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

心室间解耦是小儿肺动脉高压右心室心肌应激和功能障碍的一个被忽视的因素

基本信息

批准号：
10246380
负责人：
Vitaly Kheyfets
金额：
$ 12.1万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2023-01-31
项目状态：
已结题

项目摘要

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.

项目摘要小儿肺动脉高压（PAH）是一种退化性疾病最终可以导致正确的心力衰竭。最近，提议的临床技术评估疾病进展和风险分层已利用和心脏MR（CMR）图像中可用的大量信息。这些技术允许直接的功能和形态测量，可用于进行特定于患者的计算模拟，以预测生物力学在不同情况下的心脏状态。标记的MRI是一种相对较新的技术这也可以揭示菌株和局部心室扭曲。这个项目将结合MR 成像（带有和没有组织标签）和小儿pH中的计算建模患者和大鼠的组织基因表达完全右心型表型小儿肺动脉高压功能障碍，并提高我们对疾病的生物力学/生化进展。右心（RV）功能障碍通常归因于压力或体积过载，但通常会忽略左心室（LV）的直接贡献。然而，先前的多项研究表明，RV依赖于机械能从LV收缩转移多达80％的抽水性能。最初单个心室的功能障碍可以触发相邻的重塑响应心室，这将进一步导致前者的功能障碍。所以，在PAH中看到的LV扭曲率的变化可能既是最终的原因和影响 RV功能障碍。这项研究的目的是：（1）提供明确的证据表明小儿PAH的LV扭转率降低，这与降低有关 RV收缩性；（2）使用计算建模进行调查，如果恢复LV扭转 - 速率将提高RV功能，因此建立LV扭转率作为 RV功能下降的生物力学原因；（3）确定差异表达的 pH大鼠模型的血液和心肌中的基因。成功完成这些目标将：（1）导致新颖的预后标记，并更好地理解与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；（3）生成未来NIH R01应用程序的初步数据，以研究功能性RV-LV代偿代理和基因表达的变化。