What triggers RV Fiber Re-Orientation in response to RV pressure overload, and what is its Consequence on Inter-Ventricular Decoupling?

是什么触发了右心室纤维重新定向以响应右心室压力过载，以及它对心室间解耦的影响是什么？

• 批准号: 10587587
• 负责人: Vitaly Kheyfets
• 金额: $ 49.18万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587587
• 关键词: Adopted; Animals; Biological; Cardiac; Cardiac Myocytes; Catheterization; Cause of Death; Characteristics; Child; Collagen; Computer Models; Contracts; Coupling; Data; Data Set; Deterioration; Diffusion; Energy Transfer; Failure; Female; Fiber; Fibrosis; Focal Adhesions; Future; Gender; Gene Expression; Genes; Genetic Transcription; Geometry; Heart; Image; Interruption; Left; Left ventricular structure; Lung; Machine Learning; Magnetic Resonance Imaging; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Modeling; Mus; Myocardial; Myosin Heavy Chains; Observational Study; Operative Surgical Procedures; Pathway interactions; Patient-Focused Outcomes; Physiologic intraventricular pressure; Process; Progressive Disease; Protein Isoforms; Pulmonary Heart Disease; Pulmonary Hypertension; Pump; Research; Right Ventricular Dysfunction; Right Ventricular Function; Right ventricular structure; Role; Signal Transduction Pathway; Stress; Systole; Time; Tissues; Torsion; Ventricular; Ventricular Ejection Fractions; aorta constriction; clinical practice; connectin; coping; functional decline; improved; improved outcome; in silico; innovation; male; mechanical energy; mechanical stimulus; mortality; mouse model; preservation; pressure; protein expression; pulmonary vascular disorder; response; right ventricular failure; right ventricular remodeling; simulation; targeted treatment; therapeutic target

PROJECT SUMMARY Pulmonary hypertension (PH) is a cardiopulmonary disease that ultimately leads to right ventricular (RV) failure. Currently there are no approved therapies targeting the RV and most research is focused on reducing fibrosis, although it is unclear if this will ultimately improve RV pumping function. However, the orientation of collagen and cardiomyocyte fibers likely have a major influence on RV function and are largely overlooked in ongoing research and clinical practice. Furthermore, the role of the left ventricle (LV) in RV function is almost completely discounted, but previous research from the 90’s has suggested that the LV is more important for RV function than the contracting RV free wall. Our preliminary data shows that LV torsion rate is reduced in children with PH and in mice after pulmonary arterial banding (PAB), which is correlated with reduced RV ejection fraction in both species. However, when we induced LV pressure overload in the PAB mice (by partial aortic constriction), we improved their LV torsion rate and RV systolic function. This was further validated with in silico studies of the bi-ventricular heart, which showed that targeting LV torsion rate could improve RV systolic function, but it depends on RV free wall fiber orientation. Therefore, these results left us with the following questions: (1) What new orientation do the fibers adopt in response to pressure overload (our preliminary results are not consistent with others), and does this new orientation improve or worsen RV function? (2) How does RV fiber re-orientation impact LV-to-RV mechanical assistance during systole? (3) How does the transient fiber re-orientation and stiffening impact mechanical stress/strain within the tissue, and how does that impact -or is driven by- gene expression? In this study, we will combine the PAB mouse model with in silico simulations to investigate how changes in RV fiber orientation and stiffening, in the RV free wall, impact RV pumping function. Then, we will combine PAB with aortic constriction to study how RV remodeling interferes with LV torsion and if this interrupts LV-to-RV mechanical assistance during systole. Finally, by collecting a time course dataset of imaging and gene expression, we will identify genes that are directly impacted by changes in mechanical stress and expose how they trigger their downstream remodeling pathways. The questions being answered in this project will lead to a better understanding of how RV structural remodeling, in response to pressure overload, impacts RV function and interventricular coupling, and identify target genes governing this process for future studies.

项目概要 肺动脉高压（PH）是一种心肺疾病，最终会导致右肺疾病。 目前还没有针对 RV 的批准治疗方法。 研究重点是减少纤维化，尽管尚不清楚这是否最终会改善 RV 然而，胶原蛋白和心肌细胞纤维的方向可能具有一定的差异。 对 RV 功能有重大影响，但在正在进行的研究和临床中很大程度上被忽视 此外，左心室 (LV) 在 RV 功能中的作用几乎完全。 打折，但 90 年代之前的研究表明 LV 更重要 RV功能比收缩RV自由墙要好。 我们的初步数据表明，患有 PH 的儿童和患有 PH 的儿童的 LV 扭转率降低 肺动脉结扎 (PAB) 后的小鼠，这与 RV 射血减少相关 然而，当我们在 PAB 小鼠中诱导左心室压力超负荷时（通过 部分主动脉缩窄），我们改善了他们的左心室扭转率和右心室收缩功能。 通过双心室心脏的计算机模拟研究进一步验证，该研究表明，针对 LV 扭转率可以改善 RV 收缩功能，但取决于 RV 游离壁纤维方向。 因此，这些结果给我们留下了以下问题：（1）新的方向是什么？ 纤维采用以应对压力过载（我们的初步结果与 (2)RV纤维如何 重新定向对收缩期 LV 至 RV 机械辅助有何影响？ 瞬时纤维重新定向和硬化影响组织内的机械应力/应变，以及 这如何影响基因表达或由基因表达驱动？ 在本研究中，我们将 PAB 小鼠模型与计算机模拟相结合 研究 RV 游离壁中 RV 纤维取向和硬度的变化如何影响 RV 然后，我们将 PAB 与主动脉缩窄结合起来研究 RV 的泵血功能。 重塑会干扰左心室扭转，并且如果这会中断左心室到右心室的机械辅助 最后，通过收集成像和基因表达的时间过程数据集，我们 将识别受机械应力变化直接影响的基因，并揭示如何影响 它们触发下游重塑途径。 该项目中回答的问题将有助于更好地理解如何 RV 结构重塑，以应对压力过载，影响 RV 功能和 室间耦合，并确定控制该过程的靶基因以供未来研究。