Altered high-energy phosphate metabolism predicts contractile dysfunction and subsequent ventricular remodeling in pressure-overload hypertrophy mice

To study the role of early energetic abnormalities in the subsequent development of heart failure, we performed serial in vivo combined magnetic resonance imaging ( MRI) and P-31 magnetic resonance spectroscopy ( MRS) studies in mice that underwent pressure- overload following transverse aorta constriction ( TAC). After 3 wk of TAC, a significant increase in left ventricular ( LV) mass ( 74 +/- 4 vs. 140 +/- 26 mg, control vs. TAC, respectively; P < 0.000005), size [ end- diastolic volume ( EDV): 48 +/- 3 vs. 61 +/- 8 mu l; P < 0.005], and contractile dysfunction [ ejection fraction ( EF): 62 +/- 4 vs. 38 +/- 10%; P < 0.000005] was observed, as well as depressed cardiac energetics ( PCr/ATP: 2.0 +/- 0.1 vs. 1.3 +/- 0.4, P < 0.0005) measured by combined MRI/ MRS. After an additional 3 wk, LV mass ( 140 +/- 26 vs. 167 +/- 36 mg; P < 0.01) and cavity size ( EDV: 61 +/- 8 vs. 76 +/- 8 mu l; P < 0.001) increased further, but there was no additional decline in PCr/ ATP or EF. Cardiac PCr/ ATP correlated inversely with end- systolic volume and directly with EF at 6 wk but not at 3 wk, suggesting a role of sustained energetic abnormalities in evolving chamber dysfunction and remodeling. Indeed, reduced cardiac PCr/ ATP observed at 3 wk strongly correlated with changes in EDV that developed over the ensuing 3 wk. These data suggest that abnormal energetics due to pressure overload predict subsequent LV remodeling and dysfunction.