Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice

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 β-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 mmHg in GAMT(-/-); P < 0.05). P-31-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 inWT and 51 +/- 5 mmHg 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.