Inter-ventricular decoupling is an overlooked contributor to right ventricular myocardial stress and dysfunction in pediatric pulmonary hypertension

项目摘要 儿童肺动脉高压(PAH)是一种退行性疾病 最终会导致右心衰竭。最近，提出了临床治疗技术 评估疾病进展和风险分层利用了相对安全的， 和丰富的信息，心脏磁共振(CMR)图像。这些技术 允许直接进行功能和形态测量，并可用于 执行特定于患者的计算模拟，可以预测生物力学 不同场景下的心脏状态。标记核磁共振是一种相对较新的技术 这也可以揭示出劳损和局部的脑室扭曲。该项目将结合MR 儿科PH的成像(有或无组织标记)和计算模型 患者和大鼠的组织基因表达，以完全表型右室 儿童肺动脉高压的功能障碍与提高认识 疾病的生物力学/生化进展。 右室功能不全通常归因于压力或容量。 超负荷，但左心室(LV)的直接贡献通常被忽视。然而， 先前的多项研究表明，房车依赖于机械能 从LV收缩转换到其泵送性能的高达80%。首字母 单个脑室功能障碍可触发邻近脑室的重塑反应 这将进一步加剧前者的功能障碍。因此， 在PAH中看到的LV扭转率的变化可能是终极的原因和结果 右室功能障碍。这项研究的目的是：(1)提供确凿的证据 儿童PAH患者的LV扭转率降低，这与其心脏功能减退有关 右室收缩能力；(2)使用计算模型研究，如果恢复左室扭转- 心率将改善右室功能，从而将左心室扭转率确立为 右室功能下降的生物力学原因；以及(3)识别差异表达 PH大鼠模型血液和心肌中的基因。圆满完成 这些目标将：(1)导致新的预后标志物和更好地理解 与PAH相关的心肺病理生理学；(2)提供职业 动物建模、基因组分析和生物信息学的发展培训；以及(3) 为未来的NIH R01应用程序生成初步数据，以研究 功能性RV-LV失代偿和基因表达的变化。

Project Summary Pediatric pulmonary arterial hypertension (PAH) is a degenerative disease that can ultimately lead to right heart failure. Lately, proposed clinical techniques for assessing disease progression and risk stratification have utilized the relative safety of, and abundant information available in, Cardiac MR (CMR) images. These techniques allow for direct functional and morphological measurements, and can be used to perform patient-specific computational simulations that can predict the biomechanical state of the heart under different scenarios. Tagged MRI is a relatively new technique that can also reveal strain and local ventricular twisting. This project will combine MR imaging (with and without tissue tagging) and computational modeling in pediatric PH patients, and tissue gene expression in rats, to completely phenotype right ventricular dysfunction in pediatric pulmonary hypertension and improve our understanding of the biomechanical/biochemical progression of the disease. Right ventricular (RV) dysfunction is commonly attributed to pressure or volume overload, but direct contribution of the left ventricle (LV) is usually overlooked. However, multiple previous studies have shown that the RV is relying on the mechanical energy transfer from LV contraction for up to 80% of its pumping performance. The initial dysfunction of a single ventricle can trigger a remodeling response in the neighboring ventricle, which would further contribute to the dysfunction of the former. Therefore, changes to LV twisting-rate seen in PAH is likely both the cause and effect of ultimate RV dysfunction. The objective of this study is to: (1) provide definitive evidence that LV torsion-rate is decreased in pediatric PAH, which is associated with a decrease in RV contractility; (2) investigate, using computational modeling, if restoring LV torsion- rate would improve RV function and consequently establish LV torsion-rate as the biomechanical cause for declining RV function; and (3) identify differentially expressed genes in the blood and myocardium of a PH rat model. The successful completion of these objectives will: (1) lead to novel prognostic markers and a better understanding of the cardio-pulmonary pathophysiology associated with PAH; (2) provide career development training for animal modeling, genomic analysis, and bioinformatics; and (3) generate preliminary data for a future NIH R01 application to study the link between functional RV-LV decompensation and changes in gene expression.