Targeting Mitochondria in Single Ventricle Heart Disease

靶向线粒体治疗单心室心脏病

• 批准号: 10554324
• 负责人: Shelley Deanne Miyamoto
• 金额: $ 67.56万
• 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: 2021-03-15 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10554324
• 关键词: Acute; Adult; Age; Anatomy; Animal Model; Blood flow; Cardiac; Cardiac Myocytes; Cardiomyopathies; Childhood; Chronic; Clinical; Clinical Trials; Common Ventricle; Complex; Congenital Abnormality; Data; Deacetylation; Development; Disease; Electron Spin Resonance Spectroscopy; Exercise; Generations; Genetic; Goals; Guidelines; Heart; Heart Diseases; Heart Transplantation; Heart failure; Hematological Disease; Impairment; Infant; Institution; Investigation; Literature; Lung; Mediating; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Muscle Cells; Myocardial; Myocardium; National Heart, Lung, and Blood Institute; Neonatal; Operative Surgical Procedures; Palliative Surgery; Patients; Perioperative; Permeability; Pharmaceutical Preparations; Physiology; 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; Spirometry; Techniques; Tissues; Transplantation; Treatment Failure; Ventricular; 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; postnatal; pre-clinical; pressure; prospective; response; 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, 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，有越来越多的 存活到童年及以后的单心室先天性心脏病(SV)患者。到期 对于施加在单个体脑室的慢性压力和容量负荷，这些患者保持在 心力衰竭的发展和进展的持续风险。不幸的是，人们对此知之甚少 心动过速衰竭的心脏与衰竭的儿童或成人双室心有何不同。此外，过渡 对于发生在SV心脏的心力衰竭也不完全了解。在这个问题上缺乏理解 心力衰竭的发病机制是确定有效靶向治疗的主要障碍。 此外，SV的罕见使常规的前瞻性对照药物研究非常困难。 在成人心力衰竭人群中进行，因此，治疗是基于临床试验的推断 来自不同的患者群体、轶事经验或潜在的理论感知益处。 磷酸二酯酶-5抑制剂(PDE5i)，如西地那非，就是这种疗法的一个例子 在现有证据基础有限的SV患者群体中越来越多地使用。广为流传，而且公平 对SV患者不分青红皂白地使用PDE5i的部分原因是几篇临床研究呈阳性的出版物 结果出现了小系列的SV患者。最近发表的NHLBI Fuel(Fontan udenafil练习 纵向评估)试验表明，400名Fontan患者的次极量运动有所改善。这些 令人鼓舞的研究结合我们最近的出版物显示PDE5表达增加和 心衰心脏的活动提示心肌可能是PDE5i的活性靶点。 虽然历史上在SV中使用PDE5i的基本原理是增加肺血流，但我们假设 衰竭的SV心肌，特别是线粒体，也是PDE5i治疗的靶点。 我们的初步数据显示：(1)线粒体功能障碍，sirtuin信号改变，并增加 心力衰竭时室性心动过速心肌线粒体蛋白乙酰化；(2)降低线粒体反应性 电子顺磁共振(EPR)检测心衰时氧物种(ROS)的产生 体外用PDE5i治疗；(3)减少蛋白质乙酰化和改善线粒体功能 PDE5i体外治疗心力衰竭心脏；(4)心力衰竭患者线粒体功能受损(SVNF) (初级移植或诺伍德标本)体外用PDE5i处理的心脏；和(5)线粒体 SVHF患者血清处理的原代心肌细胞功能障碍和ROS增加 通过添加PDE5i或SIRT 3激活剂和厚朴酚(HNK)进行改进。我们假设线粒体 心脏功能障碍与心动过速有关，PDE5i可改善心脏线粒体功能。 心力衰竭的心脏以依赖于Sirtuin的方式。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。本项目的目的是了解向高频的过渡 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，改善结局。