Cardiac 1H MRS assessment of NAD+ after Tetralogy of Fallot repair

法洛四联症修复术后 NAD 的心脏 1H MRS 评估

• 批准号: 10597519
• 负责人: Sophia Swago
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10597519
• 关键词: Address; Affect; Agreement; Animal Model; Animals; Antioxidants; Arrhythmia; Biopsy; Brain; Cardiac; Cardiomyopathies; Cardiovascular Physiology; Cardiovascular system; Child; Childhood; Chronic; Clinic; Clinical; Complex; Congenital Heart Defects; DNA Damage; DNA Repair Gene; Data; Data Analyses; Development; Dilatation - action; Dilated Cardiomyopathy; Disease Progression; Exercise; Fibrosis; Functional disorder; Gold; Heart; Heart Diseases; High Pressure Liquid Chromatography; Human; Imaging Techniques; Investigation; Knowledge; Lead; Life; Live Birth; Lung; Magnetic Resonance; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Measurement; Measures; Medical Imaging; Medicine; Mentorship; Metabolism; Methods; Molecular; Morphologic artifacts; Motion; Muscle; Myocardial; NADH; Nicotinamide adenine dinucleotide; Noise; Obstruction; Operative Surgical Procedures; Organ; Oxidative Stress; Pathologic; Pathology; Patients; Pediatrics; Penetration; Pennsylvania; Performance; Phosphorus; Physics; Physiologic pulse; Physiological; Poly(ADP-ribose) Polymerases; Production; Protons; Publishing; Pulmonary Valve Insufficiency; RF coil; Radiology Specialty; Relaxation; Research; Resolution; Right ventricular structure; Risk; Role; Scientific Advances and Accomplishments; Sheep; Signal Transduction; Sirtuins; Skeletal Muscle; Superoxide Dismutase; Supplementation; Symptoms; Techniques; Tetralogy of Fallot; Thiobarbituric Acid Reactive Substances; Tissue Sample; Tissues; Training; Translating; Universities; Ventricular; Ventricular Dysfunction; Water; Work; adverse outcome; cardioprotection; cardiovascular imaging; congenital heart disorder; design; experience; glutathione peroxidase; human tissue; improved; in vivo; insight; liquid chromatography mass spectrometry; pulmonary valve replacement; radio frequency; repaired; respiratory; response; sheep model; standard care; structural heart disease; success; sudden cardiac death; symposium; targeted treatment; valve replacement

PROJECT SUMMARY Tetralogy of Fallot (TOF) is a common form of congenital heart defect that occurs in 1 in 3,000 live births. Surgical correction often results in pulmonary valve insufficiency (PI), or pulmonary regurgitation, which negatively impacts the right heart, increasing preload and causing right ventricular (RV) dilatation. Because arrythmia and sudden cardiac death are potential severe adverse outcomes, PI is often an indication for valve replacement. The timing of valve replacement is controversial and there is an increasing focus on determining optimal timing prior to the onset of overt symptoms. This requires a better understanding of the pathophysiology of the chronic RV volume overload condition that results from TOF repair. Ventricular volume overload is associated with pathologic metabolism and increased oxidative stress. In particular, nicotinamide adenine dinucleotide (NAD+) has a central role in the response to oxidative stress. However, the relationship between NAD+ and oxidative stress in RV volume overload is poorly understood in part due to limitations of in vivo methods. Current methods to measure NAD+ include high performance liquid chromatography and 31P magnetic resonance spectroscopy (MRS), but these methods are limited by their invasiveness and low sensitivity, respectively, and are difficult to translate into clinical use. 1H downfield MRS is an emerging MRS technique that measures the resonances of elusive signals in downfield (>4.7 ppm) part of the MR spectrum. Downfield MRS has remained underexplored, yet emerging spectrally-selective RF excitation for the downfield spectrum has shown the possibility to measure NAD+ in vivo using 1H MRS. I hypothesize that downfield 1H MRS techniques will be able to measure myocardial NAD+ noninvasively for the investigation of the relationship between NAD+ and myocardial oxidative stress in RV volume overload post-TOF repair. I plan to use downfield MRS to measure myocardial NAD+ ex vivo in the RV in an ovine model of TOF repair. I will then associate NAD+ measured with downfield MRS with NAD+ and markers of oxidative stress measured using invasive molecular techniques. I will further develop a pulse sequence to measure NAD+ in vivo using downfield MRS in the myocardial septum and validate it with explant measurement of NAD+. I anticipate the results of this investigation will advance scientific knowledge regarding the pathologic metabolism of RV volume overload. This study will also result in the development of new methods to measure NAD+ in other myocardial diseases. This training experience will provide opportunities to build my expertise in cardiovascular physiology, congenital heart disease pathophysiology, medical imaging physics, and data analysis. I will be publishing articles on my downfield MRS findings and communicating the impact of this work in medicine at various internal and external symposia. This research will be conducted under the mentorship of experts at the University of Pennsylvania in cardiovascular MRI (Walter Witschey), pediatric MR and congenital heart disease (Mark Fogel) and animal models of heart disease (Robert Gorman).

项目概要 法洛四联症 (TOF) 是一种常见的先天性心脏病，每 3,000 名活产儿中就有 1 人患有法洛四联症。外科 纠正通常会导致肺动脉瓣关闭不全（PI）或肺动脉瓣反流，这会对 影响右心，增加前负荷并导致右心室 (RV) 扩张。因为心律失常和 心源性猝死是潜在的严重不良后果，PI通常是瓣膜置换术的指征。 瓣膜置换的时机存在争议，人们越来越关注确定最佳时机 在出现明显症状之前。这需要更好地了解慢性病的病理生理学 TOF 修复导致的 RV 容量过载状况。心室容量超负荷与 病理代谢和氧化应激增加。特别是烟酰胺腺嘌呤二核苷酸 (NAD+) 在氧化应激反应中发挥核心作用。然而，NAD+与氧化之间的关系 由于体内方法的局限性，人们对右心室容量超负荷时的应激知之甚少。目前的方法 测量 NAD+ 包括高效液相色谱法和 31P 磁共振波谱法 （MRS），但这些方法分别因其侵入性和低敏感性而受到限制，并且难以 转化为临床应用。 1H 低场 MRS 是一种新兴的 MRS 技术，可测量 MR 频谱的低场 (>4.7 ppm) 部分中难以捉摸的信号。前场 MRS 尚未得到充分开发， 然而，针对低场频谱的新兴光谱选择性射频激励已显示出测量的可能性 使用 1H MRS 进行体内 NAD+。我假设低场 1H MRS 技术将能够测量心肌 NAD+无创研究NAD+与心肌氧化应激的关系 TOF 修复后 RV 容量过载。我计划使用低场 MRS 来离体测量心肌 NAD+ TOF 修复绵羊模型中的 RV。然后，我会将用前场 MRS 测量的 NAD+ 与 NAD+ 关联起来， 使用侵入性分子技术测量的氧化应激标志物。我将进一步发展脉搏 使用心肌隔膜中的低场 MRS 体内测量 NAD+ 的序列，并用外植体进行验证 NAD+ 的测量。我预计这项调查的结果将增进以下方面的科学知识 右心室容量超负荷的病理代谢。这项研究还将导致新方法的开发 测量其他心肌疾病中的 NAD+。这次培训经历将为我提供机会 心血管生理学、先天性心脏病病理生理学、医学成像物理学等方面的专业知识 数据分析。我将发表有关我的前场 MRS 发现的文章，并传达其影响 在各种内部和外部研讨会上从事医学工作。这项研究将在导师的指导下进行 宾夕法尼亚大学心血管 MRI (Walter Witschey)、儿科 MR 和 先天性心脏病（马克·福格尔）和心脏病动物模型（罗伯特·戈尔曼）。