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

项目摘要 法洛四联症（TOF）是一种常见的先天性心脏病，每3,000例活产婴儿中就有1例发生。手术 纠正通常会导致肺动脉瓣关闭不全（PI）或肺动脉瓣反流，这会产生负面影响 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 心源性猝死是潜在严重不良结局，PI通常是瓣膜置换的指征。 瓣膜置换的时机是有争议的，并且越来越关注于确定最佳时机 在出现明显症状之前这需要更好地理解慢性炎症的病理生理学， TOF修复导致的右心室容量超负荷状况。心室容量超负荷与 病理代谢和增加的氧化应激。具体地，烟酰胺腺嘌呤二核苷酸（NAD+） 在对氧化应激的反应中起核心作用。然而，NAD+与氧化应激之间的关系 由于体内方法的局限性，对RV容量超负荷中的应力了解很少。当前方法 测定NAD+的方法包括高效液相色谱法和31P磁共振波谱法 (MRS)，但这些方法分别受到其侵入性和低灵敏度的限制，并且难以 转化为临床应用。1H低场MRS是一种新兴的MRS技术， MR谱的低场（> 4.7ppm）部分中的难以捉摸的信号。后场MRS仍然没有得到充分的探索， 然而，出现的低场频谱的频谱选择性RF激励已经显示出测量的可能性， 使用1H MRS的体内NAD+。我假设低场1H MRS技术将能够测量心肌 无创性检测心肌组织中NAD~+水平，探讨NAD~+与心肌氧化应激的关系 TOF修复后右心室容量超负荷。我计划使用低场MRS测量心肌NAD+离体， TOF修复绵羊模型中的RV。然后，我将用低场MRS测量的NAD+与NAD+相关联， 使用侵入性分子技术测量的氧化应激标志物。我将进一步发展一种脉搏 使用心肌间隔中的低场MRS在体内测量NAD+序列，并使用外植体进行验证 测量NAD+。我预计这次调查的结果将促进科学知识， RV容量超负荷的病理代谢。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+。这一培训经验将提供机会，建立我的 心血管生理学、先天性心脏病病理生理学、医学影像物理学方面的专业知识， 数据分析我将发表文章，我的后场MRS的调查结果和沟通的影响，这 在各种内部和外部研讨会上从事医学工作。这项研究将在导师制下进行。 宾夕法尼亚大学心血管MRI（Walter Witschey）、儿科MR和 先天性心脏病（Mark Fogel）和心脏病动物模型（Robert Gorman）。

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).