AIMS: Understanding changes in ATP metabolism may lead to improved risk stratification in severe primary mitral regurgitation (MR). Here, we seek to compare the energetic phenotype of volume-overload pathological hypertrophy with athletic hypertrophy and with the normal heart under catecholamine stress. METHODS AND RESULTS: Nineteen severe-MR patients underwent cardiac magnetic resonance and 31P-spectroscopy for energetics, including phosphocreatine to adenosine triphosphate ratio (PCr/ATP), the pseudo-first-order forward rate constant of the creatine kinase reaction (k f) and CK flux (k f × [PCr]). When compared with 20 healthy controls, severe MR was associated with lower PCr/ATP (1.58 ± 0.32 vs. 2.08 ± 0.28, P < 0.001). This is related to the severity of regurgitation (r -0.59, P < 0.001) but not to LVEF (r -0.20, P = 0.23) or LV systolic strain (P = 0.18). When compared to 17 athletes with similarly increased end-diastolic volume (athletes 107 ± 10 mL/m2 vs. 114 ± 22, P = 0.29), severe MR had greater total cardiac output (by 42%, P < 0.001), and lower PCr/ATP (by 28%, P < 0.001) and CK flux (by 41%, P = 0.04). When compared to normal hearts during dobutamine stress at matched cardiac output levels, median k f (by 45%, P = 0.08) and CK flux (by 53%, P = 0.02) were lower in severe MR. PCr/ATP increased (by 17%, P = 0.04) following mitral valve repair (MVR) in a subset of patients (n = 14, median 7 months). Seven patients during MVR and six patients without volume loading donated LV biopsy, revealing that creatine was not lower in severe MR. CONCLUSION: Even with normal LVEF, severe MR is associated with reduced PCr/ATP, CK k f, and CK flux. PCr/ATP reduction resolved with MVR. Thus, targeting CK capacity and/or flux may be a therapeutic strategy to prevent/treat systolic failure in MR.