Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography

Abstract

To test the ability of ketone bodies to inhibit myocardial fatty acid oxidation in vivo, the myocardial clearance kinetics of [1-11C]palmitate was assessed with positron emission tomography in six fasted volunteers and six instrumented dogs, studied repeatedly before and during infusion of 3-hydroxybutyrate (17 mumol.kg-1 x min-1). With the use of multiexponential fitting of tissue time-activity curves, the size, half time (T1/2), and index of the early rapid phase of 11C myocardial clearance, reflecting palmitate oxidation, were calculated. In humans, the relative size (-28%, P < 0.001) and index (-37%, P < 0.01) of the early rapid phase decreased significantly during infusion of 3-hydroxybutyrate, consistent with decreased fatty acid oxidation. Paradoxically, T1/2 decreased from 10.1 +/- 1.6 to 7.4 +/- 1.1 min (P < 0.01). To elucidate possible mechanisms, multiple coronary arteriovenous samples were obtained from the dogs to assess the efflux of oxidized and nonmetabolized tracer. Infusion of 3-hydroxybutyrate resulted in decreased myocardial [11C]CO2 production (-40%, P < 0.05) and reduced palmitate retention (-38%, P < 0.05). In three dogs, the arteriovenous difference in radiolabeled palmitate became negative 10 min after injection, indicating backdiffusion of nonmetabolized tracer from the myocardium. Thus a steady-state infusion of 3-hydroxybutyrate, resulting in physiological plasma levels, alters [1-11C]palmitate kinetics in vivo by decreasing myocardial long-chain fatty acid oxidation and by increasing backdiffusion of nonmetabolized tracer.

Stereoselective effects of 3-hydroxybutyrate on glucose utilization of rat cardiomyocytes

“…In addition, the heart was also chosen because ketone bodies competed with glucose (Chen et al, 1984), fatty acid (Forsey et al, 1987) or palmitate (Vanoverschelde et al, 1993) as the metabolic fuel for the heart. Table 1 depicts the distributions of d-and l-3HB in these organs.…”

Substrate oxidation and cardiac performance during exercise in disorders of long chain fatty acid oxidation

“…In contrast to the oxidation of long-chain fatty acids and glucose, the oxidation of ketones is simple, requiring only a few steps and is not subject to any regulatory processes. In comparison with other tissues in the body, the enzymes required for the conversion of 3-hydroxybutyrate to acetyl CoA are highly active in the heart and facilitate the use of ketone bodies as an alternative energy source 15,16 .…”

Ketone body metabolism and cardiovascular disease

“…Hepatic ketogenesis is stimulated and ketone bodies circulate at increased concentrations in the setting of heart failure in a relationship directly proportional to filling pressure (115,124,125,145,158). As previously noted, the myocardium oxidizes ketone bodies at the expense of fatty acid oxidation (22,82,196,218), and thus reductions of myocardial fatty acid oxidation that occur during the development of advanced cardiomyopathy may not be coupled to reductions of ketone body oxidation (1,10,127). A study in humans with advanced heart failure indicated that myocardial extraction of delivered ketone bodies is maintained in the failing heart but not skeletal muscle (96).…”