Ketones can become the major fuel source for the heart but do not increase cardiac efficiency.

AIMS: Ketones have been proposed to be a "thrifty" fuel for the heart and increasing cardiac ketone oxidation can be cardioprotective. However, it is unclear how much ketone oxidation can contribute to energy production in the heart, nor whether increasing ketone oxidation increases cardiac efficiency. Therefore, our goal was to determine to what extent high levels of the ketone body, β-hydroxybutyrate (βOHB), contributes to cardiac energy production, and whether this influences cardiac efficiency. METHODS AND RESULTS: Isolated working mice hearts were aerobically perfused with palmitate (0.8mM or 1.2mM), glucose (5mM) and increasing concentrations of βOHB (0, 0.6, 2.0mM). Subsequently, oxidation of these substrates, cardiac function and cardiac efficiency were assessed. Increasing βOHB concentrations increased myocardial ketone oxidation rates without affecting glucose or fatty acid oxidation rates where normal physiological levels of glucose (5mM) and fatty acid (0.8mM) are present. Notably, ketones became the major fuel source for the heart at 2.0mM βOHB (at both low or high fatty acid concentrations), with the elevated ketone oxidation rates markedly increasing TCA cycle activity, producing a large amount of reducing equivalents and finally, increasing myocardial oxygen consumption. However, the marked increase in ketone oxidation at high concentrations of βOHB was not accompanied by an increase in cardiac work, suggesting that a mismatch between excess reduced equivalents production from ketone oxidation and cardiac ATP production. Consequently, cardiac efficiency decreased when the heart was exposed to higher ketone levels. CONCLUSIONS: We demonstrate that while ketones can become the major fuel source for the heart, they do not increase cardiac efficiency, which also underscores the importance of recognizing ketones as a major fuel source for the heart in times of starvation, consumption of a ketogenic diet or poorly controlled diabetes. TRANSLATIONAL PERSPECTIVE: Recent clinical interest has focused on ketones as a potential fuel source for the failing heart, primarily because ketones have been popularized as a "thrifty" fuel that may increase cardiac efficiency. However, we have directly assessed cardiac ketone oxidation rates alongside their competing energy substrates and found that: not only can ketones become the major fuel of the heart with no inhibitory effect on cardiac glucose oxidation, but they can provide the healthy heart with an excess energy supply, with no changes to cardiac function, resulting in a mismatch between reducing equivalents supply and cardiac ATP production, ultimately contributing to a decrease in cardiac efficiency.