Myocardial Metabolic Flexibility Following Ketone Infusion Demonstrated by Hyperpolarized [2-C]pyruvate MRS in Pigs

This study aims to investigate the effects of β-3-hydroxybutyrate (β-3-OHB) infusion on myocardial metabolic flexibility using hyperpolarized [2-C]pyruvate magnetic resonance spectroscopy (MRS) in the pig heart. We hypothesized that β-3-OHB infusion will cause rapid, quantifiable alterations in tricarboxylic acid (TCA) cycle flux as measured non-invasively by C MRS and reflect myocardial work. Five female Danish landrace pigs underwent β-3-OHB infusion during a hyperinsulinemic euglycemic clamp (HEC). Cardiac metabolism and hemodynamics were monitored using hyperpolarized [2-C]pyruvate MRS and cardiac MRI. β-3-OHB infusion during HEC resulted in significant increases in cardiac output over baseline (from 1.9 to 3.8 L/min, p = 0.0011) and heart rate (from 51 to 85 bpm, p = 0.0004). Metabolic analysis showed a shift towards increased lactate production and decreased levels of acetyl-carnitine and glutamate during β-3-OHB infusion. Following the termination of the infusion, a normalization of these metabolic markers was observed. These results demonstrate the profound metabolic adaptability of the myocardium to ketone body utilization. The infusion of Na-β-3-OHB significantly alters both the hemodynamics and metabolism of the porcine heart. The observed increase in cardiac output and metabolic shifts towards lactate production suggest that ketone bodies could potentially enhance cardiac function by providing an efficient-energy substrate that, if provided, is preferentially used. This study provides new insights into the metabolic flexibility of the heart and hints at the potential therapeutic benefits of ketone interventions in heart failure treatment.