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

• 批准号: 9754863
• 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
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9754863
• 关键词: Address; Animal Model; Attention; Biochemical; Biochemistry; Bioinformatics; Biomechanics; Blood; Blood flow; Blood specimen; Canis familiaris; Cardiac; Cardiac Catheterization Procedures; Cardiopulmonary; Child; Childhood; Clinical; Common Ventricle; Complex; Computer Simulation; Contracts; Coupled; Coupling; Data; Degenerative Disorder; Disease; Disease Progression; Down-Regulation; EFRAC; Energy Transfer; Engineering; Etiology; Evaluation; Event; Failure; Functional disorder; Future; Gene Expression; Generations; Genes; Genomics; Heart; Heart failure; Human; Hypoxia; Lead; Left; Left ventricular structure; Link; Lung; Magnetic Resonance Imaging; Measurement; Measures; Mechanical Stress; Mechanics; Modeling; Morphology; Myocardial; Myocardial tissue; Myocardium; Myosin Heavy Chains; Nature; Patients; Performance; Phenotype; Physiologic intraventricular pressure; Population; Prognostic Marker; Progressive Disease; Pulmonary Hypertension; Pump; Rat-1; Rattus; Research; Right Ventricular Dysfunction; Right Ventricular Function; Right ventricular structure; Risk stratification; Rodent; Safety; Specialist; Stress; Systole; Systolic Pressure; Techniques; Tissues; Torsion; Training; United States National Institutes of Health; Up-Regulation; Ventricular; Work; base; blood pump; career development; diagnostic biomarker; differential expression; disorder risk; functional decline; improved; mRNA Expression; mortality; multidisciplinary; normotensive; novel; preservation; pressure; pulmonary arterial hypertension; recruit; research clinical testing; response; skills; transcriptome sequencing

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）是一种退行性疾病， 最终会导致右心衰竭最近，提出的临床技术， 评估疾病进展和危险分层已经利用了以下的相对安全性， 并且在心脏MR（CMR）图像中可用的信息丰富。这些技术 允许直接的功能和形态测量，并可用于 进行患者特定的计算模拟，可以预测生物力学 不同场景下的心脏状态。标记MRI是一种相对较新的技术 这也能揭示紧张和局部心室扭曲该项目将联合收割机MR 儿科PH的成像（有和没有组织标记）和计算建模 患者和大鼠的组织基因表达，以完全表型右心室 小儿肺动脉高压的功能障碍，提高我们对 疾病的生物力学/生物化学进展。 右心室（RV）功能障碍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。但是，在这方面， 先前的多项研究表明，RV依赖于机械能， 从左心室收缩转移到左心室收缩，最高可达泵送性能的80%。初始 单个心室的功能障碍可以触发邻近心室的重构反应， 心室，这将进一步促进前者的功能障碍。因此，我们认为， 在PAH中观察到的LV扭转率变化可能是最终的原因和影响。 右心室功能障碍。本研究的目的是：（1）提供明确的证据， 儿童PAH患者的LV扭转率降低，这与 RV收缩性;（2）使用计算建模研究是否恢复LV扭转- 心率将改善右心室功能，从而将左心室扭转率确定为 RV功能下降的生物力学原因;（3）识别差异表达的 PH大鼠模型的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了解 与PAH相关的心肺病理生理学;（2）提供职业生涯 动物建模、基因组分析和生物信息学的开发培训;以及（3） 为未来的NIH R 01应用程序生成初步数据，以研究 功能性RV-LV代偿失调和基因表达变化。