Published Online
on May 9, 2005

A more recent version of this article appeared on May 17, 2005

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Submitted on November 18, 2004
Revised on December 23, 2004
Accepted on January 11, 2005

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, and 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.).

^* To whom correspondence should be addressed. E-mail: michiel.tenhove{at}well.ox.ac.uk.

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 -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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