Cardiac Myosin Activation Enhances Contractility While Preserving Myocardial Energetics Compared With β-Adrenergic Stimulation

Technical Summary: Cardiac Myosin Activation vs. β-Adrenergic Stimulation

Problem Statement
Heart failure with reduced ejection fraction (HFrEF) is characterized by impaired contractility and a diminished myocardial energetic reserve. Current therapeutic strategies often rely on catecholaminergic inotropes, such as dobutamine, to augment cardiac output. However, the mechanism of action for these agents involves increasing calcium (Ca2+) cycling, which significantly elevates adenosine triphosphate (ATP) demand. This increased energy consumption exacerbates the existing energetic stress in failing hearts, potentially worsening the metabolic state of the myocardium. There is a need to identify inotropic agents that can enhance contractility without compromising myocardial energetics.

Methodology
This study utilized isolated rat hearts perfused with escalating concentrations of either the myosin activator CK-138 or the β-adrenergic agonist dobutamine. The experimental design focused on comparing the relationship between contractile performance and the myocardial energetic state.

• Contractility Assessment: Measured via left ventricular (LV) pressure and the rate-pressure product.
• Energetic Analysis: Myocardial high-energy phosphate balance was analyzed using 31P-NMR spectroscopy.
• Metabolic Flux Analysis: Substrate-specific metabolic fluxes were quantified using 13C NMR and mass spectrometry.
• Parameters Evaluated: The study specifically examined ATP and phosphocreatine (PCr) levels, the PCr-to-ATP ratio, the free energy of ATP hydrolysis, glycolytic flux, lactate production, and anaplerotic flux.

Key Results
The study demonstrated distinct physiological and metabolic profiles between the two agents:

• Contractility and Hemodynamics: Both agents increased LV contractility. However, unlike dobutamine, CK-138 increased contractility without increasing heart rate or LV end-diastolic pressure.
• Energetic Preservation: CK-138 preserved ATP and phosphocreatine levels, maintaining a stable PCr-to-ATP ratio and the free energy of ATP hydrolysis. In contrast, dobutamine treatment led to the progressive depletion of both ATP and phosphocreatine.
• Metabolic Flux and Efficiency: At comparable workloads, dobutamine exhibited higher glycolytic flux and lactate production, indicating a shift toward glycolysis relative to mitochondrial oxidative metabolism. Conversely, CK-138 treatment resulted in a 13% higher rate of ATP synthesis and approximately 50% lower anaplerotic flux compared to dobutamine. These findings suggest that CK-138 supports mitochondrial efficiency and preserves oxidative metabolism.

Key Contributions
The primary contribution of this work is the characterization of CK-138 as an inotrope that decouples contractile enhancement from the energetic costs typically associated with calcium cycling. By directly activating myosin, CK-138 avoids the added energetic burden of Ca2+ handling. The study provides comparative data showing that while β-adrenergic stimulation depletes ATP reserves and forces a metabolic shift toward glycolysis, myosin activation maintains ATP homeostasis and supports oxidative metabolism.

Significance
The authors conclude that cardiac myosin activators, including CK-138 and omecamtiv mecarbil, represent a mechanistically distinct class of energy-efficient inotropes. The findings support the potential of these agents to enhance cardiac contractility while preserving the myocardial energetic state and substrate utilization, offering a therapeutic profile that avoids the energetic stress induced by traditional catecholaminergic inotropes.