The development and application of new hyperpolarized magnetic resonance spectroscopy techniques for the non-invasive assessment of metabolism in the rodent heart

Thesis

The aim of this thesis was to develop and apply new hyperpolarized magnetic resonance spectroscopy techniques, to assess in vivo metabolism in the rodent heart. Initial work using rat models of heart disease has provided key findings, such as significant increases in pyruvate dehydrogenase flux in the hypertensive rat heart and metabolic alterations in the TCA cycle during the progression into heart failure. Both could provide future non-invasive markers for the metabolic alterations associated with hypertrophy and heart failure in patients. Whilst both of these models provided useful information regarding the metabolic abnormalities of the diseased heart there is also a need to better characterize the individual metabolic pathways that are modified during heart disease. This requires the study of genetically modified animals, namely transgenic mouse models. However, the translation of the hyperpolarized technique from rat to mouse is particularly challenging, mainly due to the mouse heart being a tenth of the size of the rat heart and with a heart rate at least twice as fast. Work in this thesis details the development of mouse cardiac dynamic nuclear polarization (DNP). The development of this technique allowed interesting insights in to differences in the in vivo metabolic phenotype of commonly used “control” mouse strains, and of mouse models of defects associated with β-oxidation. This work also demonstrated that hyperpolarized [1-¹³C]pyruvate could be used to monitor anaplerotic pathways in the stressed mouse heart, potentially increasing its power for clinical use. In combination with cine-MRI and ³¹P MRS, this work has highlighted that DNP could play an important role in the diagnosis and prognosis of cardiovascular diseases.

Authors: Dodd, MS

• Publication date: 2012
• DOI: 10.5287/ora-obavjvyy1
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: MRS; MRI; metabolism; cardiovascular; hyperpolarized
• Subjects: Metabolism; Biochemistry