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: 10677856
• 负责人: Sophia Swago
• 金额: $ 4.77万
• 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/10677856
• 关键词: Address; Affect; Agreement; Animal Model; Animals; Antioxidants; Arrhythmia; Biopsy; Brain; Cardiac; Cardiomyopathies; Cardiovascular Physiology; Cardiovascular system; Child; Childhood; Chronic; Clinic; Clinical; Communication; Complex; Congenital Heart Defects; DNA Repair; DNA Repair Gene; Data; Data Analyses; Development; Dilatation - action; Dilated Cardiomyopathy; Disease Progression; Exercise; Fibrosis; Functional disorder; Heart; Heart Diseases; High Pressure Liquid Chromatography; Human; Image; Investigation; Knowledge; 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; Non-Invasive Detection; 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).

项目摘要 Fallot（TOF）的四部曲是先天性心脏缺陷的一种常见形式，发生在3,000分之三的活产中。外科 校正通常会导致肺动脉瓣不足（PI）或肺部流失，肺瓣膜不足，造成负面影响 影响正确的心脏，增加预紧力并引起右心（RV）扩张。因为Arrythmia和 猝死是潜在的严重不良结果，PI通常是瓣膜置换的指示。 更换阀的时间是有争议的，并且越来越重视确定最佳时机 在明显症状发作之前。这需要更好地了解慢性的病理生理学 RV体积过载条件是由TOF修复导致的。心室体积超负荷与 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+） 在对氧化应激的反应中具有核心作用。但是，NAD+与氧化之间的关系 RV体积超负荷中的压力部分由于体内方法的局限性，部分原因很少。当前方法 测量NAD+包括高性能液相色谱和31p磁共振光谱 （MRS），但是这些方法分别受到其侵入性和低灵敏度的限制，很难 转化为临床用途。 1H下场MRS是一种新兴的MRS技术，可衡量 MR Spectrum的下场（> 4.7 ppm）的难以捉摸的信号。下菲尔德太太仍然没有被忽视， 然而，新兴的下场频谱的频谱选择性RF激发表明有可能测量 NAD+体内使用1H MRS。我假设下场1H MRS技术将能够测量心肌 NAD+无创的，以研究NAD+与心肌氧化应激之间的关系 RV体积过载后修复后。我计划使用下场MRS测量心肌NAD+ ex Vivo RV在TOF修复的卵巢模型中。然后，我将将NAD+与下场MRS与NAD+相关联 使用侵入性分子技术测量氧化应激的标记。我将进一步发展一个脉搏 使用心肌隔中的下场MRS测量NAD+体内的序列，并用epplant对其进行验证 NAD+的测量。我预计这项调查的结果将提高有关科学知识 RV体积超负荷的病理代谢。这项研究还将导致新方法的发展 测量其他心肌疾病中的NAD+。这种培训经验将为建立我的机会提供机会 心血管生理学，先天性心脏病病理生理学，医学成像和 数据分析。我将发表有关我的下场MRS调查结果的文章，并传达其影响的影响 在各种内部和外部研讨会上从事医学工作。这项研究将在指导下进行 宾夕法尼亚大学心血管MRI（Walter Witschey）的专家，儿科MR和 先天性心脏病（Mark Fogel）和心脏病的动物模型（Robert Gorman）。