Back to Search
Start Over
Reduced inotropic reserve and increased susceptibility to cardiac ischemia/reperfusion injury in phosphocreatine-deficient guanidinoacetate-N-methyltransferase-knockout mice.
- Source :
-
Circulation [Circulation] 2005 May 17; Vol. 111 (19), pp. 2477-85. Date of Electronic Publication: 2005 May 09. - Publication Year :
- 2005
-
Abstract
- 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.<br />Methods and Results: GAMT-/- mice did not show cardiac hypertrophy (myocyte cross-sectional areas, hypertrophy markers atrial natriuretic factor and beta-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). (31)P-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.<br />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.
- Subjects :
- Animals
Cardiomegaly etiology
Creatine Kinase physiology
Disease Susceptibility
Guanidinoacetate N-Methyltransferase genetics
Heart Function Tests
Hemodynamics
Mice
Mice, Knockout
Myocardial Ischemia
Myocardial Reperfusion Injury metabolism
Phosphocreatine physiology
Stress, Physiological
Energy Metabolism physiology
Guanidinoacetate N-Methyltransferase deficiency
Myocardial Contraction
Myocardial Reperfusion Injury etiology
Phosphocreatine deficiency
Subjects
Details
- Language :
- English
- ISSN :
- 1524-4539
- Volume :
- 111
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Circulation
- Publication Type :
- Academic Journal
- Accession number :
- 15883212
- Full Text :
- https://doi.org/10.1161/01.CIR.0000165147.99592.01