Evolving Concepts of Myocardial Energy Metabolism
2016; Lippincott Williams & Wilkins; Volume: 119; Issue: 11 Linguagem: Inglês
10.1161/circresaha.116.310078
ISSN1524-4571
AutoresGary D. Lopaschuk, John R. Ussher,
Tópico(s)Cardiovascular Function and Risk Factors
ResumoHomeCirculation ResearchVol. 119, No. 11Evolving Concepts of Myocardial Energy Metabolism Free AccessDiscussionPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessDiscussionPDF/EPUBEvolving Concepts of Myocardial Energy MetabolismMore Than Just Fats and Carbohydrates Gary D. Lopaschuk and John R. Ussher Gary D. LopaschukGary D. Lopaschuk From the Cardiovascular Translational Science Institute (G.D.L., J.R.U.), Alberta Diabetes Institute (G.D.L., J.R.U.), Faculty of Pharmacy and Pharmaceutical Sciences (J.R.U.), and Department of Pediatrics (G.D.L.), University of Alberta, Edmonton, Canada. and John R. UssherJohn R. Ussher From the Cardiovascular Translational Science Institute (G.D.L., J.R.U.), Alberta Diabetes Institute (G.D.L., J.R.U.), Faculty of Pharmacy and Pharmaceutical Sciences (J.R.U.), and Department of Pediatrics (G.D.L.), University of Alberta, Edmonton, Canada. Originally published11 Nov 2016https://doi.org/10.1161/CIRCRESAHA.116.310078Circulation Research. 2016;119:1173–1176Although mitochondrial fatty acid and carbohydrate oxidation are the major source of ATP production in the heart, it is becoming increasingly clear that oxidation of other energy substrates, such as ketones and branched chain amino acids (BCAAs), can also contribute to energy production. Of importance is that alterations in cardiac ketone and branched chain amino acids metabolism may also impact the severity of heart failure through alterations in cellular signaling, despite these fuels providing a lower contribution to overall energy production.Dating back to the first studies investigating glucose uptake in the isolated rabbit heart by Locke and Rosenheim in 1907 to the first studies in humans in the late 1940s by Richard Bing and colleagues assessing cardiac substrate extraction via measurement of arterial coronary sinus differences, cardiac energy metabolism has been a topic of interest for cardiologists and scientists alike. The importance of energy metabolism in the heart has become widely appreciated, as has the dynamic nature of the heart's ability to metabolize a wide range of energy substrates to meet its energy requirements. Fatty acids are recognized as a key source of energy for the heart, as well as carbohydrates, such as glucose and lactate (Figure).1 In 1961, Shipp et al2 were the first to demonstrate that increasing fatty acid availability to the heart results in a marked inhibition of glucose oxidation, though credit for the reciprocal relationship between fatty acids and glucose metabolism (glucose/fatty acid cycle) is attributed to the work of Randle et al.3 Confirmation of Randle's glucose/fatty acid cycle in the rodent heart has since been demonstrated in the human heart.1Download figureDownload PowerPointFigure. Interaction of energy substrates for oxidative energy production and branched chain amino acid (BCAA)/ketone body regulation of cellular signaling in the heart.The figure depicts how energy substrates compete for mitochondrial oxidative energy metabolism via generation of acetyl CoA for the tricarboxylic acid (TCA) cycle. However, as both BCAAs and ketone bodies are not major providers of overall acetyl CoA for oxidative energy metabolism, they may influence cardiac function and cardiovascular disease progression via regulating various cardiac signaling processes. This includes influencing mitochondrial protein acetylation or mTOR (mammalian target of rapamycin) signaling, both of which may influence important cardiac processes, such as insulin sensitivity and cellular growth. BCKD indicates branched chain α-keto acid dehydrogenase; BDH, β-hydroxybutyrate dehydrogenase; mTOR, mammalian target of rapamycin; and PDH, pyruvate dehydrogenase.Because the heart is the most metabolically demanding organ in the body, alterations in cardiac intermediary energy metabolism are major contributors to several cardiovascular pathologies. Some of these metabolic alterations include an increased reliance on fatty acids for oxidative energy production in the obese or diabetic heart, or a reduction in fatty acid oxidation and increase in glycolysis in the decompensated failing heart.1 To date, the vast majority of studies investigating intermediary energy metabolism in the normal and diseased myocardium have focused on carbohydrate and fatty acid metabolism, where oxidation of carbohydrates and fatty acids accounts for ≈90% to 95% of ATP production in the heart. However, in light of recent findings demonstrating that metabolism of other substrates, such as BCAAs and ketone bodies, may be altered in various cardiovascular pathologies, the field has become increasingly aware that myocardial intermediary metabolism extends beyond fatty acids and carbohydrates. There have been several advances in our understanding of myocardial BCAA and ketone body metabolism, as well as their impact on cardiovascular disease pathology.Energy Substrate Competition for Mitochondrial Oxidative MetabolismIt is widely accepted that glucose and fatty acids compete as a source of acetyl CoA for the tricarboxylic acid cycle and subsequent mitochondrial oxidative energy production (Figure). Based on this premise, it could be anticipated that in situations where circulating BCAAs or ketone bodies are elevated, such as diabetes mellitus or heart failure, that increased BCAA or ketone body oxidation would compete for tricarboxylic acid cycle acetyl CoA, resulting in an impairment of fatty acid or carbohydrate oxidation. However, what is often not considered is the actual percent contribution these fuels provide toward total myocardial oxidative ATP production. Indeed, few studies, to date, have measured actual flux for oxidation of BCAAs and other amino acids, with one study demonstrating a minimal contribution of leucine oxidation to overall energy production in the isolated rat heart (3%–5% of overall cardiac oxygen consumption rates).4 Likewise, few studies have determined actual flux rates in the heart for ketone body oxidation. Data in our laboratories support these limited findings because the presence of BCAAs or β-hydroxybutyrate (βHB) at clinically relevant concentrations has no effect on myocardial glucose and fatty acid oxidation rates in the isolated working mouse heart, with each substrate accounting for 10% at most of total ATP production (Figure; unpublished data). If ketone bodies and BCAAs are not major contributors to overall myocardial ATP production with negligible actions on myocardial carbohydrate and fatty acid oxidation, this leads to the important question of how altering energy metabolism of these substrate fuels impacts myocardial function during disease progression. Recent evidence illustrates that changes in myocardial ketone body and BCAA metabolism/oxidation modulate ventricular function via influencing various cardiac myocyte signaling processes (see below).Energy Substrates as Signaling MoleculesIn addition to being important energy substrates for the heart, fatty acids and their intermediates are also important signaling molecules. This includes acting as ligands for transcription factors, such as PPARα (peroxisome proliferator–activated receptor α), serving as precursors for fatty acid derivatives, such as diacylglycerol and ceramides, while also impacting insulin signaling and modifying apoptosis.5 Hence, alterations in flux through fatty acid oxidation may potentially modify the levels of these fatty acid intermediates, thereby impacting these various signaling pathways. Glucose and glycolytic intermediates also have multiple signaling functions, and similar to fatty acids, altering glucose metabolism can impact these signaling pathways.It is now clear that ketone bodies and BCAAs also have important roles in myocardial signaling. For instance, βHB can act at a nuclear level as an inhibitor of histone deacetylases, which can inhibit prohypertrophic transcription.6 Circulating βHB levels are decreased in obese females,7 as well as in obese mice with heart failure,8 which can potentially contribute to the decrease in cardiac βHB and increased histone deacetylase activity, thereby increasing histone acetylation, leading to a decrease in forkhead box protein O1 acetylation and atrogin-1 expression, while also activating calcineurin/NFAT (nuclear factor of activated T-cells) signaling.6BCAAs, such as leucine, can stimulate mTOR (mammalian target of rapamycin), which as part of the mTORC1 (mammalian target of rapamycin complex 1) complex has multiple functions in regulating cell growth/proliferation and insulin signaling through activating p70S6 kinase and increasing serine phosphorylation of the insulin-receptor substrate to block insulin signaling.9 In addition, accumulation of branched chain α-keto acids, the products of BCAAs, due to defects in BCAA oxidation, has also been proposed to promote insulin resistance.10These energy substrates may also influence cardiac signaling via posttranslational modification of lysine acetylation, which has an important role in regulating mitochondrial metabolic pathways. Ketone body oxidation has recently been proposed to be an important source of acetyl CoA for this acetylation, and in the failing heart (both humans and animals), ketone body oxidation rates appear to be increased.8,11 This increase in ketone body oxidation may provide surplus acetyl CoA for mitochondrial protein hyperacetylation, which could possibly lead to metabolic dearrangements in the failing heart.BCAA metabolism also seems to be affected by heart failure because a defect in BCAA metabolism into their corresponding branched chain α-keto acids (α-ketoisovalerate, α-ketoisocaproate, and α-keto-β-methylvalerate) is observed in the myocardium of both mice and humans with heart failure.10 Intriguingly, pharmacological interventions aimed at enhancing branched chain α-keto acid metabolism via inhibiting the kinase that phosphorylates and inhibits branched chain α-keto acid dehydrogenase improved ventricular function after pressure overload–induced heart failure.10Of interest, advances in the field of small metabolites and cellular signaling have also revealed that various energy substrates and their metabolites bind receptors that are likely to influence several cellular signaling processes (eg, second messenger-mediated signal transduction). This includes the G-protein–coupled receptor GPR81, which lactate has been shown to activate in adipocytes,12 or the G-protein–coupled receptor GPR109A, which is activated by βHB.6 Whether BCAAs also activate receptor-mediated mechanisms to influence cellular signaling remains to be determined, as is whether these receptors are even expressed in cardiac myocytes. These important questions will hopefully be answered by the field in coming years, and it will be important to determine whether these substrate fuels contribute to cardiac signaling or cardiovascular disease progression independently from their role in myocardial energy provision, which now seems to be a more realistic possibility.Fuel Use and Cardiac EfficiencyIt has long been recognized that there are significant disparities in the efficiency of different energy substrates in producing ATP.1 In particular, although fatty acids are a plentiful source of energy for the heart, they are less efficient than carbohydrates at producing ATP (ie, ATP produced per oxygen consumed).1 How other energy substrates impact on cardiac efficiency is less well defined. Interest in this has come to the forefront with the recent demonstration that the SGLT2 inhibitor, empagliflozin, has profound cardioprotective effects in high-risk patients with diabetes mellitus.13 Because SGLT2 inhibitors also increase βHB levels, it has been suggested that this increases ketone body oxidation in the heart and that ketone bodies are a superfuel that is oxidized by the heart in preference to fatty acids and glucose, and that ketones not only improve cardiac function in the failing heart, but also improve cardiac efficiency.14 However, despite oxidation of βHB providing more energy per 2 carbon moiety than glucose or pyruvate, it actually produces less energy than oxidation of a fatty acid. Conversely, on the basis of ATP produced per oxygen consumed (P/O ratio), metabolism of βHB is more efficient than that of fatty acids, but less efficient than that of glucose. Because fatty acids, glucose, and βHB may all compete for tricarboxylic acid cycle acetyl CoA (Figure), increasing the metabolism of βHB should decrease glucose oxidation, thereby potentially actually decreasing cardiac efficiency. However, to date, the relationship between ketone body, fatty acid, and glucose oxidation and cardiac efficiency is not clear.As mentioned previously, ketone body oxidation is increased in the failing heart. Whether this is an adaptive or maladaptive process is unclear. Although increased ketone body oxidation may maintain fuel supply for oxidative metabolism, the potential also exists for an increase in mitochondrial protein acetylation (which compromises cardiac energetics). Ketone body oxidation may also lead to a depletion of tricarboxylic acid cycle intermediates (ie, decreased anaplerosis), leading to a decrease in mitochondrial oxidative phosphorylation.15 Therefore, enhancing βHB oxidation in the setting of diabetes mellitus and heart failure may be potentially undesirable. Hence, the relationship between myocardial ketone body oxidation and cardiac efficiency remains enigmatic.Implications for the Field of Myocardial Energy MetabolismFor decades, the field appreciated the importance of fatty acids and carbohydrates to myocardial energy metabolism and subsequent cardiac function and contractile efficiency. In the past decade, however, the field has become more aware that intermediary metabolism of other substrate fuels, such as BCAAs and ketone bodies, are also important contributors to cardiac function, especially in the context of underlying cardiac disease. It should be noted, though, that a lot of the landmark studies illustrating an important role for these fuels with regards to myocardial energy metabolism in health and disease were identified via unbiased metabolite profiling using metabolomics-based screening methods.8,10,11 Such findings highlight the power of unbiased metabolomics approaches to identify novel metabolic processes that may be implicated in disease pathogenesis, thereby acting as a hypothesis-generating tool that can lead to intricate molecular explorations in animal models of cardiovascular disease. On the contrary, these findings tell us nothing about the actual contribution to myocardial ATP production because metabolomics assessments provide no information on actual substrate flux, and as already mentioned, work in our laboratories suggest that BCAAs and ketone bodies are not major providers of overall ATP production in the heart (unpublished data). Nonetheless, myocardial metabolism of BCAAs and ketone bodies is still important because they can influence several cellular signaling processes, some of which are key regulators of cellular growth that may influence the progression of cardiac hypertrophy.Taken together, it is obvious that metabolism of various substrate fuels in the heart can influence cardiac function during the progression of several cardiovascular pathologies. However, it is now clear that the role(s) metabolism of these fuels play extends beyond energy provision to the myocardium, despite the primary role of intermediary metabolism in the heart being to support the massive energy demand for constant contractile activity. Future studies will have to take into account the numerous signaling processes influenced by the plethora of substrate fuels the heart simultaneously oxidizes. As such, understanding these cardiac signaling changes will likely yield a better understanding of whether targeting myocardial metabolism will be a feasible approach to treat cardiovascular disease, in comparison to a body of historical research that surmised either increasing cardiac energy production or enhancing contractile efficiency as the mechanisms of benefit.Sources of FundingSupported by grants from the Canadian Institutes of Health Research, the Canadian Diabetes Association (CDA), and the Heart and Stroke Foundation of Canada. G.D. Lopaschuk is a Scientist of the Alberta Innovates Health Solutions. J.R. Ussher is a Scholar of the CDA and a New Investigator of the Heart and Stroke Foundation of Alberta, NWT & Nunavut.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to Gary Lopaschuk, 423 Heritage Medical Research Center, University of Alberta, Edmonton, Canada T6G 2S2. E-mail [email protected]References1. Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease.Physiol Rev. 2010; 90:207–258. doi: 10.1152/physrev.00015.2009.CrossrefMedlineGoogle Scholar2. Shipp JC, Opie LH, Challoner D. Fatty acid and glucose metabolism in the perfused heart.Nature. 1961; 189:1018–1019.CrossrefGoogle Scholar3. Randle PJ, Garland PB, Hales CN, Newsholme EA. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.Lancet. 1963; 1:785–789.CrossrefMedlineGoogle Scholar4. Ichihara K, Neely JR, Siehl DL, Morgan HE. Utilization of leucine by working rat heart.Am J Physiol. 1980; 239:E430–E436.MedlineGoogle Scholar5. Muoio DM, Neufer PD. Lipid-induced mitochondrial stress and insulin action in muscle.Cell Metab. 2012; 15:595–605. doi: 10.1016/j.cmet.2012.04.010.CrossrefMedlineGoogle Scholar6. Newman JC, Verdin E. Ketone bodies as signaling metabolites.Trends Endocrinol Metab. 2014; 25:42–52. doi: 10.1016/j.tem.2013.09.002.CrossrefMedlineGoogle Scholar7. Vice E, Privette JD, Hickner RC, Barakat HA. Ketone body metabolism in lean and obese women.Metabolism. 2005; 54:1542–1545. doi: 10.1016/j.metabol.2005.05.023.CrossrefMedlineGoogle Scholar8. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Kruger M, Hoppel CL, Lewandowski ED, Crawford PA, Muoio DM, Kelly DP. The Failing Heart Relies on Ketone Bodies as a Fuel.Circulation. 2016; 133:698–705.LinkGoogle Scholar9. Jewell JL, Russell RC, Guan KL. Amino acid signalling upstream of mTOR.Nat Rev Mol Cell Biol. 2013; 14:133–139. doi: 10.1038/nrm3522.CrossrefMedlineGoogle Scholar10. Sun H, Olson KC, Gao C, et al. Catabolic Defect of Branched-Chain Amino Acids Promotes Heart Failure.Circulation. 2016; 133:2038–2049. doi: 10.1161/CIRCULATIONAHA.115.020226.LinkGoogle Scholar11. Bedi KC, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, Wang LL, Javaheri A, Blair IA, Margulies KB, Rame JE. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure.Circulation. 2016; 133:706–716. doi: 10.1161/CIRCULATIONAHA.115.017545.LinkGoogle Scholar12. Ahmed K, Tunaru S, Tang C, Müller M, Gille A, Sassmann A, Hanson J, Offermanns S. An autocrine lactate loop mediates insulin-dependent inhibition of lipolysis through GPR81.Cell Metab. 2010; 11:311–319. doi: 10.1016/j.cmet.2010.02.012.CrossrefMedlineGoogle Scholar13. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE; EMPA-REG OUTCOME Investigators. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373:2117–2128. doi: 10.1056/NEJMoa1504720.CrossrefMedlineGoogle Scholar14. Ferrannini E, Mark M, Mayoux E. CV Protection in the EMPA-REG OUTCOME Trial: a "Thrifty Substrate" hypothesis.Diabetes Care. 2016; 39:1108–1114. doi: 10.2337/dc16-0330.CrossrefMedlineGoogle Scholar15. Russell RR, Taegtmeyer H. Changes in citric acid cycle flux and anaplerosis antedate the functional decline in isolated rat hearts utilizing acetoacetate.J Clin Invest. 1991; 87:384–390. doi: 10.1172/JCI115008.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Liu Y, Zhang Q, Yang L, Tian W, Yang Y, Xie Y, Li J, Yang L, Gao Y, Xu Y, Liu J, Wang Y, Yan J, Li G, Shen Y and Qi Z (2022) Metformin Attenuates Cardiac Hypertrophy Via the HIF-1α/PPAR-γ Signaling Pathway in High-Fat Diet Rats, Frontiers in Pharmacology, 10.3389/fphar.2022.919202, 13 Olkowicz M, Ribeiro R, Yu F, Alvarez J, Xin L, Yu M, Rosales R, Adamson M, Bissoondath V, Smolenski R, Billia F, Badiwala M and Pawliszyn J (2022) Dynamic Metabolic Changes During Prolonged Ex Situ Heart Perfusion Are Associated With Myocardial Functional Decline, Frontiers in Immunology, 10.3389/fimmu.2022.859506, 13 Liu W, Zhang L, Shi X, Shen G and Feng J (2022) Cross-comparative metabolomics reveal sex-age specific metabolic fingerprints and metabolic interactions in acute myocardial infarction, Free Radical Biology and Medicine, 10.1016/j.freeradbiomed.2022.03.008, 183, (25-34), Online publication date: 1-Apr-2022. Haidar A and Taegtmeyer H (2022) Strategies for Imaging Metabolic Remodeling of the Heart in Obesity and Heart Failure, Current Cardiology Reports, 10.1007/s11886-022-01650-3, 24:4, (327-335), Online publication date: 1-Apr-2022. Yu F, McLean B, Badiwala M and Billia F (2022) Heart Failure and Drug Therapies: A Metabolic Review, International Journal of Molecular Sciences, 10.3390/ijms23062960, 23:6, (2960) Ni J, Liu Z, Jiang M, Li L, Deng J, Wang X, Su J, Zhu Y, He F, Mao J, Gao X and Fan G (2022) Ginsenoside Rg3 ameliorates myocardial glucose metabolism and insulin resistance via activating the AMPK signaling pathway, Journal of Ginseng Research, 10.1016/j.jgr.2021.06.001, 46:2, (235-247), Online publication date: 1-Mar-2022. Yu Y, Chen W, Yu M, Liu J, Sun H and Yang P (2022) Exercise-Generated β-Aminoisobutyric Acid (BAIBA) Reduces Cardiomyocyte Metabolic Stress and Apoptosis Caused by Mitochondrial Dysfunction Through the miR-208b/AMPK Pathway, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2022.803510, 9 Shao-mei W, Li-fang Y and Li-hong W (2022) Traditional Chinese medicine enhances myocardial metabolism during heart failure, Biomedicine & Pharmacotherapy, 10.1016/j.biopha.2021.112538, 146, (112538), Online publication date: 1-Feb-2022. Kambis T, Shahshahan H and Mishra P (2022) Metabolites and Genes behind Cardiac Metabolic Remodeling in Mice with Type 1 Diabetes Mellitus, International Journal of Molecular Sciences, 10.3390/ijms23031392, 23:3, (1392) Wu C, Zhang Z, Zhang W and Liu X (2022) Mitochondrial dysfunction and mitochondrial therapies in heart failure, Pharmacological Research, 10.1016/j.phrs.2021.106038, 175, (106038), Online publication date: 1-Jan-2022. Kolwicz S (2021) Ketone Body Metabolism in the Ischemic Heart, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.789458, 8 Liu H, Sridhar V, Montemayor D, Lovblom L, Lytvyn Y, Ye H, Kim J, Ali M, Scarr D, Lawler P, Perkins B, Sharma K and Cherney D (2021) Changes in plasma and urine metabolites associated with empagliflozin in patients with type 1 diabetes, Diabetes, Obesity and Metabolism, 10.1111/dom.14489, 23:11, (2466-2475), Online publication date: 1-Nov-2021. Tang J, Chen L, Qin Z and Sheng R (2021) Structure, regulation, and biological functions of TIGAR and its role in diseases, Acta Pharmacologica Sinica, 10.1038/s41401-020-00588-y, 42:10, (1547-1555), Online publication date: 1-Oct-2021. Liao S, Tang Y, Yue X, Gao R, Yao W, Zhou Y and Zhang H (2021) β-Hydroxybutyrate Mitigated Heart Failure with Preserved Ejection Fraction by Increasing Treg Cells via Nox2/GSK-3β, Journal of Inflammation Research, 10.2147/JIR.S331320, Volume 14, (4697-4706) Ketema E and Lopaschuk G (2021) Post-translational Acetylation Control of Cardiac Energy Metabolism, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2021.723996, 8 Hundertmark M, Agbaje O, Coleman R, George J, Grempler R, Holman R, Lamlum H, Lee J, Milton J, Niessen H, Rider O, Rodgers C, Valkovič L, Wicks E, Mahmod M and Neubauer S (2021) Design and rationale of the EMPA‐VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure, ESC Heart Failure, 10.1002/ehf2.13406, 8:4, (2580-2590), Online publication date: 1-Aug-2021. Luo X, Zhong Z, Chong A, Zhang W and Wu X (2021) Function and Mechanism of Trimetazidine in Myocardial Infarction-Induced Myocardial Energy Metabolism Disorder Through the SIRT1–AMPK Pathway, Frontiers in Physiology, 10.3389/fphys.2021.645041, 12 Greenwell A, Gopal K, Altamimi T, Saed C, Wang F, Tabatabaei Dakhili S, Ho K, Zhang L, Eaton F, Kruger J, Al Batran R, Lopaschuk G, Oudit G and Ussher J (2021) Barth syndrome-related cardiomyopathy is associated with a reduction in myocardial glucose oxidation, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00873.2020, 320:6, (H2255-H2269), Online publication date: 1-Jun-2021. Zhao Y, Bai Y, Li Y, Dong Y, Guo Y, Wang W and Liu H (2021) Disturbance of myocardial metabolism participates in autoantibodies against β 1 ‐adrenoceptor‐induced cardiac dysfunction , Clinical and Experimental Pharmacology and Physiology, 10.1111/1440-1681.13485, 48:6, (846-854), Online publication date: 1-Jun-2021. Bowman P, Smith G and Gould G (2021) Run for your life: can exercise be used to effectively target GLUT4 in diabetic cardiac disease?, PeerJ, 10.7717/peerj.11485, 9, (e11485) Pillai V, Samant S, Hund S, Gupta M and Gupta M (2021) The nuclear sirtuin SIRT6 protects the heart from developing aging-associated myocyte senescence and cardiac hypertrophy, Aging, 10.18632/aging.203027, 13:9, (12334-12358), Online publication date: 15-May-2021. Honka H, Solis-Herrera C, Triplitt C, Norton L, Butler J and DeFronzo R (2021) Therapeutic Manipulation of Myocardial Metabolism, Journal of the American College of Cardiology, 10.1016/j.jacc.2021.02.057, 77:16, (2022-2039), Online publication date: 1-Apr-2021. Guo L, Chen K, Sun M, Wang A, Gao F, Zheng Y and Ma X (2021) Metabonomics: A Useful Tool to Reveal Underlying Relationships between Altered Chinese Medicine Syndromes and Ultrafiltration in Treatment of Heart Failure, Chinese Journal of Integrative Medicine, 10.1007/s11655-020-3479-7, 27:4, (259-264), Online publication date: 1-Apr-2021. Ho K, Karwi Q, Wagg C, Zhang L, Vo K, Altamimi T, Uddin G, Ussher J and Lopaschuk G (2020) Ketones can become the major fuel source for the heart but do not increase cardiac efficiency, Cardiovascular Research, 10.1093/cvr/cvaa143, 117:4, (1178-1187), Online publication date: 21-Mar-2021. Monzo L, Sedlacek K, Hromanikova K, Tomanova L, Borlaug B, Jabor A, Kautzner J and Melenovsky V (2021) Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester, Metabolism, 10.1016/j.metabol.2020.154452, 115, (154452), Online publication date: 1-Feb-2021. Lopaschuk G, Karwi Q, Ho K, Pherwani S and Ketema E (2020) Ketone metabolism in the failing heart, Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 10.1016/j.bbalip.2020.158813, 1865:12, (158813), Online publication date: 1-Dec-2020. Karwi Q, Biswas D, Pulinilkunnil T and Lopaschuk G (2020) Myocardial Ketones Metabolism in Heart Failure, Journal of Cardiac Failure, 10.1016/j.cardfail.2020.04.005, 26:11, (998-1005), Online publication date: 1-Nov-2020. Gambardella J, Lombardi A and Santulli G (2020) Metabolic Flexibility of Mitochondria Plays a Key Role in Balancing Glucose and Fatty Acid Metabolism in the Diabetic Heart, Diabetes, 10.2337/dbi20-0024, 69:10, (2054-2057), Online publication date: 1-Oct-2020. Greenwell A, Gopal K and Ussher J (2020) Myocardial Energy Metabolism in Non-ischemic Cardiomyopathy, Frontiers in Physiology, 10.3389/fphys.2020.570421, 11 Qian N and Wang Y (2019) Ketone body metabolism in diabetic and non-diabetic heart failure, Heart Failure Reviews, 10.1007/s10741-019-09857-3, 25:5, (817-822), Online publication date: 1-Sep-2020. Bertrand L, Auquier J, Renguet E, Angé M, Cumps J, Horman S and Beauloye C (2020) Glucose transporters in cardiovascular system in health and disease, Pflügers Archiv - European Journal of Physiology, 10.1007/s00424-020-02444-8, 472:9, (1385-1399), Online publication date: 1-Sep-2020. Juszczyk A, Jankowska K, Zawiślak B, Surdacki A and Chyrchel B (2020) Depressed Cardiac Mechanical Energetic Efficiency: A Contributor to Cardiovascular Risk in Common Metabolic Diseases—From Mechanisms to Clinical Applications, Journal of Clinical Medicine, 10.3390/jcm9092681, 9:9, (2681) Abdul Kadir A, Clarke K and Evans R (2020) Cardiac ketone body metabolism, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 10.1016/j.bbadis.2020.165739, 1866:6, (165739), Online publication date: 1-Jun-2020. Al Batran R, Gopal K, Capozzi M, Chahade J, Saleme B, Tabatabaei-Dakhili S, Greenwell A, Niu J, Almutairi M, Byrne N, Masson G, Kim R, Eaton F, Mulvihill E, Garneau L, Masters A, Desta Z, Velázquez-Martínez C, Aguer C, Crawford P, Sutendra G, Campbell J, Dyck J and Ussher J (2020) Pimozide Alleviates Hyperglycemia in Diet-Induced Obesity by Inhibiting Skeletal Muscle Ketone Oxidation, Cell Metabolism, 10.1016/j.cmet.2020.03.017, 31:5, (909-919.e8), Online publication date: 1-May-2020. Glatz J, Nabben M, Young M, Schulze P, Taegtmeyer H and Luiken J (2020) Re-balancing cellular energy substrate metabolism to mend the failing heart, Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 10.1016/j.bbadis.2019.165579, 1866:5, (165579), Online publication date: 1-May-2020. Wang S, Ye L and Wang L (2020) Shenmai Injection Improves Energy Metabolism in Patients With Heart Failure: A Randomized Controlled Trial, Frontiers in Pharmacology, 10.3389/fphar.2020.00459, 11 Carreau A, Noll C, Blondin D, Frisch F, Nadeau M, Pelletier M, Phoenix S, Cunnane S, Guérin B, Turcotte E, Lebel S, Biertho L, Tchernof A and Carpentier A (2020) Bariatric Surgery Rapidly Decreases Cardiac Dietary Fatty Acid Partitioning and Hepatic Insulin Resistance Through Increased Intra-abdominal Adipose Tissue Storage and Reduced Spillover in Type 2 Diabetes, Diabetes, 10.2337/db19-0773, 69:4, (567-577), Online publication date: 1-Apr-2020. Ulmer B and Eschenhagen T (2020) Human pluripotent stem cell-derived cardiomyocytes for studying energy metabolism, Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 10.1016/j.bbamcr.2019.04.001, 1867:3, (118471), Online publication date: 1-Mar-2020. Lim L, Lau E, Fung E, Lee H, Ma R, Tam C, Wong W, Ng A, Chow E, Luk A, Jenkins A, Chan J and Kong A (2020) Circulating branched‐chain amino acids and incident heart failure in type 2 diabetes: The Hong Kong Diabetes Register, Diabetes/Metabolism Research and Reviews, 10.1002/dmrr.3253, 36:3, Online publication date: 1-Mar-2020. Seo D, Ko J, Jang J, Kim T, Youm J, Kwak H, Bae J, Kim A, Ko K, Rhee B and Han J (2019) Exercise as A Potential Therapeutic Target for Diabetic Cardiomyopathy: Insight into the Underlying Mechanisms, International Journal of Molecular Sciences, 10.3390/ijms20246284, 20:24, (6284) Abdurrachim D, Woo C, Teo X, Chan W, Radda G and Lee P (2019) A new hyperpolarized 13C ketone body probe reveals an increase in acetoacetate utilization in the diabetic rat heart, Scientific Reports, 10.1038/s41598-019-39378-w, 9:1, Online publication date: 1-Dec-2019. Wu G, Zhang W and Li H (2019) Application of metabolomics for unveiling the therapeutic role of traditional Chinese medicine in metabolic diseases, Journal of Ethnopharmacology, 10.1016/j.jep.2019.112057, 242, (112057), Online publication date: 1-Oct-2019. Harvey K, Holcomb L and Kolwicz S (2019) Ketogenic Diets and Exercise Performance, Nutrients, 10.3390/nu11102296, 11:10, (2296) Zarkasi K, Jen-Kit T and Jubri Z Molecular Understanding of the Cardiomodulation in Myocardial Infarction and the Mechanism of Vitamin E Protections, Mini-Reviews in Medicinal Chemistry, 10.2174/1389557519666190130164334, 19:17, (1407-1426) Ho K, Zhang L, Wagg C, Al Batran R, Gopal K, Levasseur J, Leone T, Dyck J, Ussher J, Muoio D, Kelly D and Lopaschuk G (2019) Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency, Cardiovascular Research, 10.1093/cvr/cvz045, 115:11, (1606-1616), Online publication date: 1-Sep-2019. Müller O, Heckmann M, Ding L, Rapti K, Rangrez A, Gerken T, Christiansen N, Rennefahrt U, Witt H, González Maldonado S, Ternes P, Schwab D, Ruf T, Hille S, Remes A, Jungmann A, Weis T, Kreußer J, Gröne H, Backs J, Schatz P, Katus H and Frey N (2018) Comprehensive plasma and tissue profiling reveals systemic metabolic alterations in cardiac hypertrophy and failure, Cardiovascular Research, 10.1093/cvr/cvy274, 115:8, (1296-1305), Online publication date: 1-Jul-2019. Gropler R and Peterson L (2019) PET Imaging of Myocardial Metabolism in Health and Disease Cardiac CT, PET & MR, 10.1002/9781118754467.ch5, (175-202) Nielsen R, Møller N, Gormsen L, Tolbod L, Hansson N, Sorensen J, Harms H, Frøkiær J, Eiskjaer H, Jespersen N, Mellemkjaer S, Lassen T, Pryds K, Bøtker H and Wiggers H (2019) Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients, Circulation, 139:18, (2129-2141), Online publication date: 30-Apr-2019. Bois J and Gropler R (2017) Is it time to reassess the role of myocardial metabolic modulation for the treatment of heart failure?, Journal of Nuclear Cardiology, 10.1007/s12350-017-1068-8, 26:2, (598-601), Online publication date: 1-Apr-2019. Abdurrachim D, Teo X, Woo C, Chan W, Lalic J, Lam C and Lee P (2018) Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: A hyperpolarized 13 C magnetic resonance spectroscopy study , Diabetes, Obesity and Metabolism, 10.1111/dom.13536, 21:2, (357-365), Online publication date: 1-Feb-2019. Chen L, Song J and Hu S (2018) Metabolic remodeling of substrate utilization during heart failure progression, Heart Failure Reviews, 10.1007/s10741-018-9713-0, 24:1, (143-154), Online publication date: 1-Jan-2019. Kolwicz S (2018) An "Exercise" in Cardiac Metabolism, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2018.00066, 5 McGarrah R, Crown S, Zhang G, Shah S and Newgard C (2018) Cardiovascular Metabolomics, Circulation Research, 122:9, (1238-1258), Online publication date: 27-Apr-2018.Panagia M, Chen H, Croteau D, Iris Chen Y, Ran C, Luptak I, Josephson L, Colucci W and Sosnovik D (2018) Multiplexed Optical Imaging of Energy Substrates Reveals That Left Ventricular Hypertrophy Is Associated With Brown Adipose Tissue Activation, Circulation: Cardiovascular Imaging, 11:3, Online publication date: 1-Mar-2018. Bois J, Gropler R and Peterson L (2018) Contemporary Advances in Myocardial Metabolic Imaging and Their Impact on Clinical Care: a Focus on Positron Emission Tomography (PET), Current Cardiovascular Imaging Reports, 10.1007/s12410-018-9444-6, 11:2, Online publication date: 1-Feb-2018. Bernardo B, Ooi J, Weeks K, Patterson N and McMullen J (2018) Understanding Key Mechanisms of Exercise-Induced Cardiac Protection to Mitigate Disease: Current Knowledge and Emerging Concepts, Physiological Reviews, 10.1152/physrev.00043.2016, 98:1, (419-475), Online publication date: 1-Jan-2018. Thiriet M (2018) Hyperglycemia and Diabetes Vasculopathies, 10.1007/978-3-319-89315-0_4, (301-330), . Gillingham M, Heitner S, Martin J, Rose S, Goldstein A, El-Gharbawy A, Deward S, Lasarev M, Pollaro J, DeLany J, Burchill L, Goodpaster B, Shoemaker J, Matern D, Harding C and Vockley J (2017) Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial, Journal of Inherited Metabolic Disease, 10.1007/s10545-017-0085-8, 40:6, (831-843), Online publication date: 1-Nov-2017. Adrian L, Lenski M, Tödter K, Heeren J, Böhm M and Laufs U (2017) AMPK Prevents Palmitic Acid-Induced Apoptosis and Lipid Accumulation in Cardiomyocytes, Lipids, 10.1007/s11745-017-4285-7, 52:9, (737-750), Online publication date: 1-Sep-2017. November 11, 2016Vol 119, Issue 11 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.116.310078PMID: 28051784 Manuscript receivedOctober 3, 2016Manuscript acceptedOctober 6, 2016Originally publishedNovember 11, 2016 Keywordsenergy metabolismheart failureheartketone bodybranched-chain amino acid cardiac efficiencyPDF download Advertisement SubjectsHeart FailureMetabolism
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