Impaired ATP kinetics in failing in vivo mouse heart

Background-The hypothesis that the failing heart may be energy-starved is supported in part by observations of reduced rates of adenosine 5′-triphosphate (ATP) synthesis through the creatine kinase (CK) reaction, the primary myocardial energy reservoir, in patients with heart failure (HF). Although murine models have been used to probe HF pathophysiology, it has not been possible to noninvasively measure the rate of ATP synthesis through CK in the in vivo mouse heart. The purpose of this work was to exploit noninvasive spatially localized magnetic resonance spectroscopy techniques to measure ATP flux through CK in in vivo mouse hearts and determine the extent of any reductions in murine HF. Methods and Results-The Triple Repetition Time Saturation Transfer (TRiST) magnetic resonance spectroscopy method of measuring ATP kinetics was first validated in skeletal muscle, rendering similar results to conventional saturation transfer magnetic resonance spectroscopy. In normal mouse hearts, the in vivo CK pseudo-first-order-rate constant, kF, was 0.32±0.03 s^-1 (mean±SD) and the rate of ATP synthesis through CK was 3.16±0.47 μmol/g/s. Thoracic aortic constriction reduced k_F by 31% (0.23±0.03 s^-1, P<0.0001) and ATP synthesis through CK by 51% (1.54±0.25 μmol/g/s, P<0.0001), values analogous to those in failing human hearts. Conclusions-Despite the small size and high murine heart rate, the ATP synthesis rate through CK is similar in vivo in murine and human hearts and comparably reduced in HF. Because murine thoracic aortic constriction shares fundamental energetic similarities with human HF, this model and new magnetic resonance spectroscopy approach promise a powerful means to noninvasively probe altered energetics in HF.