Recent studies have shown that the ketone body beta-hydroxybutyrate (beta OHB) acts not only as a carrier of energy but also as a signaling molecule that has a role in diverse cellular functions. Circulating levels of ketone bodies have been previously reported to be increased in patients with congestive heart failure (HF). In this study, we investigated regulatory mechanism and pathophysiological role of beta OHB in HF. First, we revealed that beta OHB level was elevated in failing hearts, but not in blood, using pressure overloaded mice. We also measured cellular beta OHB levels in both cardiomyocytes and noncardiomyocytes stimulated with or without H2O2 and revealed that increased myocardial beta OHB was derived from cardiomyocytes but not non-cardiomyocytes under pathological states. Next, we sought to elucidate the mechanisms of myocardial beta OHB elevation and its implication under pathological states. The gene and protein expression levels of CoA transferase (SCOT), a key enzyme involved in ketone body oxidation, was decreased in failing hearts. In cardiomyocytes, H2O2 stimulation caused beta OHB accumulation concomitantly with SCOT downregulation, implying that the accumulation of myocardial beta OHB occurs because of the decline in its utilization. Finally, we checked the effects of beta OHB on cardiomyocytes under oxidative stress. We found that beta OHB induced FOXO3a, an oxidative stress resistance gene, and its target enzyme, SOD2 and catalase. Consequently, beta OHB attenuated reactive oxygen species production and alleviated apoptosis induced by oxidative stress. It has been reported that hyperadrenergic state in HF boost lipolysis and result in elevation of circulating free fatty acids, which can lead hepatic ketogenesis for energy metabolism alteration. The present findings suggest that the accumulation of beta OHB also occurs as a compensatory response against oxidative stress in failing hearts. (C) 2016 Elsevier Inc. All rights reserved.