Targeting mitochondria in SV heart disease

SV 心脏病中的靶向线粒体

• 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
• 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

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.

项目摘要 随着手术技术和围手术期管理的进步，有一个 单脑室先天性心脏病（SV）的患者数量增加 生存到童年及以后。由于慢性压力和体积负荷 单一的系统性心室，这些患者仍处于发育和 心力衰竭的进展。不幸的是，关于失败的SV心脏的了解很少 儿科或成人双心脏心脏不同。另外，过渡到心 SV心脏中发生的失败也未完全理解。缺乏理解 SV心力衰竭的基础机制是确定有效的主要障碍 靶向疗法。此外，SV的稀有性使得执行前瞻性非常困难 与成人心力衰竭人群通常进行的受控药物研究，结果 治疗是基于从不同患者人群中推断出临床试验的， 轶事经验或理论感知利益的潜力。磷酸二酯酶5 抑制剂（PDE5I），例如西地那非，是这种疗法的一个例子，越来越多地使用 在现有证据基础有限的SV患者中。广泛，公平 SV患者的PDE5I不分青红皂白典的使用部分是由几个出版物驱动的 一系列SV患者的阳性临床结果。最近出版的NHLBI燃料 （fontan udenafil练习纵向评估）试验证明了次最大的改进 在400名方坦患者中运动。这些令人鼓舞的研究与我们最近的 出版物表明SV心脏失败的PDE5表达和活性增加 表明心肌可能是PDE5I的可行靶标。 从历史上看 我们假设失败的SV心肌，尤其是线粒体，代表 PDE5I治疗的靶标。我们的初步数据证明：（1）线粒体 失败的线粒体蛋白乙酰化功能障碍，改变的Sirtuin信号转导和增加 SV心肌（SVHF）; （2）线粒体活性氧（ROS）降低 通过电子顺磁共振（EPR）检测到失败的SV心脏的发电 带有pde5i的体内; （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）（原发性移植或诺伍德标本）用PDE5i治疗的心脏； （5）用治疗的原发性心肌细胞中的线粒体功能障碍和ROS增加 SVHF患者血清，通过添加PDE5I或SIRT 3激活剂得到改善， Honokiol（HNK）。我们假设线粒体功能障碍参与HF转变 SV心脏，该PDE5i在Sirtuin-中的SV心脏中提高了线粒体功能 依赖方式。我们建议使用人体组织和心肌细胞模型 完成提出的实验。该项目的目的是了解过渡 向SV人群中的HF，并提供临床前证据，以告知更多针对性的使用 优化临床护理和改善结果的目的。