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：
10553520
负责人：
Shelley Deanne Miyamoto
金额：
$ 16.11万
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/10553520
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.

项目概要随着手术技术和围术期管理的进步，越来越多的患者接受了手术。患有单心室先天性心脏病 (SV) 并存活到儿童期及以后的患者。到期的对于施加在单个体循环心室上的慢性压力和容量负荷，这些患者仍处于心力衰竭发生和进展的持续风险。不幸的是，人们对此知之甚少衰竭的 SV 心脏与衰竭的儿童或成人双心室心脏有何不同。此外，过渡 SV 心脏中发生的心力衰竭的机制尚不完全清楚。这种缺乏理解的情况 SV 心力衰竭的潜在机制是识别有效靶向治疗的主要障碍。此外，SV 的罕见性使得常规的前瞻性对照药物研究变得非常困难。在成人心力衰竭人群中进行，因此治疗方法基于临床试验的推断来自不同患者群体、轶事经验或理论上感知益处的潜力。磷酸二酯酶 5 抑制剂 (PDE5i)，例如西地那非，就是此类疗法的一个例子越来越多地用于 SV 患者群体，但现有证据基础有限。广泛且相当对 SV 患者不加区别地使用 PDE5i 的部分原因是一些出版物表明积极的临床结果小系列 SV 患者的结果。最近发布的 NHLBI FUEL（Fontan Udenafil 练习）纵向评估）试验证明 400 名 Fontan 患者的次最大运动量有所改善。这些令人鼓舞的研究与我们最近发表的文章相结合，证明 PDE5 表达增加，衰竭 SV 心脏中的活性表明心肌可能是 PDE5i 的可行目标。虽然历史上在 SV 中使用 PDE5i 的基本原理是增加肺血流量，但我们假设衰竭的 SV 心肌，特别是线粒体，也是 PDE5i 治疗的目标。我们的初步数据表明：(1) 线粒体功能障碍、sirtuin 信号传导改变以及增加衰竭 SV 心肌 (SVHF) 中线粒体蛋白乙酰化； (2)线粒体反应性降低通过电子顺磁共振 (EPR) 检测衰竭 SV 心脏中氧物质 (ROS) 的产生用 PDE5i 离体处理； (3) 蛋白质乙酰化减少和线粒体功能改善用 PDE5i 离体治疗衰竭的 SV 心脏； (4) SV 非衰竭 (SVNF) 中线粒体功能受损（初次移植或 Norwood 标本）用 PDE5i 离体处理的心脏； (5) 线粒体用 SVHF 患者血清处理的原代心肌细胞功能障碍和 ROS 增加，这是通过添加 PDE5i 或 SIRT 3 激活剂和厚朴酚 (HNK) 可以改善这一情况。我们假设线粒体功能障碍参与了 SV 心脏的 HF 转变，PDE5i 改善了 SV 心脏的线粒体功能以sirtuin依赖性方式衰竭的SV心脏。我们建议使用人体组织和心肌细胞模型来完成所提出的实验。该项目的目的是了解向 HF 的过渡在 SV 人群中，并提供临床前证据，以告知更有针对性的使用，目标是优化临床护理并改善结果。