Failing Heart and Starving Brain
2016; Lippincott Williams & Wilkins; Volume: 134; Issue: 4 Linguagem: Inglês
10.1161/circulationaha.116.022141
ISSN1524-4539
Autores Tópico(s)Metabolism and Genetic Disorders
ResumoHomeCirculationVol. 134, No. 4Failing Heart and Starving Brain Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBFailing Heart and Starving BrainKetone Bodies to the Rescue Heinrich Taegtmeyer, MD, DPhil Heinrich TaegtmeyerHeinrich Taegtmeyer From McGovern Medical School at The University of Texas Health Science Center at Houston, Department of Internal Medicine, Division of Cardiology, Houston, TX. Originally published26 Jul 2016https://doi.org/10.1161/CIRCULATIONAHA.116.022141Circulation. 2016;134:265–266IntroductionOne of my favorite quotes in literature comes from the biochemist-turned-writer Isaac Asimov (1920–1992), who wrote, "The saddest aspect of life right now is that science gathers knowledge faster than society gathers wisdom."1 Two recent articles2,3 published back to back in Circulation seem to challenge this notion by exposing results of strategic value. Both studies analyzed and sorted vast amounts of metabolites, proteins, and gene transcripts in failing human heart muscle,2,3 and both came independently to the same conclusions: Of all of the energy-providing substrates for the heart, the enzymes regulating ketone body metabolism are upregulated while those regulating glucose and fatty acid metabolism are downregulated. In other words, a strong signal emerged from a mountain of data. What does this mean? Here are my thoughts.When I am in congenial company, and especially over a glass of wine, I like to reflect on the story of metabolism, which is actually the story of people. It has been said that I am the only practicing cardiologist with a living connection to the Krebs cycle. Krebs often referred to metabolism as "biochemistry with a purpose". More specifically, contraction and metabolism in the heart are inextricably linked and obey the First Law of Thermodynamics (energy in=energy out). Notable exceptions are futile cycles and the uncoupling of oxidative phosphorylation of ADP. As one of Krebs' last graduate students, I used the isolated working rat heart as a model for probing cardiac metabolism and function under simulated physiologic conditions. We speculated that ketone bodies would be an excellent fuel for respiration because of their direct access to the enzymes of the Krebs cycle. To our surprise, when provided as the only fuel for respiration, ketone bodies induced an acute contractile dysfunction reversed by the addition of glucose as a second fuel.4 Biochemically, ketone bodies inhibited the Krebs cycle by sequestering coenzyme A and by robbing the cycle of its intermediates downstream of one of its dehydrogenases. Subsequently, my graduate student Raymond Russell and I were able to show that replenishing the Krebs cycle intermediates through a group of reactions, collectively called anaplerosis, also restored contractile function of the heart. How do these observations fit into the present reports? Let me explain why they may fit and may offer a new strategy for the treatment of the failing heart.First, one needs to recognize that in vivo the heart, a metabolic omnivore, is always exposed to >1 substrate. Second, we need to consider the role of the liver as a major regulator of substrate supply for the heart and for the body as a whole. This story begins with a group of brave students in the 1960s recruited by George Cahill5 for a study probing substrate metabolism of the brain during starvation. The students were divinity students because they were considered trustworthy for a study like this. What happens with a 36-hour fast? The brain, as we know, prefers glucose to all other substrates. Does the brain continue to rely on glucose, produced by the liver as an emergency fuel, or does the brain switch to an alternate energy-providing substrate?The answer was fascinating because it revealed that organs talk to each other not only through hormones but also through metabolites. This much we know about the wisdom of the body. When its main fuel, glucose, is in short supply, a vital organ such as the brain switches to ketone bodies made in the liver by incomplete oxidation of fatty acids.5 For the brain, there is a distinct evolutionary advantage from this switch as our distant ancestors adapted to cycles of feast and famine. Now we find that the failing heart also relies on ketone body metabolism when the other pathways of energy substrate metabolism begin to shut down. The question is: Are there any parallels between the starving brain and the failing heart? One parallel is that the liver sends ketone bodies to both, and both organs begin to derive ATP from them.Are there any practical implications of this line of reasoning? More specifically, would it be possible to introduce a metabolic substrate to support the nonischemic failing heart, a heart that fails in the midst of plenty and has been likened to an engine out of fuel, at least at the cellular level? First, we do not know whether the footprints of enhanced ketone body metabolism are causes or consequences of heart failure. Second, we do not know whether boosting ketone body metabolism in the heart would also boost ATP production. Because of their association with diabetes mellitus and starvation, ketone bodies (or ketones) have earned a somewhat morbid connotation. However, Cahill and Veech6 have proposed that D-β-hydroxybutyrate, the principal ketone body, may actually be a "superfuel," producing ATP more efficiently than glucose or fatty acids. Indeed, the early success of a ketogenic diet in epilepsy treatment holds great promise. Admittedly, however, the reasons for this success are complex.The footprints of ketone body metabolism are clearly present in the failing heart, although the rates of ketone body oxidation and their effect of contractile function in the failing heart are still to be determined. Additionally, it may be risky to place patients with heart failure on a ketogenic diet. A concomitant rise in fatty acids in the circulation may suppress the metabolism of glucose as anaplerotic substrate for the Krebs cycle. Although there may be an alternative, in the form of ketone esters, giving ketone bodies to patients with heart failure seems almost paradoxical. Krebs would have probably used the same 3 words he wrote across the cover page for the first draft of my thesis: "Main conclusion missing" (Figure), and he would have quoted John Hunter8 (1728–1793): "Why argue and not do the experiment?" That is what is on my mind right now.Download figureDownload PowerPointFigure. The handwriting of Hans A. Krebs ("Main conclusion missing") on the first draft of my DPhil thesis titled, "Metabolic Activities of the Isolated Rat Heart" (Oxford, 1981).7AcknowledgementsI am indebted to all members of my laboratory for their input.Sources of FundingWork in my laboratory is supported by the US Public Health Service (R01-HL 061483).DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Circulation is available at http://circ.ahajournals.org.Correspondence to: Heinrich Taegtmeyer, MD, DPhil, McGovern Medical School, The University of Texas Health Science Center at Houston, Department of Internal Medicine, Division of Cardiology, 6431 Fannin St, MSB 1.246, Houston, TX 77030. E-mail [email protected]References1. Asimov I, Shulman JA, Isaac Asimov's Book of Science and Nature Questions.New York: Weidenfeld & Nicholson, 1988: 281.Google Scholar2. Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, Koves T, Gardell SJ, Krüger 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. doi: 10.1161/CIRCULATIONAHA.115.017355.LinkGoogle Scholar3. 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 Scholar4. Taegtmeyer H, Hems R, Krebs HA. Utilization of energy-providing substrates in the isolated working rat heart.Biochem J. 1980; 186:701–711.CrossrefMedlineGoogle Scholar5. Cahill GF. Starvation in man.N Engl J Med. 1970; 282:668–675. doi: 10.1056/NEJM197003192821209.CrossrefMedlineGoogle Scholar6. Cahill GF, Veech RL. Ketoacids? Good medicine?Trans Am Clin Climatol Assoc. 2003; 114:149–161.MedlineGoogle Scholar7. Taegtmeyer H. Metabolic Activities of the Isolated Rat Heart. University of Oxford, 1981.Google Scholar8. Harding Rains AJ. Letters From the Past: From John Hunter to Edward Jenner. London: Royal College of Surgeons, Reprint edition, 1976.Google Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited BySelvaraj S, Fu Z, Jones P, Kwee L, Windsor S, Ilkayeva O, Newgard C, Margulies K, Husain M, Inzucchi S, McGuire D, Pitt B, Scirica B, Lanfear D, Nassif M, Javaheri A, Mentz R, Kosiborod M and Shah S (2022) Metabolomic Profiling of the Effects of Dapagliflozin in Heart Failure With Reduced Ejection Fraction: DEFINE-HF, Circulation, 146:11, (808-818), Online publication date: 13-Sep-2022. Wang X, Ni J, Guo R, Li L, Su J, He F and Fan G (2021) SGLT2 inhibitors break the vicious circle between heart failure and insulin resistance: targeting energy metabolism, Heart Failure Reviews, 10.1007/s10741-021-10096-8, 27:3, (961-980), Online publication date: 1-May-2022. Lorenzo-Almorós A, Cepeda-Rodrigo J and Lorenzo Ó (2022) Diabetic cardiomyopathy, Revista Clínica Española (English Edition), 10.1016/j.rceng.2019.10.012, 222:2, (100-111), Online publication date: 1-Feb-2022. Lorenzo-Almorós A, Cepeda-Rodrigo J and Lorenzo Ó (2022) Miocardiopatía diabética, Revista Clínica Española, 10.1016/j.rce.2019.10.013, 222:2, (100-111), Online publication date: 1-Feb-2022. Salvatore T, Pafundi P, Galiero R, Albanese G, Di Martino A, Caturano A, Vetrano E, Rinaldi L and Sasso F (2021) The Diabetic Cardiomyopathy: The Contributing Pathophysiological Mechanisms, Frontiers in Medicine, 10.3389/fmed.2021.695792, 8 Morciano G, Vitto V, Bouhamida E, Giorgi C and Pinton P (2021) Mitochondrial Bioenergetics and Dynamism in the Failing Heart, Life, 10.3390/life11050436, 11:5, (436) Bizy A and Klos M (2020) Optimizing the Use of iPSC-CMs for Cardiac Regeneration in Animal Models, Animals, 10.3390/ani10091561, 10:9, (1561) Møller N (2020) Ketone Body, 3-Hydroxybutyrate: Minor Metabolite - Major Medical Manifestations, The Journal of Clinical Endocrinology & Metabolism, 10.1210/clinem/dgaa370, 105:9, (2884-2892), Online publication date: 1-Sep-2020. 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. Li H, Hastings M, Rhee J, Trager L, Roh J and Rosenzweig A (2020) Targeting Age-Related Pathways in Heart Failure, Circulation Research, 126:4, (533-551), Online publication date: 14-Feb-2020.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. 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. Maack C, Lehrke M, Backs J, Heinzel F, Hulot J, Marx N, Paulus W, Rossignol P, Taegtmeyer H, Bauersachs J, Bayes-Genis A, Brutsaert D, Bugger H, Clarke K, Cosentino F, De Keulenaer G, Dei Cas A, González A, Huelsmann M, Iaccarino G, Lunde I, Lyon A, Pollesello P, Rena G, Riksen N, Rosano G, Staels B, van Laake L, Wanner C, Farmakis D, Filippatos G, Ruschitzka F, Seferovic P, de Boer R and Heymans S (2018) Heart failure and diabetes: metabolic alterations and therapeutic interventions: a state-of-the-art review from the Translational Research Committee of the Heart Failure Association–European Society of Cardiology, European Heart Journal, 10.1093/eurheartj/ehy596, 39:48, (4243-4254), Online publication date: 21-Dec-2018. Cannon C, McGuire D, Pratley R, Dagogo-Jack S, Mancuso J, Huyck S, Charbonnel B, Shih W, Gallo S, Masiukiewicz U, Golm G, Cosentino F, Lauring B and Terra S (2018) Design and baseline characteristics of the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes trial (VERTIS-CV), American Heart Journal, 10.1016/j.ahj.2018.08.016, 206, (11-23), Online publication date: 1-Dec-2018. Geng J, Zhang Y, Li S, Li S, Wang J, Wang H, Aa J and Wang G (2018) Metabolomic Profiling Reveals That Reprogramming of Cerebral Glucose Metabolism Is Involved in Ischemic Preconditioning-Induced Neuroprotection in a Rodent Model of Ischemic Stroke, Journal of Proteome Research, 10.1021/acs.jproteome.8b00339 Fulghum K and Hill B (2018) Metabolic Mechanisms of Exercise-Induced Cardiac Remodeling, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2018.00127, 5 Johnson V and Maack C (2018) Herzinsuffizienz bei DiabetesHeart failure in diabetes, Der Diabetologe, 10.1007/s11428-018-0363-6, 14:6, (384-392), Online publication date: 1-Sep-2018. Karwi Q, Uddin G, Ho K and Lopaschuk G (2018) Loss of Metabolic Flexibility in the Failing Heart, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2018.00068, 5 Smith J (2017) Molecular Epidemiology of Heart Failure, JACC: Basic to Translational Science, 10.1016/j.jacbts.2017.07.010, 2:6, (757-769), Online publication date: 1-Dec-2017. 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. Muthuramu I, Amin R, Postnov A, Mishra M, Jacobs F, Gheysens O, Van Veldhoven P and De Geest B (2017) Coconut Oil Aggravates Pressure Overload-Induced Cardiomyopathy without Inducing Obesity, Systemic Insulin Resistance, or Cardiac Steatosis, International Journal of Molecular Sciences, 10.3390/ijms18071565, 18:7, (1565) Eduardo Rame J (2017) Hemodynamic unloading and the molecular-functional phenotype dissociation in myocardial recovery, The Journal of Heart and Lung Transplantation, 10.1016/j.healun.2017.03.007, 36:7, (715-717), Online publication date: 1-Jul-2017. Staels B (2017) Cardiovascular Protection by Sodium Glucose Cotransporter 2 Inhibitors: Potential Mechanisms, The American Journal of Cardiology, 10.1016/j.amjcard.2017.05.013, 120:1, (S28-S36), Online publication date: 1-Jul-2017. Staels B (2017) Cardiovascular Protection by Sodium Glucose Cotransporter 2 Inhibitors: Potential Mechanisms, The American Journal of Medicine, 10.1016/j.amjmed.2017.04.009, 130:6, (S30-S39), Online publication date: 1-Jun-2017. Gormsen L, Svart M, Thomsen H, Søndergaard E, Vendelbo M, Christensen N, Tolbod L, Harms H, Nielsen R, Wiggers H, Jessen N, Hansen J, Bøtker H and Møller N (2017) Ketone Body Infusion With 3‐Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study, Journal of the American Heart Association, 6:3, Online publication date: 1-Mar-2017. Puchalska P and Crawford P (2017) Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics, Cell Metabolism, 10.1016/j.cmet.2016.12.022, 25:2, (262-284), Online publication date: 1-Feb-2017. Rame J and Birks E (2016) Metabolic Reprogramming After Left Ventricular Assist Device, JACC: Basic to Translational Science, 10.1016/j.jacbts.2016.09.003, 1:6, (445-448), Online publication date: 1-Oct-2016. July 26, 2016Vol 134, Issue 4 Advertisement Article InformationMetrics © 2016 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.116.022141PMID: 27462050 Originally publishedJuly 26, 2016 Keywordsmetabolismcardiomyopathiesheart failureketone bodiescardiovascular diseasesPDF download Advertisement SubjectsCardiomyopathyCardiovascular DiseaseHeart FailureMetabolism
Referência(s)