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Abstract #4325

Investigating Pharmacological Modification of Cardiac Pyruvate Metabolism Using Hyperpolarized Magnetic Resonance

Lydia M. Le Page1, Michael S. Dodd1, Daniel R. Ball1, Vicky Ball1, Huw B. Jones2, Edvin Johansson3, Damian J. Tyler1

1University of Oxford, Oxford, United Kingdom; 2AstraZeneca, Alderley Park, Macclesfield, United Kingdom; 3AstraZeneca, Mlndal, Sweden

Increasing flux through the pyruvate dehydrogenase (PDH) enzyme has been considered as a potential treatment for type 2 diabetes, as it should lead to reduced blood glucose levels. In this study the ability to assess pharmacologically stimulated increases in PDH flux, both in vivo and ex vivo, has been demonstrated using hyperpolarized [1-13C]pyruvate in combination with magnetic resonance spectroscopy. The generic PDH kinase inhibitor, dichloroacetate, was seen to significantly increase PDH flux both in vivo and ex vivo, whilst the PDH kinase 2 specific inhibitor, AZD7545, did not result in changes to PDH flux in either situation.