Targeting Mitochondria in Single Ventricle Heart Disease

靶向线粒体治疗单心室心脏病

基本信息

批准号：
10371230
负责人：
Shelley Deanne Miyamoto
金额：
$ 68.6万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-15 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10371230
关键词：
Acute Adult Age Anatomy Animal Model Blood Blood flow Cardiac Cardiac Myocytes Childhood Chronic Clinical Clinical Trials Common Ventricle Complex Congenital Abnormality Data Deacetylation Development Disease Electron Spin Resonance Spectroscopy Exercise Generations Goals Guidelines Heart Heart Transplantation Heart failure Impairment Infant Investigation Literature Lung Mediating Mitochondria Mitochondrial Proteins Modeling Molecular Genetics Muscle Cells Myocardial Myocardium National Heart, Lung, and Blood Institute Neonatal Operative Surgical Procedures Palliative Surgery Patients Perioperative Pharmaceutical Preparations Population Populations at Risk Post-Translational Protein Processing Protein Acetylation Proteome Publications Publishing Rattus Reactive Oxygen Species Recommendation Research Respiration Risk Series Serum Signal Transduction Single ventricle congenital heart disease Sirtuins Specimen Techniques Tissues Transplantation Treatment Failure Ventricular base biobank care outcomes clinical care congenital heart disorder exercise capacity experience experimental study honokiol human tissue improved improved outcome inhibitor inhibitor therapy innovation mitochondrial dysfunction new therapeutic target novel palliation patient population phosphodiesterase V pre-clinical pressure prospective response sildenafil targeted treatment

项目摘要

Project Summary With advancements in operative techniques and perioperative management, there is an increasing number of patients with single ventricle congenital heart disease (SV) that are surviving into childhood and beyond. Due to the chronic pressure and volume load placed on the single systemic ventricle, these patients remain at constant risk for the development and progression of cardiac failure. Unfortunately, very little is known about how the failing SV heart differs from the failing pediatric or adult biventricular heart. Additionally, the transition to heart failure that occurs in the SV heart is also incompletely understood. This lack of understanding in the mechanisms underlying SV heart failure are a major hurdle in the identification of effective targeted therapies. In addition, the rarity of SV makes it very difficult to perform prospective controlled drug studies as is routinely done in the adult heart failure population and as a result, treatments are based on extrapolation of clinical trials from different patient populations, anectdotal experience, or potential for theoretic perceived benefit. Phosphodiesterase-5 inhibitors (PDE5i), such as sildenafil, are an example of such a therapy that is increasingly used in the SV patient population with a limited existing evidence-basis. Widespread, and fairly indiscriminate use of PDE5i for SV patients is driven in part by several publications suggesting positive clinical results in small series of SV patients. The recently published NHLBI FUEL (Fontan Udenafil Exercise Longitudinal assessment) trial demonstrated improved submaximal exercise in 400 fontan patients. These encouraging studies combined with our recent publication demonstrating increased PDE5 expression and activity in failing SV hearts suggesting that the myocardium may be a viable target of PDE5i. While historically the rationale for the use of PDE5i in SV is to augment pulmonary blood flow, we hypothesize that the failing SV myocardium, and specifically the mitochondria, represent a target of PDE5i therapy as well. Our preliminary data demonstrate: (1) Mitochondrial dysfunction, altered sirtuin signaling, and increased mitochondrial protein acetylation in failing SV myocardium (SVHF); (2) Decreased mitochondrial reactive oxygen species (ROS) generation detected by Electron Paramagnetic Resonance (EPR) in failing SV hearts treated ex vivo with PDE5i; (3) Decreased protein acetylation and improvement in mitochondrial function in failing SV hearts treated ex vivo with PDE5i; (4) Impaired mitochondria function in SV Non-Failing (SVNF) (primary transplant or Norwood specimens) hearts treated ex vivo with PDE5i; and (5) Mitochondrial dysfunction and increased ROS in primary cardiomyocytes treated with SVHF patient serum, which is improved by the addition of PDE5i or the SIRT 3 activator, honokiol (HNK). We hypothesize that mitochondrial dysfunction is involved in the HF transition of SV hearts, and that PDE5i improves mitochondrial function in failing SV hearts in a sirtuin-dependent manner. We propose the use of human tissue and a cardiomyocyte model to complete the proposed experiments. The purpose of this project is to understand the transition to HF in the SV population and provide pre-clinical evidence to inform more targeted use of, with the goal of optimizing clinical care and improving outcomes.

项目摘要随着手术技术和围手术期管理的进步，越来越多的单脑室先天性心脏病（SV）的患者生存到童年及以后。到期的对于慢性压力和在单个全身性心室上施加的体积负荷，这些患者仍在心力衰竭发展和发展的恒定风险。不幸的是，对失败的SV心脏与失败的儿科或成人双心脏心脏有何不同。另外，过渡在SV心中发生的心力衰竭也未完全理解。这种缺乏理解 SV心力衰竭的基础机制是确定有效靶向疗法的主要障碍。此外，SV的稀有性使得进行前瞻性受控研究变得非常困难在成人心力衰竭人群中完成，因此，治疗是基于临床试验的外推来自不同的患者人群，典型经验或理论感知益处的潜力。磷酸二酯酶5抑制剂（PDE5I），例如西地那非，是这种治疗的例子现有证据基础有限的SV患者人群中越来越多地使用。广泛，公平 SV患者的不加区别使用PDE5I的一部分是由一些出版物驱动的，表明临床阳性导致一系列SV患者。最近出版的NHLBI Fuel（Fontan Udenafil练习纵向评估）试验显示，400名方坦患者的次最大运动改善。这些令人鼓舞的研究加上我们最近的出版物，表明PDE5表达增加和 SV心脏失败的活性表明心肌可能是PDE5I的可行靶标。从历史上看，在SV中使用PDE5I的基本原理是增加肺血流，但我们假设 SV心肌，尤其是线粒体也代表了PDE5I治疗的靶标。我们的初步数据证明：（1）线粒体功能障碍，改变了Sirtuin信号并增加 SV心肌（SVHF）中的线粒体蛋白乙酰化；（2）线粒体反应性降低通过电子顺磁共振（EPR）检测到的氧气（ROS）在失败的SV心脏中检测到用pDE5i处理过体内；（3）蛋白质乙酰化降低和线粒体功能的改善失败的SV心用PDE5I治疗了离体；（4）线粒体在SV非失败（SVNF）中的功能受损（SVNF）（原发性移植或诺伍德标本）用pDe5i治疗的心脏；（5）线粒体用SVHF患者血清处理的原发性心肌细胞中功能障碍和ROS增加，这是通过添加PDE5I或SIRT 3激活剂Honokiol（HNK）改进。我们假设线粒体功能障碍参与SV心脏的HF过渡，PDE5I改善了线粒体功能以Sirtuin依赖的方式失败的SV心。我们建议使用人体组织和心肌细胞模型以完成建议的实验。该项目的目的是了解向HF的过渡在SV人群中，提供临床前证据以告知更多针对性的使用，目的是优化临床护理并改善结果。