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:
- 金额:$ 7.62万
- 依托单位:
- 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:
- 关键词:AdultBlood flowCardiac MyocytesChildhoodChronicClinicalClinical TrialsCommon VentricleDataDevelopmentElectron Spin Resonance SpectroscopyExerciseGenerationsGoalsHeartHeart DiseasesHeart failureImpairmentLungMitochondriaMitochondrial ProteinsModelingMyocardiumNational Heart, Lung, and Blood InstitutePatientsPerioperativePharmaceutical PreparationsPopulationProtein AcetylationPublicationsPublishingReactive Oxygen SpeciesRiskSeriesSerumSignal TransductionSingle ventricle congenital heart diseaseSirtuinsSpecimenTechniquesTransplantationbasecare outcomesclinical careexperienceexperimental studyhonokiolhuman tissueimprovedimproved outcomeinhibitor/antagonistmitochondrial dysfunctionnovelpatient populationphosphodiesterase Vpre-clinicalpressureprospectivesildenafiltargeted 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.
项目摘要
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
一直存活到童年和以后。由于长期的压力和体积负荷,
单系统心室,这些患者仍然处于发展的恒定风险中,
心力衰竭进展。不幸的是,很少有人知道,
与衰竭的儿童或成人双心室心脏不同。此外,过渡到心脏
在SV心脏中发生的衰竭也不完全清楚。这种缺乏理解,
SV心力衰竭的潜在机制是确定有效的
靶向治疗。此外,SV的罕见性使得很难进行前瞻性研究。
对照药物研究是在成人心力衰竭人群中常规进行的,因此,
治疗基于从不同患者群体的临床试验的外推,
轶事经验,或潜在的理论感知的好处。磷酸二酯酶-5
抑制剂(PDE 5i),如西地那非,是这种治疗的一个例子,
在SV患者人群中,现有证据基础有限。广泛而公平地
在SV患者中不分青红皂白地使用PDE 5i的部分原因是一些出版物表明,
SV患者小系列的阳性临床结果。最近发布的NHLBI FUEL
(Fontan Udenafil运动纵向评估)试验证明次最大
400例Fontan患者的运动。这些令人鼓舞的研究结合了我们最近的
发表文献证实了衰竭SV心脏中PDE 5表达和活性增加
提示心肌可能是PDE 5i的可行靶点。
虽然历史上在SV中使用PDE 5i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
PDE 5i治疗的靶点。初步研究结果表明:(1)线粒体
功能障碍,改变sirtuin信号转导,并增加线粒体蛋白乙酰化在失败
SV心肌(SVHF);(2)线粒体活性氧(ROS)减少
电子顺磁共振(EPR)检测到的SV衰竭心脏中,
(3)PDE 5i的蛋白乙酰化降低和线粒体功能改善,
用PDE 5i离体治疗的衰竭SV心脏;(4)SV非-
用PDE 5 i离体处理的衰竭(SVNF)(初次移植或诺伍德样本)心脏;
和(5)用抗氧化剂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,其通过添加PDE 5i或SIRT 3激活剂而得到改善,
honokalloy(HNK)。我们推测线粒体功能障碍参与了心衰的转变
的SV心脏,PDE 5i改善线粒体功能,在失败的SV心脏在sirtuin-
依赖的方式。我们建议使用人体组织和心肌细胞模型,
完成拟议的实验。这个项目的目的是了解过渡
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Shelley Deanne Miyamoto其他文献
Shelley Deanne Miyamoto的其他文献
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{{ truncateString('Shelley Deanne Miyamoto', 18)}}的其他基金
Targeting Mitochondria in Single Ventricle Heart Disease
靶向线粒体治疗单心室心脏病
- 批准号:
10156031 - 财政年份:2021
- 资助金额:
$ 7.62万 - 项目类别:
Targeting Mitochondria in Single Ventricle Heart Disease
靶向线粒体治疗单心室心脏病
- 批准号:
10554324 - 财政年份:2021
- 资助金额:
$ 7.62万 - 项目类别:
Targeting Mitochondria in Single Ventricle Heart Disease
靶向线粒体治疗单心室心脏病
- 批准号:
10553520 - 财政年份:2021
- 资助金额:
$ 7.62万 - 项目类别:
Targeting Mitochondria in Single Ventricle Heart Disease
靶向线粒体治疗单心室心脏病
- 批准号:
10371230 - 财政年份:2021
- 资助金额:
$ 7.62万 - 项目类别:
Targeting Mitochondria in Single Ventricle Heart Disease
靶向线粒体治疗单心室心脏病
- 批准号:
10759249 - 财政年份:2021
- 资助金额:
$ 7.62万 - 项目类别:
Myocardial Effects of PDE5 Inhibition in Single Ventricle Heart Disease
PDE5 抑制对单心室心脏病的心肌影响
- 批准号:
9237302 - 财政年份:2015
- 资助金额:
$ 7.62万 - 项目类别:
Myocardial Effects of PDE5 Inhibition in Single Ventricle Heart Disease
PDE5 抑制对单心室心脏病的心肌影响
- 批准号:
8860501 - 财政年份:2015
- 资助金额:
$ 7.62万 - 项目类别:
Myocardial Effects of PDE5 Inhibition in Single Ventricle Heart Disease
PDE5 抑制对单心室心脏病的心肌影响
- 批准号:
9033944 - 财政年份:2015
- 资助金额:
$ 7.62万 - 项目类别:
Myocardial Effects of PDE5 Inhibition in Single Ventricle Heart Disease
PDE5 抑制对单心室心脏病的心肌影响
- 批准号:
9416752 - 财政年份:2015
- 资助金额:
$ 7.62万 - 项目类别:
Cardiac Beta-Adrenergic Adaptation in Pediatric Heart Failure
小儿心力衰竭的心脏β-肾上腺素能适应
- 批准号:
7707055 - 财政年份:2009
- 资助金额:
$ 7.62万 - 项目类别:
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