Impaired contractility and reduced myocardial energetic reserve underlie heart failure with reduced ejection fraction. Catecholaminergic inotropes such as dobutamine are used to augment cardiac output. However, dobutamine increases Ca2+ cycling, raising ATP demand and worsening energetic stress. The myotrope CK-138 increases contractility by directly activating myosin, sparing the added energetic cost of Ca2+ handling. This study compares CK-138 and dobutamine with respect to the relationship between contractile performance and myocardial energetic state, including high-energy phosphate balance, energetic efficiency, and substrate-specific metabolic fluxes. Isolated rat hearts were perfused with escalating concentrations of CK-138 or dobutamine. Contractility was assessed by measuring left ventricular pressure and rate-pressure product. Myocardial energetics were analyzed using 31P-NMR, and metabolic fluxes by 13C NMR and mass spectrometry. Unlike dobutamine, CK-138 increased LV contractility without increasing heart rate or LV end-diastolic pressure. CK-138 preserved ATP and phosphocreatine levels, maintaining a stable phosphocreatine-to-ATP ratio and free energy of ATP hydrolysis, whereas dobutamine progressively depleted both. At comparable workload, dobutamine exhibited higher glycolytic flux and lactate production, indicating greater reliance on glycolysis relative to mitochondrial oxidative metabolism, whereas CK-138 exhibited a 13% higher rate of ATP synthesis and ~50% lower anaplerotic flux, consistent with preserved mitochondrial efficiency. In conclusion, CK-138 enhances cardiac contractility while preserving myocardial energetic state and substrate utilization. Unlike dobutamine, which depletes ATP reserves and shifts metabolism toward glycolysis, CK-138 maintains ATP homeostasis and supports oxidative metabolism. These findings support cardiac myosin activators, including CK-138 and omecamtiv mecarbil, as a mechanistically distinct class of energy-efficient inotropes.
Rahim, M., Baka, T., He, H., Steczina, S., Redd, M. A., Balschi, J. A., Hwee, D. T., Hartman, J. J., Malik, F. I., Murphy, A. N., Luptak, I.
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