Cause and effect of transient changes in stress, gene expression, and RV fiber orientation during RV remodeling, and its impact on RV function and inter-ventricular coupling in pulmonary hypertension

右心室重塑过程中应激、基因表达和右心室纤维方向短暂变化的原因和影响，及其对肺动脉高压中右心室功能和心室间耦合的影响

• 批准号: 10209842
• 负责人: Vitaly Kheyfets
• 金额: $ 40.44万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10209842
• 关键词: Acute; Animals; Cardiac; Cardiac Myocytes; Catheterization; Characteristics; Child; Collagen; Computer Models; Contracts; Coupling; Data; Data Set; Deterioration; Diffusion; Drug Targeting; Energy Transfer; Failure; Fiber; Fibrosis; Focal Adhesions; Functional disorder; Future; Gene Expression; Gene Proteins; Genes; Genetic Transcription; Geometry; Heart; Image; Interruption; Lead; Left; Left Ventricular Remodeling; Left ventricular structure; Lung; Machine Learning; Magnetic Resonance Imaging; Mathematics; Matrix Metalloproteinases; Mechanical Stress; Mechanics; Modeling; Mus; Myocardial; Myosin Heavy Chains; 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; Stimulus; Stress; Structure; Systole; Time; Tissues; Torsion; Vascular Diseases; Ventricular; Ventricular Remodeling; clinical practice; connectin; constriction; functional decline; improved; improved outcome; in silico; innovation; mortality; mouse model; preservation; pressure; protein expression; response; simulation; survival prediction; 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 LV in RV function is almost completely discounted, but previous research from the 90’s has suggested that the left ventricle (LV) is more important for RV function than the contracting RV free wall. Our previous data has shown that the mechanics of LV contraction is drastically different in children with PH and in mice after pulmonary arterial banding (PAB). Furthermore, mathematical simulations of the heart in our lab have shown that the mechanical burden of the remodeling and pressure-overloaded RV can result in the mechanistic problems we see in both ventricles in children with PH. However, two critical questions remain unanswered: how do changes in RV structure impact RV and LV contractile mechanics, and how do these changes in LV contractile mechanics impact RV function? 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 how they trigger their downstream remodeling pathways. By bridging the gap between gene expression, structure, function, and inter-ventricular contractile mechanics, this project could lead to a better understanding of adaptive vs. maladaptive remodeling pathways. Furthermore, our research is focused on identifying those remodeling characteristics with the biggest influence on function and could expose gene expression pathways that will serve as drug targets in future studies.

项目总结 肺动脉高压(PH)是一种心肺疾病，最终导致右 心室(RV)衰竭。目前还没有批准的针对RV的治疗方法，大多数 研究的重点是减少纤维化，尽管尚不清楚这是否最终会改善RV 泵送功能。然而，胶原和心肌细胞纤维的取向可能有一个 对RV功能的主要影响，在正在进行的研究和临床中基本上被忽视 练习一下。此外，LV在RV功能中的作用几乎完全打折扣，但 此前来自90年代的S的研究表明，左心室(LV)对 房车功能优于收缩房车自由壁。 我们之前的数据表明，左心室收缩的机制截然不同 对肺动脉高压患儿和肺动脉结扎术(PAB)后的小鼠。此外， 我们实验室对心脏的数学模拟表明，心脏的机械负荷 改建和压力过载的房车可能会导致我们在这两个项目中看到的机械问题 高血压病患儿的脑室。然而，有两个关键问题仍然没有得到回答：如何 RV结构的变化影响RV和LV的收缩力学，这些变化是如何在 LV收缩力学影响RV功能？ 在这项研究中，我们将结合PAB小鼠模型和电子计算机模拟来 研究RV游离壁中RV纤维取向和僵化的变化如何影响RV 泵送功能。然后，我们将结合PAB和主动脉收缩来研究RV如何 重塑会干扰LV扭转，如果这中断了LV到RV的机械辅助 在收缩期间。最后，通过收集成像和基因表达的时间进程数据集，我们 将确定直接受机械应力变化影响的基因以及它们是如何 触发它们下游的重塑通路。 通过弥合基因表达、结构、功能和心室间的鸿沟 收缩力学，这个项目可能导致更好地理解自适应与 适应不良的重塑途径。此外，我们的研究集中在识别那些 对功能影响最大且可能暴露基因的重塑特征 在未来的研究中将作为药物靶点的表达途径。

项目成果

Tensions in Taxonomies: Current Understanding and Future Directions in the Pathobiologic Basis and Treatment of Group 1 and Group 3 Pulmonary Hypertension.

• DOI: 10.1002/cphy.c220010
• 发表时间: 2023-01-30
• 期刊: COMPREHENSIVE PHYSIOLOGY
• 影响因子: 5.8
• 作者: Gu, Sue;Goel, Khushboo;Forbes, Lindsay M.;Kheyfets, Vitaly O.;Yu, Yen-rei A.;Tuder, Rubin M.;Stenmark, Kurt R.
• 通讯作者: Stenmark, Kurt R.

Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload.

• DOI: 10.3390/ijms24119746
• 发表时间: 2023-06-05
• 期刊: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
• 影响因子: 5.6
• 作者: Kheyfets, Vitaly O.;Kumar, Sushil;Heerdt, Paul M.;Ichimura, Kenzo;Brown, R. Dale;Lucero, Melissa;Essafri, Ilham;Williams, Sarah;Stenmark, Kurt R.;Spiekerkoetter, Edda
• 通讯作者: Spiekerkoetter, Edda

Novel left ventricular mechanical index in pulmonary arterial hypertension.

• DOI: 10.1002/pul2.12216
• 发表时间: 2023-04
• 期刊: PULMONARY CIRCULATION
• 影响因子: 2.6
• 作者: Ichimura, Kenzo;Santana, Everton J.;Kuznetsova, Tatiana;Cauwenberghs, Nicholas;Sabovcik, Frantisek;Chun, Lindsey;Francisco, Nadia L. C.;Kheyfets, Vitaly O.;Salerno, Michael;Zamanian, Roham T.;Spiekerkoetter, Edda;Haddad, Francois
• 通讯作者: Haddad, Francois

Hemodynamically Unloading the Distal Pulmonary Circulation in Pulmonary Hypertension: A Modeling Study.

肺动脉高压中远端肺循环的血流动力学卸载：建模研究。

• DOI: 10.1115/1.4051719
• 发表时间: 2022
• 期刊: Journal of biomechanical engineering
• 作者: Walter,Rachelle;Hunter,Kendall;Stenmark,Kurt;Kheyfets,VitalyO
• 通讯作者: Kheyfets,VitalyO