Abstract
Ketone bodies can become a major source of adenosine triphosphate production during
stress to maintain bioenergetic homeostasis in the brain, heart, and skeletal muscles.
In the normal heart, ketone bodies contribute from 10% to 15% of the cardiac adenosine
triphosphate production, although their contribution during pathologic stress is still
not well-characterized and currently represents an exciting area of cardiovascular
research. This review focuses on the mechanisms that regulate circulating ketone levels
under physiologic and pathologic conditions and how this impacts cardiac ketone metabolism.
We also review the current understanding of the role of augmented ketone metabolism
as an adaptive response in different types and stages of heart failure. This analysis
includes the emerging experimental and clinical evidence of the potential favorable
effects of boosting ketone metabolism in the failing heart and the possible mechanisms
of action through which these interventions may mediate their cardioprotective effects.
We also critically appraise the emerging data from animal and human studies which
characterize the role of ketones in mediating the cardioprotection established by
the new class of antidiabetic drugs, namely sodium-glucose co-transporter inhibitors.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Cardiac FailureAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Loss of metabolic flexibility in the failing heart.Front Cardiovasc Med. 2018; 5: 68
- Myocardial fatty acid metabolism in health and disease.Physiol Rev. 2010; 90: 207-258
- Metabolic Modulators in heart disease: past, present, and future.Can J Cardiol. 2017; 33: 838-849
- Evolving concepts of myocardial energy metabolism.Circ Res. 2016; 119: 1173-1176
- Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes.Circ Res. 2013; 113: 603-616
- Rethinking cardiac metabolism: metabolic cycles to refuel and rebuild the failing heart.F1000Prime Rep. 2014; 6: 90
- Plasma fatty acid levels in infants and adults after myocardial ischemia.Am Heart J. 1994; 128: 61-67
- Cardiac branched-chain amino acid oxidation is reduced during insulin resistance in the heart.Am J Physiol Endocrinol Metab. 2018; 315: E1046-E1052
- 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
- Metabolic remodelling in heart failure.Nat Rev Cardiol. 2018; 15: 457-470
- 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
- Normalization of cardiac substrate utilization and left ventricular hypertrophy precede functional recovery in heart failure regression.Cardiovasc Res. 2016; 110: 249-257
- ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4.Am J Physiol Heart Circ Physiol. 2013; 304: H1103-H1113
- Agonist-induced hypertrophy and diastolic dysfunction are associated with selective reduction in glucose oxidation: a metabolic contribution to heart failure with normal ejection fraction.Circ Heart Fail. 2012; 5: 493-503
- Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload.Cardiovasc Res. 2013; 97: 676-685
- The failing heart — an engine out of fuel.N Engl J Med. 2007; 356: 1140-1151
- Allosteric, transcriptional and post-translational control of mitochondrial energy metabolism.Biochem J. 2019; 476: 1695-1712
- Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure.Circulation. 2016; 133: 706-716
- The failing heart relies on ketone bodies as a fuel.Circulation. 2016; 133: 698-705
- Ketone body metabolism and cardiovascular disease.Am J Physiol Heart Circ Physiol. 2013; 304: H1060-H1076
- Ketone bodies as signaling metabolites.Trends in Endocrinol Metab. 2014; 25: 42-52
- Physiological roles of ketone bodies as substrates and signals in mammalian tissues.Physiol Rev. 1980; 60: 143-187
- Hormone-fuel interrelationships during fasting.J Clin Invest. 1966; 45: 1751-1769
- Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics.Cell Metab. 2017; 25: 262-284
- Characterization of splice variants of the genes encoding human mitochondrial HMG-CoA lyase and HMG-CoA synthase, the main enzymes of the ketogenesis pathway.Mol Biol Rep. 2012; 39: 4777-4785
- Developmental changes in mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene expression in rat liver, intestine and kidney.Biochem J. 1993; 292: 493-496
- Impact of exhaled breath acetone in the prognosis of patients with heart failure with reduced ejection fraction (HFrEF). One year of clinical follow-up.PLoS One. 2016; 11e0168790
- Breath acetone as a potential marker in clinical practice.J Breath Res. 2017; 11024002
- Preparation of a homogeneous soluble D-beta-hydroxybutyrate apodehydrogenase from mitochondria.J Biol Chem. 1975; 250: 5761-5774
- d-β-hydroxybutyric dehydrogenase of mitochondria.J Biol Chem. 1960; 235: 2450-2455
- The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver.Biochem J. 1967; 103: 514-527
- Acetoacetate as fuel of respiration in the perfused rat heart.Biochem J. 1961; 80: 540-547
- Effect of carnitine on the oxidation of alpha-oxoglutarate to succinate in the presence of acetoacetate or pyruvate.Biochim Biophys Acta. 1964; 93: 166-168
- Effect of ketone bodies on cardiac metabolism.Am J Physiol. 1965; 208: 162-168
- Competition between palmitate and ketone bodies as fuels for the heart: study with positron emission tomography.Am J Physiol. 1993; 264: H701-H707
- Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency.Cardiovasc Res. 2019; 115: 1606-1616
- The monocarboxylate transporter family–structure and functional characterization.IUBMB Life. 2012; 64: 1-9
- The monocarboxylate transporter family–role and regulation.IUBMB Life. 2012; 64: 109-119
- Pathways and control of ketone body metabolism: on the fringe of lipid biochemistry.Prostag Leukotr Ess. 2004; 70: 243-251
- Pseudoketogenesis in the perfused rat heart.J Biol Chem. 1988; 263: 18036-18042
- Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate.Am J Physiol. 1991; 261: H1756-H1762
- 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
- Pyruvate carboxylase. IX. Some properties of the activation by certain acyl derivatives of coenzyme A.J Biol Chem. 1967; 242: 1723-1735
- On the inability of ketone bodies to serve as the only energy providing substrate for rat heart at physiological work load.Basic Res Cardiol. 1983; 78: 435-450
- Coenzyme A sequestration in rat hearts oxidizing ketone bodies.J Clin Invest. 1992; 89: 968-973
- Ketones can become the major fuel source for the heart but do not increase cardiac efficiency.Cardiovasc Res. 2020; https://doi.org/10.1093/cvr/cvaa143
- 1H-NMR-based metabolic analysis of human serum reveals novel markers of myocardial energy expenditure in heart failure patients.PLoS One. 2014; 9: e88102
- beta-Hydroxybutyrate elevation as a compensatory response against oxidative stress in cardiomyocytes.Biochem Biophys Res Commun. 2016; 475: 322-328
- The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense.JCI Insight. 2019; 4
- Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling.Circ Heart Fail. 2018; 11e004953
- Empagliflozin blunts worsening cardiac dysfunction associated with reduced NLRP3 (nucleotide-binding domain-like receptor protein 3) inflammasome activation in heart failure.Circ Heart Fail. 2020; 13e006277
- Studies on myocardial metabolism. VI. Myocardial metabolism in congestive failure.. Am J Med. 1956; 20: 820-833
- Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and cardiac remodeling in pressure overload-induced heart failure.Circ Heart Fail. 2017; 10e004417
- Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling.Mol Metab. 2014; 3: 754-769
- A 6-bp deletion at the splice donor site of the first intron resulted in aberrant splicing using a cryptic splice site within exon 1 in a patient with succinyl-CoA: 3-ketoacid CoA transferase (SCOT) deficiency.Mol Genet Metab. 2006; 89: 280-282
- Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients.Circulation. 2019; 139: 2129-2141
- Cardiac metabolic modulation upon low-carbohydrate low-protein ketogenic diet in diabetic rats studied in vivo using hyperpolarized (13) C pyruvate, butyrate, and acetoacetate probes.Diabetes Obes Metab. 2018; 21: 357-365
- 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; 6e005066
- Targeting the glucagon receptor improves cardiac function and enhances insulin sensitivity following a myocardial infarction.Cardiovasc Diabetol. 2019; 18: 1
- Weight loss enhances cardiac energy metabolism and function in heart failure associated with obesity.Diabetes Obes Metab. 2019; 21: 1944-1955
- Is the failing heart energy starved? On using chemical energy to support cardiac function.Circ Res. 2004; 95: 135-145
- The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus.Lancet. 1963; 1: 785-789
- Malonyl CoA decarboxylase inhibition improves cardiac function post-myocardial infarction.JACC Basic Transl Sci. 2019; 4: 385-400
- Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy.J Am Coll Cardiol. 2002; 40: 271-277
- Myocardial metabolism in congestive heart failure.Medicine (Baltimore). 1951; 30: 21-41
- Total-body and myocardial substrate oxidation in congestive heart failure.Metabolism. 1994; 43: 174-179
- Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts.Am J Physiol Heart Circ Physiol. 2005; 288: H2979-H2985
- CV protection in the EMPA-REG OUTCOME Trial: a “thrifty substrate” hypothesis.Diabetes Care. 2016; 39 (1108 LP-14)
- Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: a randomized trial.JAMA. 2005; 293: 43-53
- Effects of ketogenic diets on cardiovascular risk factors: evidence from animal and human studies.Nutrients. 2017; 9
- Lowcarbohydrate ketogenic diet enhances cardiac tolerance to global ischaemia.Acta Cardiol. 2007; 62: 381-389
- Lethal mitochondrial cardiomyopathy in a hypomorphic Med30 mouse mutant is ameliorated by ketogenic diet.Proc Natl Acad Sci U S A. 2011; 108: 19678-19682
- Adaptation of myocardial substrate metabolism to a ketogenic nutrient environment.J Biol Chem. 2010; 285: 24447-24456
- Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox.Diabetes. 2015; 64: 1643-1657
- New insights into the mechanisms of the ketogenic diet.Curr Opin Neurol. 2017; 30: 187-192
- SGLT2 inhibitors in the treatment of type 2 diabetes.Diabetes Res Clin Pract. 2014; 104: 297-322
- Canagliflozin and cardiovascular and renal events in type 2 diabetes.N Engl J Med. 2017; 377: 644-657
- Dapagliflozin and cardiovascular outcomes in type 2 diabetes.N Engl J Med. 2019; 380: 347-357
- Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.N Engl J Med. 2015; 373: 2117-2128
- Dapagliflozin in patients with heart failure and reduced ejection fraction.N Engl J Med. 2019; 381: 1995-2008
- Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors.JACC Basic Transl Sci. 2018; 3: 575-587
- Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics.J Am Coll Cardiol. 2019; 73: 1931-1944
- Empagliflozin prevents worsening of cardiac function in an experimental model of pressure overload-induced heart failure.JACC Basic Transl Sci. 2017; 2: 347-354
- Empagliflozin, an SGLT2 inhibitor, reduced the mortality rate after acute myocardial infarction with modification of cardiac metabolomes and anti-oxidants in diabetic rats.J Pharmacol Exp Ther. 2019; 368: 524-534
- SGLT2 inhibitors and mechanisms of cardiovascular benefit: a state-of-the-art review.Diabetologia. 2018; 61: 2108-2117
- Empagliflozin's fuel hypothesis: not so soon.Cell Metab. 2016; 24: 200-202
- 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: 862-873
- Single dose of empagliflozin increases in vivo cardiac energy status in diabetic db/db mice.Cardiovasc Res. 2018; 114: 1843-1844
- Diabetic ketoacidosis and related events in the Canagliflozin Type 2 Diabetes Clinical Program.Diabetes Care. 2015; 38: 1680-1686
- Euglycemic diabetic ketoacidosis: a potential complication of treatment with sodium-glucose cotransporter 2 inhibition.Diabetes Care. 2015; 38: 1687-1693
U.S. Food and Drug Administration. Drug Safety Communication: FDA warns that SGLT2 inhibitors for diabetes may result in a serious condition of too much acid in the blood [Internet], 15 May 2015. Available from: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM446954.pdf.
- Euglycemic diabetic ketoacidosis: a predictable, detectable, and preventable safety concern with SGLT2 inhibitors.Diabetes Care. 2015; 38: 1638-1642
Article info
Publication history
Published online: May 19, 2020
Accepted:
April 9,
2020
Received in revised form:
March 18,
2020
Received:
January 10,
2020
Footnotes
Supported by a Canadian Institutes for Health Research Foundation grant, a Heart and Stroke Foundation of Canada grant and an Alberta Heritage Foundation for Medical Research Scientist Award to G. D. L. and by the University Hospital Foundation. This work was also funded by grants to T.C.P from the Natural Sciences and Engineering Research Council of Canada (RGPIN-2014-03687), Diabetes Canada (NOD_OG-3-15-5037-TP, NOD_SC-5-16-5054-TP), the Beatrice Hunter Cancer Research Institute and the New Brunswick Health Research Foundation. D.B. is funded by Postdoctoral fellowships from the New Brunswick Health Research Foundation and Dalhousie Medicine New Brunswick. Q.G.K. is funded by Alberta Innovates Postgraduate Fellowship in Health Innovation.
ATP, adenosine triphosphate; β-OHB, beta-hydroxybutyrate; HFrEF, heart failure with reduced ejection fraction.
Identification
Copyright
© 2020 Elsevier Inc. All rights reserved.
