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

Cardiovascular Research

Volumn 115, Issue 11, 2019, Pages 1606-1616

  Ho, Kim L ^a   Zhang, Liyan ^a   Wagg, Cory ^a   Al Batran, Rami ^a   Gopal, Keshav ^a   Levasseur, Jody ^a   Leone, Teresa ^b   Dyck, Jason R B ^a   Ussher, John R ^a   Muoio, Deborah M ^c   Kelly, Daniel P ^b   Lopaschuk, Gary D ^a  

^a UNIVERSITY OF ALBERTA   (Canada)

^b UNIVERSITY OF PENNSYLVANIA   (United States)

^c DUKE UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Beta hydroxybutyrate; Cardiac Energy metabolism; Heart failure; Hypertrophy; Ketone body oxidation

Indexed keywords

3 HYDROXYACYL COENZYME A DEHYDROGENASE; 3 HYDROXYBUTYRIC ACID; ACETYL COENZYME A; ACYL COENZYME A DEHYDROGENASE; ADENOSINE TRIPHOSPHATE; GLUCOSE; GLUCOSE TRANSPORTER 4; KETONE BODY; PALMITIC ACID; PYRUVATE DEHYDROGENASE; TRICARBOXYLIC ACID; FATTY ACID; LONG CHAIN ACYL COENZYME A DEHYDROGENASE;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; AORTIC CONSTRICTION; ARTICLE; CITRIC ACID CYCLE; COMPARATIVE STUDY; CONTROLLED STUDY; DIASTOLIC DYSFUNCTION; ENERGY METABOLISM; ENERGY YIELD; EX VIVO STUDY; EXPERIMENTAL HEART FAILURE; FATTY ACID OXIDATION; GLUCOSE OXIDATION; GLYCOLYSIS; HEART EJECTION FRACTION; HEART FAILURE; HEART MUSCLE METABOLISM; HEART OUTPUT; HEART RATE; HEART STROKE VOLUME; HEART VENTRICLE HYPERTROPHY; HEART WORK; MALE; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROTEIN ACETYLATION; PROTEIN EXPRESSION; PROTEIN EXPRESSION LEVEL; SYSTOLIC BLOOD PRESSURE; TRANSTHORACIC ECHOCARDIOGRAPHY; ACETYLATION; ADAPTATION; ANIMAL; C57BL MOUSE; CARDIAC MUSCLE; DISEASE MODEL; GENETICS; HEART LEFT VENTRICLE FUNCTION; HEART LEFT VENTRICLE HYPERTROPHY; METABOLISM; OXIDATION REDUCTION REACTION; PATHOLOGY; PATHOPHYSIOLOGY;

3-HYDROXYBUTYRIC ACID; ACETYLATION; ACYL-COA DEHYDROGENASE, LONG-CHAIN; ADAPTATION, PHYSIOLOGICAL; ANIMALS; DISEASE MODELS, ANIMAL; ENERGY METABOLISM; FATTY ACIDS; GLUCOSE; HEART FAILURE; HYPERTROPHY, LEFT VENTRICULAR; MALE; MICE, INBRED C57BL; MYOCARDIUM; OXIDATION-REDUCTION; STROKE VOLUME; VENTRICULAR FUNCTION, LEFT;

EID: 85069225419     PISSN: 00086363     EISSN: 17553245     Source Type: Journal    
DOI: 10.1093/cvr/cvz045     Document Type: Article

References (64)

1. Lopaschuk GD, Ussher JR, Folmes CDL, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev 2010;90:207-258.
2. Lopaschuk GD, Ussher JR. Evolving concepts of myocardial energy metabolism. Circ Res 2016;119:1173-1176.
3. De Jong KA, Lopaschuk GD. Complex energy metabolic changes in heart failure with preserved ejection fraction and heart failure with reduced ejection fraction. Can J Cardiol 2017;33:860-871.
4. Karwi QG, Uddin GM, Ho KL, Lopaschuk GD. Loss of metabolic flexibility in the failing heart. Front Cardiovasc Med 2018;5:1-19.
5. Nagoshi T, Yoshimura M, Rosano GMC, Lopaschuk GD, Mochizuki S. Optimization of cardiac metabolism in heart failure. Curr Pharm Des 2011;17:3846-3853.
6. Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996;94: 2837-28LP-2842.
7. Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, Hintze TH, Lopaschuk GD, Recchia FA. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-a in pacing-induced heart failure. Circulation 2002;106:606-612.
8. Doenst T, Pytel G, Schrepper A, Amorim P, Farber G, Shingu Y, Mohr FW, Schwarzer M. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res 2010;86:461-470.
9. Zhang L, Jaswal JS, Ussher JR, Sankaralingam S, Wagg C, Zaugg M, Lopaschuk GD. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ Heart Fail 2013;6:1039-1048.
10. Zhabyeyev P, Gandhi M, Mori J, Basu R, Kassiri Z, Clanachan A, Lopaschuk GD, Oudit GY. Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc Res 2013;97:676-685.
11. Taylor M, Wallhaus TR, DeGrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. An evaluation of myocardial fatty acid and glucose uptake using PET with [18F]fluoro-6-thia-heptadecanoic acid and [18F]FDG in patients with congestive heart failure. J Nucl Med 2001;42:55-62.
12. Allard MF, Schonekess BO, Henning SL, English DR, Lopaschuk GD. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am J Physiol 1994;267:H742-H750.
13. 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.
14. 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.
15. Nagao M, Toh R, Irino Y, Mori T, Nakajima H, Hara T, Honjo T, Satomi-Kobayashi S, Shinke T, Tanaka H, Ishida T, Hirata K. b-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes. Biochem Biophys Res Commun 2016;475:322-328.
16. Horton JL, Martin OJ, Lai L, Riley NM, Richards AL, Vega RB, Leone TC, Pagliarini DJ, Muoio DM, Bedi KC, Margulies KB, Coon JJ, Kelly DP. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2016;1:1-14.
17. Schugar RC, Moll AR, André d'Avignon D, Weinheimer CJ, Kovacs A, Crawford PA. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol Metab 2014;3:754-769.
18. Uchihashi M, Hoshino A, Okawa Y, Ariyoshi M, Kaimoto S, Tateishi S, Ono K, Yamanaka R, Hato D, Fushimura Y, Honda S, Fukai K, Higuchi Y, Ogata T, Iwai-Kanai E, Matoba S. Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure. Circulation 2017;10: e004417.
19. Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, Petucci C, Lewandowski ED, Crawford PA, Muoio DM, Recchia FA, Kelly DP. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 2019;4: e124079.
20. Mudaliar S, Alloju S, Henry RR. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unifying hypothesis. Diabetes Care 2016;39:1115-1122.
21. Ferrannini E, Mark M, Mayoux E. CV protection in the EMPA-REG OUTCOME trial: a "Thrifty Substrate" hypothesis. Diabetes Care 2016;39:1108-1114.
22. Stanley WC, Meadows SR, Kivilo KM, Roth BA, Lopaschuk GD. beta-Hydroxybutyrate inhibits myocardial fatty acid oxidation in vivo independent of changes in malonyl-CoA content. Am J Physiol Heart Circ Physiol 2003;285: H1626-H1631.
23. Newman JC, Verdin E. Ketone bodies as signaling metabolites. Trends Endocrinol Metab 2014;25:42-52.
24. Janardhan A, Chen J, Crawford PA. Altered systemic ketone body metabolism in advanced heart failure. Tex Heart Inst J 2011;38:533-538.
25. Foster KJ, Alberti KG, Hinks L, Lloyd B, Postle A, Smythe P, Turnell DC, Walton R. Blood intermediary metabolite and insulin concentrations after an overnight fast: reference ranges for adults, and interrelations. Clin Chem 1978;24:1568-1572.
26. Kienesberger PC, Pulinilkunnil T, Sung MM, Nagendran J, Haemmerle G, Kershaw EE, Young ME, Light PE, Oudit GY, Zechner R, Dyck JR. Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction. Mol Cell Biol 2012;32:740-750.
27. Zhou YQ, Foster FS, Nieman BJ, Davidson L, Chen XJ, Henkelman RM. Comprehensive transthoracic cardiac imaging in mice using ultrasound biomicroscopy with anatomical confirmation by magnetic resonance imaging. Physiol Genomics 2004;18:232-244.
28. Bing RJ, Siegel A, Ungar I, Gilbert M. Metabolism of the human heart. II. Studies on fat, ketone and amino acid metabolism. Am J Med 1954;16:504-515.
29. Olson RE, Schwartz WB. Myocardial metabolism in congestive heart failure. Medicine 1951;30:21-41.
30. Neubauer S. The failing heart-an engine out of fuel. N Engl J Med 2007;356: 1140-1151.
31. Alrob OA, Sankaralingam S, Ma C, Wagg CS, Fillmore N, Jaswal JS, Sack MN, Lehner R, Gupta MP, Michelakis ED, Padwal RS, Johnstone DE, Sharma AM, Lopaschuk GD. Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc Res 2014;103:485-497.
32. Al Batran R, Ussher JR. Revisiting protein acetylation and myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 2017;313:H617-H619.
33. Fukushima A, Zhang L, Huqi A, Lam VH, Rawat S, Altamimi T, Wagg CS, Dhaliwal KK, Hornberger LK, Kantor PF, Rebeyka IM, Lopaschuk GD. Acetylation contributes to hypertrophy-caused maturational delay of cardiac energy metabolism. JCI Insight 2018;3:e99239.
34. Thapa D, Zhang M, Manning JR, Guimaraes DA, Stoner MW, O'Doherty RM, Shiva S, Scott I. Acetylation of mitochondrial proteins by GCN5L1 promotes enhanced fatty acid oxidation in the heart. Am J Physiol Heart Circ Physiol 2017;313:H265-H274.
35. Voros G, Ector J, Garweg C, Droogne W, Van Cleemput J, Peersman N, Vermeersch P, Janssens S. Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling. Circ Heart Fail 2018;11:e004953.
36. Ingwall JS. Energy metabolism in heart failure and remodelling. Cardiovasc Res 2008; 81:412-419.
37. Lommi J, Kupari M, Koskinen P, Näveri H, Leinonen H, Pulkki K, Härkönen M. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol 1996;28:665-672.
38. Lommi J, Koskinen P, Näveri H, Härkönen M, Kupari M. Heart failure ketosis. J Intern Med 1997;242:231-238.
39. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab 2017;25:262-284.
40. Kolwicz SC, Airhart S, Tian R. Ketones step to the plate: a game changer for metabolic remodeling in heart failure? Circulation 2016;133:689-691.
41. Gormsen LC, Svart M, Thomsen HH, Sondergaard E, Vendelbo MH, Christensen N, Tolbod LP, Harms HJ, Nielsen R, Wiggers H, Jessen N, Hansen J, Botker HE, Moller N. Ketone body infusion with 3-hydroxybutyrate reduces myocardial glucose uptake and increases blood flow in humans: a positron emission tomography study. J Am Heart Assoc 2017;6:e005066-e005066.
42. 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;281:785-789.
43. Shimazu T, Hirschey MD, Newman J, He W, Shirakawa K, Le Moan N, Grueter CA, Lim H, Saunders LR, Stevens RD, Newgard CB, Farese RV, de Cabo R, Ulrich S, Akassoglou K, Verdin E. Suppression of oxidative stress by b-hydroxybutyrate, an endogenous histone deacetylase inhibitor. Science (New York, NY) 2013;339:211-214.
44. Yu Y, Yu Y, Zhang Y, Zhang Z, An W, Zhao X. Treatment with D-beta-hydroxybutyrate protects heart from ischemia/reperfusion injury in mice. Eur J Pharmacol 2018; 829:121-128.
45. Klos M, Morgenstern S, Hicks K, Suresh S, Devaney EJ. The effects of the ketone body beta-hydroxybutyrate on isolated rat ventricular myocyte excitationcontraction coupling. Arch Biochem Biophys 2019;662:143-150.
46. Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, Broedl UC, Inzucchi SE. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-2128.
47. Byrne NJ, Parajuli N, Levasseur JL, Boisvenue J, Beker D, Masson G, Fedak PWM, Verma S, Dyck JRB. Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure. JACC Basic Transl Sci 2017; 2:347-354.
48. Lopaschuk GD, Verma S. Empagliflozin's fuel hypothesis: not so soon. Cell Metab 2016;24:200-202.
49. Kashiwaya Y, King MT, Veech RL. Substrate signaling by insulin: a ketone bodies ratio mimics insulin action in heart. Am J Cardiol 1997;80:50A-64A.
50. Keon CA, Tuschiya N, Kashiwaya Y, Sato K, Clarke K, Radda GK, Veech RL. Substrate dependence of the mitochondrial energy status in the isolated working rat heart. Biochem Soc Trans 1995;23:307S.
51. Verma S, Rawat S, Ho KL, Wagg CS, Zhang L, Teoh H, Dyck JE, Uddin GM, Oudit GY, Mayoux E, Lehrke M, Marx N, Lopaschuk GD. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic to Translational Science 2018;
52. Kolwicz SC, Olson DP, Marney LC, Garcia-Menendez L, Synovec RE, Tian R. Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ Res 2012;111:728-738.
53. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, Gropler RJ. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol 2002;40:271-277.
54. Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, Iwanaga Y, Narazaki M, Matsuda T, Soga T, Kita T, Kimura T, Shioi T. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Heart Fail 2010;3: 420-430.
55. Chandler MP, Kerner J, Huang H, Vazquez E, Reszko A, Martini WZ, Hoppel CL, Imai M, Rastogi S, Sabbah HN, Stanley WC. Moderate severity heart failure does not involve a downregulation of myocardial fatty acid oxidation. Am J Physiol Heart Circ Physiol 2004;287:H1538-H1543.
56. Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism 1994;43:174-179.
57. Funada J, Betts TR, Hodson L, Humphreys SM, Timperley J, Frayn KN, Karpe F. Substrate utilization by the failing human heart by direct quantification using arteriovenous blood sampling. PLoS One 2009;4:e7533.
58. Tuunanen H, Engblom E, Naum A, NåGren K, Hesse B, Airaksinen KEJ, Nuutila P, Iozzo P, Ukkonen H, Opie LH, Knuuti J. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 2006;114: 2130-2137.
59. Schroeder MA, Lau AZ, Chen AP, Gu Y, Nagendran J, Barry J, Hu X, Dyck JR, Tyler DJ, Clarke K, Connelly KA, Wright GA, Cunningham CH. Hyperpolarized (13)C magnetic resonance reveals early-and late-onset changes to in vivo pyruvate metabolism in the failing heart. Eur J Heart Fail 2013;15:130-140.
60. Gopal K, Almutairi M, Al Batran R, Eaton F, Gandhi M, Ussher JR. Cardiac-specific deletion of pyruvate dehydrogenase impairs glucose oxidation rates and induces diastolic dysfunction. Front Cardiovasc Med 2018;5:17.
61. Nikolaidis LA, Sturzu A, Stolarski C, Elahi D, Shen Y-T, Shannon RP. The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy. Cardiovasc Res 2004;61:297-306.
62. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res 2013;113:709-724.
63. Belke DD, Larsen TS, Lopaschuk GD, Severson DL. Glucose and fatty acid metabolism in the isolated working mouse heart. Am J Physiol Heart Circ Physiol 1999;277: R1210-R1217.
64. Bround MJ, Wambolt R, Cen H, Asghari P, Albu RF, Han J, McAfee D, Pourrier M, Scott NE, Bohunek L, Kulpa JE, Chen SR, Fedida D, Brownsey RW, Borchers CH, Foster LJ, Mayor T, Moore ED, Allard MF, Johnson JD. Cardiac ryanodine receptor (Ryr2)-mediated calcium signals specifically promote glucose oxidation via pyruvate dehydrogenase. J Biol Chem 2016;291:23490-23505.