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(Circulation. 2005;111:2477-2485.)
© 2005 American Heart Association, Inc.

Heart Failure

Reduced Inotropic Reserve and Increased Susceptibility to Cardiac Ischemia/Reperfusion Injury in Phosphocreatine-Deficient Guanidinoacetate-N-Methyltransferase–Knockout Mice

Michiel ten Hove, PhD^*; Craig A. Lygate, PhD^*; Alexandra Fischer, PhD; Jürgen E. Schneider, PhD; A. Elisabeth Sang, PhD; Karen Hulbert; Liam Sebag-Montefiore; Hugh Watkins, MD, PhD, FMedSci; Kieran Clarke, PhD; Dirk Isbrandt, PhD; Julie Wallis, PhD; Stefan Neubauer, MD

From the Department of Cardiovascular Medicine (M.t.H., C.A.L., A.F., J.E.S., K.H., L.S., H.W., J.W., S.N.) and University Laboratory of Physiology (A.E.S., K.C.), University of Oxford, Oxford, England; and Center for Molecular Neurobiology, Hamburg, Germany (D.I.).

Correspondence to Michiel ten Hove, PhD, Department of Cardiovascular Medicine, Wellcome Trust Center for Human Genetics, Roosevelt Dr, Oxford OX3 7BN, UK. E-mail michiel.tenhove{at}well.ox.ac.uk

Received November 18, 2004; revision received December 23, 2004; accepted January 11, 2005.

Background— The role of the creatine kinase (CK)/phosphocreatine (PCr) energy buffer and transport system in heart remains unclear. Guanidinoacetate-N-methyltransferase–knockout (GAMT^–/–) mice represent a new model of profoundly altered cardiac energetics, showing undetectable levels of PCr and creatine and accumulation of the precursor (phospho-)guanidinoacetate (P-GA). To characterize the role of a substantially impaired CK/PCr system in heart, we studied the cardiac phenotype of wild-type (WT) and GAMT^–/– mice.

Methods and Results— GAMT^–/– mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and ß-myosin heavy chain). Systolic and diastolic function, measured invasively (left ventricular conductance catheter) and noninvasively (MRI), were similar for WT and GAMT^–/– mice. However, during inotropic stimulation with dobutamine, preload-recruitable stroke work failed to reach maximal levels of performance in GAMT^–/– hearts (101±8 mm Hg in WT versus 59±7 mm Hg in GAMT^–/–; P<0.05). ³¹P-MR spectroscopy experiments showed that during inotropic stimulation, isolated WT hearts utilized PCr, whereas isolated GAMT^–/– hearts utilized P-GA. During ischemia/reperfusion, GAMT^–/– hearts showed markedly impaired recovery of systolic (24% versus 53% rate pressure product recovery; P<0.05) and diastolic function (eg, left ventricular end-diastolic pressure 23±9 in WT and 51±5 mm Hg in GAMT^–/– during reperfusion; P<0.05) and incomplete resynthesis of P-GA.

Conclusions— GAMT^–/– mice do not develop hypertrophy and show normal cardiac function at low workload, suggesting that a fully functional CK/PCr system is not essential under resting conditions. However, when acutely stressed by inotropic stimulation or ischemia/reperfusion, GAMT^–/– mice exhibit a markedly abnormal phenotype, demonstrating that an intact, high-capacity CK/PCr system is required for situations of increased cardiac work or acute stress.

Key Words: creatine kinase • metabolism • hemodynamics • ischemia • myocardium

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