Dataset Information

Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency.

ABSTRACT: AIMS:The failing heart is energy-starved and inefficient due to perturbations in energy metabolism. Although ketone oxidation has been shown recently to increase in the failing heart, it remains unknown whether this improves cardiac energy production or efficiency. We therefore assessed cardiac metabolism in failing hearts and determined whether increasing ketone oxidation improves cardiac energy production and efficiency. METHODS AND RESULTS:C57BL/6J mice underwent sham or transverse aortic constriction (TAC) surgery to induce pressure overload hypertrophy over 4-weeks. Isolated working hearts from these mice were perfused with radiolabelled ?-hydroxybutyrate (?OHB), glucose, or palmitate to assess cardiac metabolism. Ejection fraction decreased by 45% in TAC mice. Failing hearts had decreased glucose oxidation while palmitate oxidation remained unchanged, resulting in a 35% decrease in energy production. Increasing ?OHB levels from 0.2 to 0.6?mM increased ketone oxidation rates from 251?±?24 to 834?±?116?nmol·g dry wt-1 · min-1 in TAC hearts, rates which were significantly increased compared to sham hearts and occurred without decreasing glycolysis, glucose, or palmitate oxidation rates. Therefore, the contribution of ketones to energy production in TAC hearts increased to 18% and total energy production increased by 23%. Interestingly, glucose oxidation, in parallel with total ATP production, was also significantly upregulated in hearts upon increasing ?OHB levels. However, while overall energy production increased, cardiac efficiency was not improved. CONCLUSIONS:Increasing ketone oxidation rates in failing hearts increases overall energy production without compromising glucose or fatty acid metabolism, albeit without increasing cardiac efficiency.

SUBMITTER: Ho KL

PROVIDER: S-EPMC6704391 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency.

Ho Kim L KL Zhang Liyan L Wagg Cory C Al Batran Rami R Gopal Keshav K Levasseur Jody J Leone Teresa T Dyck Jason R B JRB Ussher John R JR Muoio Deborah M DM Kelly Daniel P DP Lopaschuk Gary D GD

Cardiovascular research 20190901 11

<h4>Aims</h4>The failing heart is energy-starved and inefficient due to perturbations in energy metabolism. Although ketone oxidation has been shown recently to increase in the failing heart, it remains unknown whether this improves cardiac energy production or efficiency. We therefore assessed cardiac metabolism in failing hearts and determined whether increasing ketone oxidation improves cardiac energy production and efficiency.<h4>Methods and results</h4>C57BL/6J mice underwent sham or transv ...[more]

PMID: 30778524

Similar Datasets

Project description:In heart, glucose and glycolysis are important for anaplerosis and potentially therefore for d-β-hydroxybutyrate (βHB) oxidation. As a glucose store, glycogen may also furnish anaplerosis. We determined the effects of glycogen content on βHB oxidation and glycolytic rates, and their downstream effects on energetics, in the isolated rat heart. High glycogen (HG) and low glycogen (LG) containing hearts were perfused with 11 mM [5-3 H]glucose and/or 4 mM [14 C]βHB to measure glycolytic rates or βHB oxidation, respectively, then freeze-clamped for glycogen and metabolomic analyses. Free cytosolic [NAD+ ]/[NADH] and mitochondrial [Q+ ]/[QH2 ] ratios were estimated using the lactate dehydrogenase and succinate dehydrogenase reaction, respectively. Phosphocreatine (PCr) and inorganic phosphate (Pi ) concentrations were measured using 31 P-nuclear magnetic resonance spectroscopy. Rates of βHB oxidation in LG hearts were half that in HG hearts, with βHB oxidation directly proportional to glycogen content. βHB oxidation decreased glycolysis in all hearts. Glycogenolysis in glycogen-replete hearts perfused with βHB alone was twice that of hearts perfused with βHB and glucose, which had significantly higher levels of the glycolytic intermediates fructose 1,6-bisphosphate and 3-phosphoglycerate, and higher free cytosolic [NAD+ ]/[NADH]. βHB oxidation increased the Krebs cycle intermediates citrate, 2-oxoglutarate and succinate, the total NADP/H pool, reduced mitochondrial [Q+ ]/[QH2 ], and increased the calculated free energy of ATP hydrolysis (∆GATP ). Although βHB oxidation inhibited glycolysis, glycolytic intermediates were not depleted, and cytosolic free NAD remained oxidised. βHB oxidation alone increased Krebs cycle intermediates, reduced mitochondrial Q and increased ∆GATP . We conclude that glycogen facilitates cardiac βHB oxidation by anaplerosis. KEY POINTS: Ketone bodies (d-β-hydroxybutyrate, acetoacetate) are increasingly recognised as important cardiac energetic substrates, in both healthy and diseased hearts. As 2-carbon equivalents they are cataplerotic, causing depletion of Krebs cycle intermediates; therefore their utilisation requires anaplerotic supplementation, and intra-myocardial glycogen has been suggested as a potential anaplerotic source during ketone oxidation. It is demonstrated here that cardiac glycogen does indeed provide anaplerotic substrate to facilitate β-hydroxybutyrate oxidation in isolated perfused rat heart, and this contribution was quantified using a novel pulse-chase metabolic approach. Further, using metabolomics and 31 P-MR, it was shown that glycolytic flux from myocardial glycogen increased the heart's ability to oxidise βHB, and βHB oxidation increased the mitochondrial redox potential, ultimately increasing the free energy of ATP hydrolysis.

Project description:In this study, a self-healing hydrogel was prepared that is transparent to visible (Vis) light while absorbing ultraviolet (UV), infrared (IR), and microwave. The optothermal features of the hydrogel were explored by monitoring temperature using an IR thermometer under an IR source. The hydrogel was synthesized using sodium tetraborate decahydrate (borax) and polyvinyl alcohol (PVA) as raw materials based on a facile thermal route. More significantly, graphene oxide (GO) and graphite-like carbon nitride (g-C3N4) nanostructures as well as carbon microsphere (CMS) were applied as guests to more dissect their influence on the microwave and optical characteristics. The morphology of the fillers was evaluated using field emission scanning electron microscopy (FE-SEM). Fourier transform infrared (FTIR) attested that the chemical functional groups of the hydrogel have been formed and the result of diffuse reflection spectroscopy (DRS) confirmed that the hydrogel absorbs UV while is transparent in Vis light. The achieved result implied that the hydrogel acts as an essential IR absorber due to its functional groups desirable for energy efficiency and harvesting. Interestingly, the achieved results have testified that the self-healing hydrogels had the proper self-healing efficiency and self-healing time. Eventually, microwave absorbing properties and shielding efficiency of the hydrogel, hydrogel/GO, g-C3N4, or CMS were investigated, demonstrating the salient microwave characteristics, originated from the established ionic conductive networks and dipole polarizations. The efficient bandwidth of the hydrogel was as wide as 3.5 GHz with a thickness of 0.65 mm meanwhile its maximum reflection loss was 75.10 dB at 14.50 GHz with 4.55 mm in thickness. Particularly, the hydrogel illustrated total shielding efficiency (SET) > 10 dB from 1.19 to 18 and > 20 dB from 4.37 to 18 GHz with 10.00 mm in thickness. The results open new windows toward improving the shielding and energy efficiency using practical ways.

Project description:AimsRecent evidence has demonstrated that ketone bodies, particularly β-hydroxybutyrate (BHB), are beneficial to the failing heart due to their potential as an alternative energy substrate as well as their anti-inflammatory and anti-oxidative properties. Exogenous supplementation of ketones also helps prevent heart failure (HF) development in rodent models, but whether ketones can be used to treat HF remains unexplored. Herein, we investigated whether chronic supplementation of ketones is beneficial for the heart in a mouse model of established HF.Methods and resultsTo elevate circulating ketone levels, we utilized (R)-3-hydroxybutyl-(R)-3-hydroxybutyrate [ketone ester (KE)]. C57Bl/6N male mice were subjected to transverse aortic constriction (TAC) surgery. After developing HF, mice were treated with either 20% KE or vehicle via drinking water for 2 weeks. In another cohort, mice 3-4 weeks post-TAC received acute intravenous infusions of BHB or saline for 1 h and their cardiac function was measured. 20% KE significantly elevated blood BHB in mice (P < 0.01) without inducing ketoacidosis or altering other metabolic parameters. Mice with overt HF (30-45% ejection fraction) treated with 20% KE displayed significantly elevated circulating ketone levels compared with vehicle-treated mice (P < 0.05). The significant cardiac dysfunction in mice with HF continued to worsen after 2 weeks of vehicle treatment, whereas this decline was absent in KE-treated mice (mean difference 4.7% ejection fraction; P < 0.01). KE treatment also alleviated TAC-induced cardiomyocyte hypertrophy (P < 0.05) and reduced the TAC-induced elevated cardiac periostin (P < 0.05), a marker of activated fibroblasts. Cardiac fibrosis was also significantly reduced with KE treatment in TAC mice (P < 0.01). In another cohort, acute BHB infusion significantly increased the cardiac output of mice with HF (P < 0.05), providing further support that ketone therapy can be used to treat HF.ConclusionsWe show that chronic treatment of exogenous ketones is of benefit to the failing heart and that chronic ketone elevation may be a therapeutic option for HF. Further investigations to elucidate the underlying mechanism(s) are warranted.

Dataset Information

Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency.

Publications

Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets