Targeting mitochondria in SV heart disease

SV 心脏病中的靶向线粒体

基本信息

批准号：
10414711
负责人：
Shelley Deanne Miyamoto
金额：
$ 7.62万
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：
2021-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10414711
关键词：
Adult Blood flow Cardiac Myocytes Childhood Chronic Clinical Clinical Trials Common Ventricle Data Development Electron Spin Resonance Spectroscopy Exercise Generations Goals Heart Heart Diseases Heart failure Impairment Lung Mitochondria Mitochondrial Proteins Modeling Myocardium National Heart, Lung, and Blood Institute Patients Perioperative Pharmaceutical Preparations Population Protein Acetylation Publications Publishing Reactive Oxygen Species Risk Series Serum Signal Transduction Single ventricle congenital heart disease Sirtuins Specimen Techniques Transplantation base care outcomes clinical care experience experimental study honokiol human tissue improved improved outcome inhibitor/antagonist mitochondrial dysfunction novel patient population phosphodiesterase V pre-clinical pressure prospective 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, anecdotal 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手术期管理的进步，越来越多的单心室先天性心脏病（SV）患者生存到童年及以后。由于长期承受的压力和体积负荷由于单系统心室，这些患者仍然面临着发展和发展的持续风险心力衰竭的进展。不幸的是，人们对衰竭的 SV 心脏如何发生知之甚少。与衰竭的儿童或成人双心室心脏不同。另外，向心的转变发生在 SV 心脏的衰竭尚不完全清楚。这种缺乏理解 SV 心力衰竭的潜在机制是识别有效治疗方法的主要障碍靶向治疗。此外，SV的稀有性使得前瞻性研究变得非常困难。对照药物研究是在成人心力衰竭人群中常规进行的，因此，治疗基于不同患者群体的临床试验的推断，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，是越来越多地使用的此类疗法的一个例子在现有证据基础有限的 SV 患者群体中。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在小系列 SV 患者中取得了积极的临床结果。最近发布的 NHLBI 燃油（Fontan Udenafil 运动纵向评估）试验证明次最大运动改善为 400 名 Fontan 患者进行锻炼。这些令人鼓舞的研究与我们最近的研究相结合出版物证明衰竭 SV 心脏中 PDE5 表达和活性增加表明心肌可能是 PDE5i 的可行靶点。虽然历史上在 SV 中使用 PDE5i 的基本原理是增加肺血流量，我们假设衰竭的 SV 心肌，特别是线粒体，代表了也是 PDE5i 治疗的目标。我们的初步数据表明：（1）线粒体功能障碍、sirtuin 信号传导改变以及线粒体蛋白乙酰化增加 SV 心肌（SVHF）； (2)线粒体活性氧(ROS)减少通过电子顺磁共振 (EPR) 检测到接受过治疗的衰竭 SV 心脏中的一代体内具有 PDE5i； (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 Non-中线粒体功能受损用 PDE5i 离体处理的衰竭 (SVNF)（初次移植或 Norwood 标本）心脏； (5) 经处理的原代心肌细胞中线粒体功能障碍和 ROS 增加 SVHF 患者血清，通过添加 PDE5i 或 SIRT 3 激活剂得到改善，和厚朴酚（HNK）。我们假设线粒体功能障碍参与了 HF 转变 SV 心脏，并且 PDE5i 改善了 Sirtuin 中衰竭的 SV 心脏的线粒体功能- 依赖方式。我们建议使用人体组织和心肌细胞模型来完成建议的实验。该项目的目的是了解转变 SV 人群中的 HF 并提供临床前证据以告知更有针对性的使用，优化临床护理和改善结果的目标。