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Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time?

  • Translational Research in Heart Failure (M. Hoes, Section Editor)
  • Published:
Current Heart Failure Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

We review the clinical benefits of altering myocardial substrate metabolism in heart failure.

Recent Findings

Modulation of cardiac substrates (fatty acid, glucose, or ketone metabolism) offers a wide range of therapeutic possibilities which may be applicable to heart failure. Augmenting ketone oxidation seems to offer great promise as a new therapeutic modality in heart failure.

Summary

The heart has long been recognized as metabolic omnivore, meaning it can utilize a variety of energy substrates to maintain adequate ATP production. The adult heart uses fatty acid as a major fuel source, but it can also derive energy from other substrates including glucose and ketone, and to some extent pyruvate, lactate, and amino acids. However, cardiomyocytes of the failing heart endure remarkable metabolic remodeling including a shift in substrate utilization and reduced ATP production, which account for cardiac remodeling and dysfunction. Research to understand the implication of myocardial metabolic perturbation in heart failure has grown in recent years, and this has raised interest in targeting myocardial substrate metabolism for heart failure therapy. Due to the interdependency between different pathways, the main therapeutic metabolic approaches include inhibiting fatty acid uptake/fatty acid oxidation, reducing circulating fatty acid levels, increasing glucose oxidation, and augmenting ketone oxidation.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, et al. Heart disease and stroke statistics—2022 update: a report from the American Heart Association. Circulation. 2022

  2. Mamas MA, Sperrin M, Watson MC, Coutts A, Wilde K, Burton C, et al. Do patients have worse outcomes in heart failure than in cancer? A primary care-based cohort study with 10-year follow-up in Scotland. Eur J Heart Fail. 2017;19:1095–104.

    Article  PubMed  Google Scholar 

  3. Bishop S, Altschuld R. Increased glycolytic metabolism in cardiac hypertrophy and congestive failure. Am J Physiol Content. 1970;218:153–9.

    Article  CAS  Google Scholar 

  4. Paolisso G, Gambardella A, Galzerano D, D’Amore A, Rubino P, Verza M, et al. Total-body and myocardial substrate oxidation in congestive heart failure. Metabolism. 1994;43:174–9.

    Article  CAS  PubMed  Google Scholar 

  5. 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;94:2837–42.

    Article  CAS  PubMed  Google Scholar 

  6. Dávila-Román VG, Vedala G, Herrero P, de las Fuentes L, Rogers JG, Kelly DP, et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 2002;40:271–7.

  7. •• Aubert G, Martin OJ, Horton JL, Lai L, Vega RB, Leone TC, et al. The failing heart relies on ketone bodies as a fuel. Circulation. 2016;133:698–705.

  8. •• Horton JL, Davidson MT, Kurishima C, Vega RB, Powers JC, Matsuura TR, et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI insight. 2019;4.

  9. Bedi KC, Snyder NW, Brandimarto J, Aziz M, Mesaros C, Worth AJ, et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation. 2016;133:706–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. •• Yurista SR, Chong C-R, Badimon JJ, Kelly DP, de Boer RA, Westenbrink BD. Therapeutic potential of ketone bodies for patients with cardiovascular disease. J Am Coll Cardiol. 2021;77:1660–9.

  11. Birkenfeld AL, Jordan J, Dworak M, Merkel T, Burnstock G. Myocardial metabolism in heart failure: purinergic signalling and other metabolic concepts. Pharmacol Ther. 2019;194:132–44.

    Article  CAS  PubMed  Google Scholar 

  12. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093–129.

    Article  CAS  PubMed  Google Scholar 

  13. •• Neubauer S. The failing heart — an engine out of fuel. N Engl J Med. 2007;356:1140–51.

  14. Ritterhoff J, Tian R. Metabolism in cardiomyopathy: every substrate matters. Cardiovasc Res. 2017;113:411–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. •• Murashige D, Jang C, Neinast M, Edwards JJ, Cowan A, Hyman MC, et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science (80- ). 2020;370:364–8.

  16. Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013;113:709–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab. 2009;20:72–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Koonen DPY, Glatz JFC, Bonen A, Luiken JJFP. Long-chain fatty acid uptake and FAT/CD36 translocation in heart and skeletal muscle. Biochim Biophys Acta. 2005;1736:163–80.

    Article  CAS  PubMed  Google Scholar 

  19. Murthy MS, Pande SV. Mechanism of carnitine acylcarnitine translocase-catalyzed import of acylcarnitines into mitochondria. J Biol Chem. 1984;259:9082–9.

    Article  CAS  PubMed  Google Scholar 

  20. Murthy MS, Pande SV. Some differences in the properties of carnitine palmitoyltransferase activities of the mitochondrial outer and inner membranes. Biochem J. 1987;248:727–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Shao D, Tian R. Glucose transporters in cardiac metabolism and hypertrophy. Compr Physiol. Wiley; 2015. p. 331–51.

  22. Becker C, Sevilla L, Tomàs E, Palacin M, Zorzano A, Fischer Y. The endosomal compartment is an insulin-sensitive recruitment site for GLUT4 and GLUT1 glucose transporters in cardiac myocytes. Endocrinology. 2001;142:5267–76.

    Article  CAS  PubMed  Google Scholar 

  23. Dhar-Chowdhury P, Malester B, Rajacic P, Coetzee WA. The regulation of ion channels and transporters by glycolytically derived ATP. Cell Mol Life Sci. 2007;64:3069–83.

    Article  CAS  PubMed  Google Scholar 

  24. • Yurista SR, Nguyen CT, Rosenzweig T, de Boer RA, Westenbrink BD, Rosenzweig A, et al. Ketone bodies for the failing heart: fuels that can fix the engine? Trends Endocrinol Metab. 2021;In press.

  25. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25:262–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Fukao T, Lopaschuk GD, Mitchell GA. Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry. Prostaglandins Leukot Essent Fat Acids. 2004;

  27. Sandermann H, McIntyre JO, Fleischer S. Site-site interaction in the phospholipid activation of D-beta-hydroxybutyrate dehydrogenase. J Biol Chem. 1986;261:6201–8.

    Article  CAS  PubMed  Google Scholar 

  28. Williamson DH, Bates MW, Page MA, Krebs HA. Activities of enzymes involved in acetoacetate utilization in adult mammalian tissues. Biochem J. 1971;121:41–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. • Weiss RG, Gerstenblith G, Bottomley PA. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc Natl Acad Sci. 2005;102:808–13.

  30. • Ingwall JS, Weiss RG. Is the failing heart energy starved? Circ Res. 2004;95:135–45.

  31. • Bottomley PA, Panjrath GS, Lai S, Hirsch GA, Wu K, Najjar SS, et al. Metabolic rates of ATP transfer through creatine kinase (CK flux) predict clinical heart failure events and death. Sci Transl Med. 2013;5.

  32. Neglia D, De Caterina A, Marraccini P, Natali A, Ciardetti M, Vecoli C, et al. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am J Physiol Circ Physiol. 2007;293:H3270–8.

    Article  CAS  Google Scholar 

  33. Yazaki Y, Isobe M, Takahashi W, Kitabayashi H, Nishiyama O, Sekiguchi M, et al. Assessment of myocardial fatty acid metabolic abnormalities in patients with idiopathic dilated cardiomyopathy using 123I BMIPP SPECT: correlation with clinicopathological findings and clinical course. Heart. 1999;81:153–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sochor H, Schelbert HR, Schwaiger M, Henze E, Phelps ME. Studies of fatty acid metabolism with positron emission tomography in patients with cardiomyopathy. Eur J Nucl Med. 1986;12(Suppl):S66–9.

    Article  PubMed  Google Scholar 

  35. Taegtmeyer H, Sen S, Vela D. Return to the fetal gene program: a suggested metabolic link to gene expression in the heart. Ann N Y Acad Sci. 2010;1188:191–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. • Funada J, Betts TR, Hodson L, Humphreys SM, Timperley J, Frayn KN, et al. Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. PLoS One. 2009;4:e7533.

  37. Vega RB, Huss JM, Kelly DP. The coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol. 2000;20:1868–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Karbowska J, Kochan Z, Smoleński RT. Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart. Cell Mol Biol Lett. 2003;8:49–53.

    CAS  PubMed  Google Scholar 

  39. Karamanlidis G, Nascimben L, Couper GS, Shekar PS, Del Monte F, Tian R. Defective DNA replication impairs mitochondrial biogenesis in human failing hearts. Circ Res. 2010;106:1541–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Nascimben L, Ingwall JS, Lorell BH, Pinz I, Schultz V, Tornheim K, et al. Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension. 2004;44:662–7.

    Article  CAS  PubMed  Google Scholar 

  41. • Schroeder MA, Lau AZ, Chen AP, Gu Y, Nagendran J, Barry J, et al. 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;15:130–40.

  42. Zhabyeyev P, Gandhi M, Mori J, Basu R, Kassiri Z, Clanachan A, et al. Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc Res. 2013;97:676–85.

    Article  CAS  PubMed  Google Scholar 

  43. Doenst T, Pytel G, Schrepper A, Amorim P, Farber G, Shingu Y, et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc Res. 2010;86:461–70.

    Article  CAS  PubMed  Google Scholar 

  44. Opie LH. Myocardial ischemia?Metabolic pathways and implications of increased glycolysis. Cardiovasc Drugs Ther. 1990;4:777–90.

    Article  PubMed  Google Scholar 

  45. • Fillmore N, Levasseur JL, Fukushima A, Wagg CS, Wang W, Dyck JRB, et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol Med. 2018;24:3.

  46. • Diakos NA, Navankasattusas S, Abel ED, Rutter J, McCreath L, Ferrin P, et al. Evidence of glycolysis up-regulation and pyruvate mitochondrial oxidation mismatch during mechanical unloading of the failing human heart: implications for cardiac reloading and conditioning. JACC Basic to Transl Sci. 2016;1:432–44.

  47. Osorio JC, Stanley WC, Linke A, Castellari M, Diep QN, Panchal AR, et al. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-α in pacing-induced heart failure. Circulation. 2002;106:606–12.

    Article  CAS  PubMed  Google Scholar 

  48. •• Voros G, Ector J, Garweg C, Droogne W, Van Cleemput J, Peersman N, et al. 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.

  49. Lommi MDJ. Blood ketone bodies in congestive heart failure. J Am Coll Cardiol. 1996;28:665–72.

    Article  CAS  PubMed  Google Scholar 

  50. • Mizuno Y, Harada E, Nakagawa H, Morikawa Y, Shono M, Kugimiya F, et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism. 2017;77:65–72.

  51. Song J-P, Chen L, Chen X, Ren J, Zhang N-N, Tirasawasdichai T, et al. Elevated plasma β-hydroxybutyrate predicts adverse outcomes and disease progression in patients with arrhythmogenic cardiomyopathy. Sci Transl Med. 2020;12:eaay8329.

  52. • Yurista SR, Rosenzweig A, Nguyen CT. Ketone bodies. J Am Coll Cardiol. 2021;78:1433–6.

  53. • Ho KL, Zhang L, Wagg C, Al Batran R, Gopal K, Levasseur J, et al. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency. Cardiovasc Res. 2019;115:1606–16.

  54. 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;3:754–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. • Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci (Lond). 2000;99:27–35.

  56. Turcani M, Rupp H. Etomoxir improves left ventricular performance of pressure-overloaded rat heart. Circulation. 1997;96:3681–6.

    Article  CAS  PubMed  Google Scholar 

  57. Rupp H, Vetter R. Sarcoplasmic reticulum function and carnitine palmitoyltransferase-1 inhibition during progression of heart failure. Br J Pharmacol. 2000;131:1748–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lee L, Campbell R, Scheuermann-Freestone M, Taylor R, Gunaruwan P, Williams L, et al. Metabolic modulation with perhexiline in chronic heart failure. Circulation. 2005;112:3280–8.

    Article  CAS  PubMed  Google Scholar 

  59. Beadle RM, Williams LK, Kuehl M, Bowater S, Abozguia K, Leyva F, et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Hear Fail. 2015;3:202–11.

    Article  Google Scholar 

  60. Senanayake EL, Howell NJ, Ranasinghe AM, Drury NE, Freemantle N, Frenneaux M, et al. Multicentre double-blind randomized controlled trial of perhexiline as a metabolic modulator to augment myocardial protection in patients with left ventricular hypertrophy undergoing cardiac surgery. Eur J Cardio-Thoracic Surg. 2015;48:354–62.

    Article  Google Scholar 

  61. Danchin N, Marzilli M, Parkhomenko A, Ribeiro JP. Efficacy comparison of trimetazidine with therapeutic alternatives in stable angina pectoris: a network meta-analysis. Cardiology. 2011;120:59–72.

    Article  CAS  PubMed  Google Scholar 

  62. • Fragasso G, Salerno A, Lattuada G, Cuko A, Calori G, Scollo A, et al. Effect of partial inhibition of fatty acid oxidation by trimetazidine on whole body energy metabolism in patients with chronic heart failure. Heart. 2011;97:1495–500.

  63. • Fragasso G, Palloshi A, Puccetti P, Silipigni C, Rossodivita A, Pala M, et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol. 2006;48:992–8.

  64. Gunes Y, Tuncer M, Guntekin U, Akdag S, Gumrukcuoglu HA. The effects of trimetazidine on P-wave duration and dispersion in heart failure patients. Pacing Clin Electrophysiol. 2009;32:239–44.

    Article  PubMed  Google Scholar 

  65. Gunes Y, Guntekin U, Tuncer M, Sahin M. Os efeitos da trimetazidina na variabilidade da frequência cardíaca (VFC) em pacientes com insuficiência cardíaca. Arq Bras Cardiol. 2009;93:154–8.

    Article  CAS  PubMed  Google Scholar 

  66. Cera M, Salerno A, Fragasso G, Montanaro C, Gardini C, Marinosci G, et al. Beneficial electrophysiological effects of trimetazidine in patients with postischemic chronic heart failure. J Cardiovasc Pharmacol Ther. 2010;15:24–30.

    Article  CAS  PubMed  Google Scholar 

  67. Tuunanen H, Engblom E, Naum A, Någren K, Scheinin M, Hesse B, et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation. 2008;118:1250–8.

    Article  CAS  PubMed  Google Scholar 

  68. • Zhao P, Zhang J, Yin X-G, Maharaj P, Narraindoo S, Cui L-Q, et al. The effect of trimetazidine on cardiac function in diabetic patients with idiopathic dilated cardiomyopathy. Life Sci. 2013;92:633–8.

  69. Di Napoli P, Di Giovanni P, Gaeta MA, D’Apolito G, Barsotti A. Beneficial effects of trimetazidine treatment on exercise tolerance and B-type natriuretic peptide and troponin T plasma levels in patients with stable ischemic cardiomyopathy. Am Heart J. 2007;154:602.e1-602.e5.

    Article  CAS  Google Scholar 

  70. Winter JL, Castro PF, Quintana JC, Altamirano R, Enriquez A, Verdejo HE, et al. Effects of trimetazidine in nonischemic heart failure: a randomized study. J Card Fail. 2014;20:149–54.

    Article  CAS  PubMed  Google Scholar 

  71. Lehtonen A. Effect of beta blockers on blood lipid profile. Am Heart J. 1985;109:1192–6.

    Article  CAS  PubMed  Google Scholar 

  72. • Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ, et al. Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation. 2001;103:2441–6.

  73. Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, et al. Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol. 1994;24:1310–20.

    Article  CAS  PubMed  Google Scholar 

  74. Beanlands RS, Nahmias C, Gordon E, Coates G, DeKemp R, Firnau G, et al. The effects of beta(1)-blockade on oxidative metabolism and the metabolic cost of ventricular work in patients with left ventricular dysfunction: a double-blind, placebo-controlled, positron-emission tomography study. Circulation. 2000;102:2070–5.

    Article  CAS  PubMed  Google Scholar 

  75. Tuunanen H, Engblom E, Naum A, Någren K, Hesse B, Airaksinen KEJ, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006;114:2130–7.

    Article  CAS  PubMed  Google Scholar 

  76. Halbirk M, Nørrelund H, Møller N, Schmitz O, Gøtzsche L, Nielsen R, et al. Suppression of circulating free fatty acids with acipimox in chronic heart failure patients changes whole body metabolism but does not affect cardiac function. Am J Physiol Heart Circ Physiol. 2010;299:H1220–5.

    Article  CAS  PubMed  Google Scholar 

  77. McDonagh TA, Metra M, Adamo M, Gardner RS, Baumbach A, Böhm M, et al. 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J. 2021;42:3599–726.

    Article  CAS  PubMed  Google Scholar 

  78. •• Bøgh N, Hansen ESS, Omann C, Lindhardt J, Nielsen PM, Stephenson RS, et al. Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure. Sci Rep. 2020;10:8158.

  79. • Kato T, Niizuma S, Inuzuka Y, Kawashima T, Okuda J, Tamaki Y, et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ Hear Fail. 2010;3:420–30.

  80. Lewis JF, Dacosta M, Wargowich T, Stacpoole P. Effects of dichloroacetate in patients with congestive heart failure. Clin Cardiol. 1998;21:888–92.

    Article  CAS  PubMed  Google Scholar 

  81. Wilson JR, Mancini DM, Ferraro N, Egler J. Effect of dichloroacetate on the exercise performance of patients with heart failure. J Am Coll Cardiol. 1988;12:1464–9.

    Article  CAS  PubMed  Google Scholar 

  82. Kurlemann G, Paetzke I, Möller H, Masur H, Schuierer G, Weglage J, et al. Therapy of complex I deficiency: peripheral neuropathy during dichloroacetate therapy. Eur J Pediatr. 1995;154:928–32.

    Article  CAS  PubMed  Google Scholar 

  83. Spruijt L, Naviaux RK, McGowan KA, Nyhan WL, Sheean G, Haas RH, et al. Nerve conduction changes in patients with mitochondrial diseases treated with dichloroacetate. Muscle Nerve. 2001;24:916–24.

    Article  CAS  PubMed  Google Scholar 

  84. Das SR, Everett BM, Birtcher KK, Brown JM, Cefalu WT, Januzzi JL, et al. 2018 ACC expert consensus decision pathway on novel therapies for cardiovascular risk reduction in patients with type 2 diabetes and atherosclerotic cardiovascular disease: a report of the American College of Cardiology Task Force on Expert Consensus Deci. J Am Coll Cardiol. 2018;72:3200–23.

    Article  PubMed  Google Scholar 

  85. Cosentino F, Grant PJ, Aboyans V, Bailey CJ, Ceriello A, Delgado V, et al. 2019 ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur Heart J. 2020;41:255–323.

    Article  PubMed  Google Scholar 

  86. Arnett DK, Blumenthal RS, Albert MA, Buroker AB, Goldberger ZD, Hahn EJ, et al. ACC/AHA guideline on the primary prevention of cardiovascular disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;2019:140.

    Google Scholar 

  87. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes—2020. Diabetes Care. 2020;43:S98–110.

  88. Bhashyam S, Fields AV, Patterson B, Testani JM, Chen L, Shen Y-T, et al. Glucagon-like peptide-1 increases myocardial glucose uptake via p38alpha MAP kinase-mediated, nitric oxide-dependent mechanisms in conscious dogs with dilated cardiomyopathy. Circ Heart Fail. 2010;3:512–21.

    Article  PubMed  PubMed Central  Google Scholar 

  89. • Nikolaidis LA, Elahi D, Hentosz T, Doverspike A, Huerbin R, Zourelias L, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004;110:955–61.

  90. Bao W, Aravindhan K, Alsaid H, Chendrimada T, Szapacs M, Citerone DR, et al. Albiglutide, a long lasting glucagon-like peptide-1 analog, protects the rat heart against ischemia/reperfusion injury: evidence for improving cardiac metabolic efficiency. PLoS ONE. 2011;6: e23570.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. • Halbirk M, Nørrelund H, Møller N, Holst JJ, Schmitz O, Nielsen R, et al. Cardiovascular and metabolic effects of 48-h glucagon-like peptide-1 infusion in compensated chronic patients with heart failure. Am J Physiol Circ Physiol. 2010;298:H1096–102.

  92. Gejl M, Søndergaard HM, Stecher C, Bibby BM, Møller N, Bøtker HE, et al. Exenatide alters myocardial glucose transport and uptake depending on insulin resistance and increases myocardial blood flow in patients with type 2 diabetes. J Clin Endocrinol Metab. 2012;97:E1165–9.

    Article  CAS  PubMed  Google Scholar 

  93. •• Yurista SR, Matsuura TR, Silljé HHW, Nijholt KT, McDaid KS, Shewale S V., et al. Ketone ester treatment improves cardiac function and reduces pathologic remodeling in preclinical models of heart failure. Circ Hear Fail. 2021;14.

  94. •• Ferrannini E, Muscelli E, Frascerra S, Baldi S, Mari A, Heise T, et al. Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients. J Clin Invest. 2014;124:499–508.

  95. •• Ferrannini E, Baldi S, Frascerra S, Astiarraga B, Heise T, Bizzotto R, et al. Shift to fatty substrate utilization in response to sodium–glucose cotransporter 2 inhibition in subjects without diabetes and patients with type 2 diabetes. Diabetes. 2016;65:1190–5.

  96. •• Yurista SR, Silljé HHW, Oberdorf-Maass SU, Schouten E, Pavez Giani MG, Hillebrands J, et al. Sodium-glucose co-transporter 2 inhibition with empagliflozin improves cardiac function in non-diabetic rats with left ventricular dysfunction after myocardial infarction. Eur J Heart Fail. 2019;21:862–73.

  97. • Kim SR, Lee S-G, Kim SH, Kim JH, Choi E, Cho W, et al. SGLT2 inhibition modulates NLRP3 inflammasome activity via ketones and insulin in diabetes with cardiovascular disease. Nat Commun. 2020;11:2127.

  98. Guo Y, Zhang C, Shang F-F, Luo M, You Y, Zhai Q, et al. Ketogenic diet ameliorates cardiac dysfunction via balancing mitochondrial dynamics and inhibiting apoptosis in type 2 diabetic mice. Aging Dis. 2020;11:229.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Deng Y, Xie M, Li Q, Xu X, Ou W, Zhang Y, et al. Targeting mitochondria-inflammation circuit by β-hydroxybutyrate mitigates HFpEF. Circ Res. 2021;128:232–45.

    Article  CAS  PubMed  Google Scholar 

  100. Zhang Y, Taufalele P V., Cochran JD, Robillard-Frayne I, Marx JM, Soto J, et al. Mitochondrial pyruvate carriers are required for myocardial stress adaptation. Nat Metab. Springer US; 2020;2:1248–64.

  101. Nakamura M, Odanovic N, Nakada Y, Dohi S, Zhai P, Ivessa A, et al. Dietary carbohydrates restriction inhibits the development of cardiac hypertrophy and heart failure. Cardiovasc Res. 2020;

  102. Xu S, Tao H, Cao W, Cao L, Lin Y, Zhao S-M, et al. Ketogenic diets inhibit mitochondrial biogenesis and induce cardiac fibrosis. Signal Transduct Target Ther. 2021;6:54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. You Y, Guo Y, Jia P, Zhuang B, Cheng Y, Deng H, et al. Ketogenic diet aggravates cardiac remodeling in adult spontaneously hypertensive rats. Nutr Metab (Lond). 2020;17:91.

    Article  CAS  Google Scholar 

  104. • Monzo L, Sedlacek K, Hromanikova K, Tomanova L, Borlaug BA, Jabor A, et al. Myocardial ketone body utilization in patients with heart failure: The impact of oral ketone ester. Metabolism. 2021;115:154452.

  105. •• Nielsen R, Møller N, Gormsen LC, Tolbod LP, Hansson NH, Sorensen J, et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation. 2019;139:2129–41.

  106. Jaumdally R, Varma C, Macfadyen RJ, Lip GYH. Coronary sinus blood sampling: an insight into local cardiac pathophysiology and treatment? Eur Heart J. 2007;28:929–40.

    Article  PubMed  Google Scholar 

  107. Samara MA, Tang WHW, Cikach F, Gul Z, Tranchito L, Paschke KM, et al. Single exhaled breath metabolomic analysis identifies unique breathprint in patients with acute decompensated heart failure. J Am Coll Cardiol. 2013;61:1463–4.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Zhou Z, Nguyen C, Chen Y, Shaw JL, Deng Z, Xie Y, et al. Optimized CEST cardiovascular magnetic resonance for assessment of metabolic activity in the heart. J Cardiovasc Magn Reson. 2017;19:95.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Rider OJ, Apps A, Miller JJJJ, Lau JYC, Lewis AJM, Peterzan MA, et al. Noninvasive in vivo assessment of cardiac metabolism in the healthy and diabetic human heart using hyperpolarized 13C MRI. Circ Res. 2020;725–36.

  110. Nakae I, Mitsunami K, Omura T, Yabe T, Tsutamoto T, Matsuo S, et al. Proton magnetic resonance spectroscopy can detect creatine depletion associated with the progression of heart failure in cardiomyopathy. J Am Coll Cardiol. Elsevier Masson SAS; 2003;42:1587–93.

  111. Weiss RG, Bottomley PA, Hardy CJ, Gerstenblith G. Regional myocardial metabolism of high-energy phosphates during isometric exercise in patients with coronary artery disease. N Engl J Med. 1990;323:1593–600.

    Article  CAS  PubMed  Google Scholar 

  112. • Gormsen LC, Svart M, Thomsen HH, Søndergaard E, Vendelbo MH, Christensen N, et al. 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.

  113. Taegtmeyer H, Young ME, Lopaschuk GD, Abel ED, Brunengraber H, Darley-Usmar V, et al. Assessing cardiac metabolism. Circ Res. 2016;118:1659–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Christe ME, Rodgers RL. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J Mol Cell Cardiol. 1994;26:1371–5.

    Article  CAS  PubMed  Google Scholar 

  115. 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 Circ Physiol. 1994;267:H742–50.

    Article  CAS  Google Scholar 

  116. •• Ingwall JS, Atkinson DE, Clarke K, Fetters JK. Energetic correlates of cardiac failure: changes in the creatine kinase system in the failing myocardium. Eur Heart J. 1990;11:108–15.

  117. Tian R. Depletion of energy reserve via the creatine kinase reaction during the evolution of heart failure in cardiomyopathic hamsters. J Mol Cell Cardiol. 1996;28:755–65.

    Article  CAS  PubMed  Google Scholar 

  118. Neubauer S, Horn M, Cramer M, Harre K, Newell JB, Peters W, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96:2190–6.

    Article  CAS  PubMed  Google Scholar 

  119. Epstein FH, Kelly DP, Strauss AW. Inherited cardiomyopathies. N Engl J Med. 1994;330:913–9.

    Article  Google Scholar 

  120. Bennett MJ, Rinaldo P, Strauss AW. Inborn errors of mitochondrial fatty acid oxidation. Crit Rev Clin Lab Sci. 2000;37:1–44.

    Article  CAS  PubMed  Google Scholar 

  121. Wallace DC. Mitochondrial defects in cardiomyopathy and neuromuscular disease. Am Heart J. 2000;139:s70-85.

    Article  CAS  PubMed  Google Scholar 

  122. Lai L, Leone TC, Keller MP, Martin OJ, Broman AT, Nigro J, et al. Energy metabolic reprogramming in the hypertrophied and early stage failing heart. Circ Hear Fail. 2014;7:1022–31.

    Article  CAS  Google Scholar 

  123. Ho KL, Karwi QG, Wagg C, Zhang L, Vo K, Altamimi T, et al. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency. Cardiovasc Res. 2020;

  124. Carley AN, Maurya SK, Fasano M, Wang Y, Selzman CH, Drakos SG, et al. Short-chain fatty acids outpace ketone oxidation in the failing heart. Circulation. 2021;143:1797–808.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Sun H, Olson KC, Gao C, Prosdocimo DA, Zhou M, Wang Z, et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation. 2016;133:2038–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Cardiovascular Research Center, Corrigan Minehan Heart Center, Massachusetts General Hospital, Harvard Medical School, 149 13th Street, Boston, MA, 02129, USA

    Salva R. Yurista, Shi Chen, Aidan Welsh & Christopher T. Nguyen

  2. Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA

    Salva R. Yurista, Shi Chen, Aidan Welsh & Christopher T. Nguyen

  3. Heart, Vascular, and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang & Christopher T. Nguyen

  4. Division of Health Science Technology, Harvard-Massachusetts Institute of Technology, Cambridge, MA, USA

    Christopher T. Nguyen

  5. Cardiovascular Innovation Research Center, Cleveland Clinic, Cleveland, OH, USA

    W. H. Wilson Tang & Christopher T. Nguyen

  6. Imaging Institute, Cleveland Clinic, Cleveland, OH, USA

    Christopher T. Nguyen

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C.T.N. is supported by grants from the National Institutes of Health (R01 HL151704, R01 HL159010, R01 HL135242). W.H.W.T. is a consultant for Sequana Medical A.G., Cardiol Therapeutics Inc, and Genomics plc, and has received honorarium from Springer Nature for authorship/editorship and American Board of Internal Medicine for exam writing committee participation, all unrelated to the contents of this paper. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. We apologize to all authors whose relevant work could not be cited due to space limitations.

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Yurista, S.R., Chen, S., Welsh, A. et al. Targeting Myocardial Substrate Metabolism in the Failing Heart: Ready for Prime Time?. Curr Heart Fail Rep 19, 180–190 (2022). https://doi.org/10.1007/s11897-022-00554-1

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