴的综合功能和生物学表型对1年和2年的临床结果提供了显著更大的预测。通过这里提出的协调、多学科的方法(涉及生物工程、成像、儿童心力衰竭、儿童肺动脉高压和Micro RNA专家),我们应:1)更好地了解在高血压负荷下人类及儿童RV如何补偿或失代偿;2)为RV-PA功能的常规评估产生新的但临床可用的技术;3)确定在这个复杂的疾病人群中最能预测预后的功能和生物表型的组合;以及4)促进我们对RV-PA偶联与RV健康之间的功能关系的理解。与以前的工作一样,我们认为本研究产生的方法、问题和结果应该有助于指导机制研究,以阐明RV和RV-PA失代偿的具体途径。

项目成果

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ROBIN SHANDAS的其他文献

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{{ truncateString('ROBIN SHANDAS', 18)}}的其他基金

Functional and Biological Phenotyping of Pediatric PH
儿科 PH 的功能和生物学表型
  • 批准号:
    8529611
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Functional and Biological Phenotyping of Pediatric PH
儿科 PH 的功能和生物学表型
  • 批准号:
    8725388
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Functional and Biological Phenotyping of Pediatric PH
儿科 PH 的功能和生物学表型
  • 批准号:
    8850551
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Functional and Biological Phenotyping of Pediatric PH
儿科 PH 的功能和生物学表型
  • 批准号:
    8353346
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Functional and Biological Phenotyping of Pediatric PH
儿科 PH 的功能和生物学表型
  • 批准号:
    9107481
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Functional and Biological Phenotyping of Pediatric PH
儿科 PH 的功能和生物学表型
  • 批准号:
    8690138
  • 财政年份:
    2012
  • 资助金额:
    $ 54.51万
  • 项目类别:
Advanced Imaging and Diagnostics for Pediatric Pulmonary Hypertension
小儿肺动脉高压的先进成像和诊断
  • 批准号:
    8214144
  • 财政年份:
    2011
  • 资助金额:
    $ 54.51万
  • 项目类别:
Comprehensive Clinical Assessment of Pediatric PHT
儿科 PHT 的综合临床评估
  • 批准号:
    7138563
  • 财政年份:
    2006
  • 资助金额:
    $ 54.51万
  • 项目类别:
Comprehensive Clinical Assessment of Pediatric PHT
儿科 PHT 的综合临床评估
  • 批准号:
    8382978
  • 财政年份:
    2006
  • 资助金额:
    $ 54.51万
  • 项目类别:
Comprehensive Clinical Assessment of Pediatric PHT
儿科 PHT 的综合临床评估
  • 批准号:
    7679689
  • 财政年份:
    2006
  • 资助金额:
    $ 54.51万
  • 项目类别:

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