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 31P 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 μl; 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 μl; 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.