Abstract
One of the characteristics of the failing human heart is a significant alteration in its energy metabolism. Recently, a ketone body, β-hydroxybutyrate (β-OHB) has been implicated in the failing heart’s energy metabolism as an alternative “fuel source.” Utilization of β-OHB in the failing heart increases, and this serves as a “fuel switch” that has been demonstrated to become an adaptive response to stress during the heart failure progression in both diabetic and non-diabetic patients. In addition to serving as an alternative “fuel,” β-OHB represents a signaling molecule that acts as an endogenous histone deacetylase (HDAC) inhibitor. It can increase histone acetylation or lysine acetylation of other signaling molecules. β-OHB has been shown to decrease the production of reactive oxygen species and activate autophagy. Moreover, β-OHB works as an NLR family pyrin domain-containing protein 3 (Nlrp3) inflammasome inhibitor and reduces Nlrp3-mediated inflammatory responses. It has also been reported that β-OHB plays a role in transcriptional or post-translational regulations of various genes’ expression. Increasing β-OHB levels prior to ischemia/reperfusion injury results in a reduced infarct size in rodents, likely due to the signaling function of β-OHB in addition to its role in providing energy. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to exert strong beneficial effects on the cardiovascular system. They are also capable of increasing the production of β-OHB, which may partially explain their clinical efficacy. Despite all of the beneficial effects of β-OHB, some studies have shown detrimental effects of long-term exposure to β-OHB. Furthermore, not all means of increasing β-OHB levels in the heart are equally effective in treating heart failure. The best timing and therapeutic strategies for the delivery of β-OHB to treat heart disease are unknown and yet to be determined. In this review, we focus on the crucial role of ketone bodies, particularly β-OHB, as both an energy source and a signaling molecule in the stressed heart and the overall therapeutic potential of this compound for cardiovascular diseases.
Highlights
The human heart has an exceptionally high metabolic activity as a pump of the body, performing the daily work of circulating 7 tons of blood
Close attention has been paid to the myocardial metabolism and increased utilization of β-OHB during cardiac stresses, such as heart failure and I/R
Most of the studies showed beneficial effects of mildly to moderately increased β-OHB in heart failure and I/R injury, there is some evidence that a prolonged exposure to or high blood levels of β-OHB are detrimental to the hearts
Summary
The human heart has an exceptionally high metabolic activity as a pump of the body, performing the daily work of circulating 7 tons of blood. As well as other disease conditions (e.g. heart failure), ketone body metabolism can undergo some changes. Several studies have shown that there is an increased myocardial delivery and oxidation of ketone bodies as an alternative fuel source in human patients with advanced heart failure, increasing their proportion from less than 10% to over 20% (Wende et al, 2017; Ho et al, 2019; Horton et al, 2019).
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