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.

项目概要 小儿肺动脉高压（PAH）是一种退行性疾病， 最终可能导致右心衰竭。最近，提出的临床技术 评估疾病进展和风险分层利用了以下方面的相对安全性： 心脏 MR (CMR) 图像中提供了大量信息。这些技巧 允许直接的功能和形态测量，并可用于 执行特定于患者的计算模拟，可以预测生物力学 不同场景下的内心状态。标记 MRI 是一项相对较新的技术 它还可以显示应变和局部心室扭转。该项目将结合MR 儿科 PH 的成像（带或不带组织标记）和计算模型 患者和大鼠的组织基因表达，以完全确定右心室表型 小儿肺动脉高压的功能障碍，提高我们对肺动脉高压的认识 疾病的生物力学/生化进展。 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。然而， 之前的多项研究表明，RV 依靠机械能 将 LV 收缩转移至 80% 的泵血性能。最初的 单心室功能障碍可引发邻近心室的重塑反应 心室，这将进一步加剧前者的功能障碍。所以， PAH 中看到的 LV 扭转率的变化可能是最终的原因和结果 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 的左心室扭转率降低，这与 右心室收缩力； (2) 使用计算模型研究是否恢复 LV 扭转- 率将改善 RV 功能，从而将 LV 扭转率确定为 右心室功能下降的生物力学原因； (3) 识别差异表达 PH 大鼠模型血液和心肌中的基因。顺利完成 这些目标将：（1）产生新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开发培训；和（3） 为未来的 NIH R01 应用生成初步数据，以研究之间的联系 功能性 RV-LV 失代偿和基因表达的变化。