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

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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).