
==== Front
Curr Heart Fail Rep
Curr Heart Fail Rep
Current Heart Failure Reports
1546-9530
1546-9549
Springer US New York

39242479
678
10.1007/s11897-024-00678-6
Review
Metabolic Adaptation in Heart Failure and the Role of Ketone Bodies as Biomarkers
Foster Michael W. 1
Riley Joshua M. 1
Kaki Praneet C. 2
Al Soueidy Amine 3
Aligholiazadeh Ehson 3
Rame J. Eduardo Eduardo.rame@jefferson.edu

1
1 https://ror.org/04zhhva53 grid.412726.4 0000 0004 0442 8581 Department of Medicine, Division of Cardiology, Thomas Jefferson University Hospital, 833 Chestnut Street, Suite 600, Philadelphia, PA 19107 USA
2 https://ror.org/04zhhva53 grid.412726.4 0000 0004 0442 8581 Sidney Kimmel Medical College, Thomas Jefferson University Hospital, Philadelphia, PA USA
3 grid.412715.4 0000 0004 0433 4833 Department of Medicine, Copper University Hospital, Camden, NJ USA
7 9 2024
7 9 2024
2024
21 5 498503
12 7 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose of Review

The development and progression of heart failure is characterized by metabolic and physiologic adaptations allowing patients to cope with cardiac insufficiency. This review explores the changes in metabolism in heart failure and the potential role of biomarkers, particularly ketone bodies, in staging and prognosticating heart failure progression.

Recent Findings

Recent insights into myocardial metabolism shed light on the heart’s response to stress, highlighting the shift towards reliance on ketone bodies as an alternative fuel source. Elevated blood ketone levels have been shown to correlate with the severity of cardiac dysfunction, emphasizing their potential as prognostic indicators. Furthermore, studies exploring therapeutic interventions targeting specific metabolic pathways offer promise for improving outcomes in heart failure.

Summary

Ketones have prognostic utility in heart failure, and potentially, an avenue for therapeutic intervention. Challenges remain in deciphering the optimal balance between metabolic support and exacerbating cardiac remodeling. Future research endeavors must address these complexities to advance personalized approaches in managing heart failure.

Keywords

Heart failure
Cardiomyopathy
Biomarkers
Ketone bodies
Myocardial metabolism
issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2024
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pmcIntroduction

Heart failure is a complex, progressive syndrome that is marked by a multitude of adaptations allowing patients to live with cardiac insufficiency [1]. Adaptations in cardiac mechanics, hemodynamics, neurohumoral activation and response, and metabolism have been elucidated and form the basis for biomarker profiling and therapeutic targets [1–3]. Despite the formidable advances in this area of study, heart failure remains a progressive affliction claiming over 1 million hospitalizations in the United States alone with a very high mortality in the advanced stages [4].

Recently, advances in our understanding of myocardial metabolism have provided great insight into how the human heart adapts to physiologic challenges such as exercise and how the failing heart adapts to stress in the setting of cardiac insufficiency [3]. The failing myocardium is best understood as “an engine out of fuel” desperately trying to adapt to a bioenergetic deficit through metabolic pathways working on multiple levels of fuel production and energy transmission to sustain the cardiac workload of the mechanically disadvantaged failing heart [5]. In the context of this metabolic paradigm, one can understand how the reversal of heart failure can be achieved by “resting” the myocardium, decreasing heart rate, and improving mechanical efficiency through hemodynamic coupling and cardiac resynchronization [6–9]. Conversely, using the same paradigm of metabolic adaptation to energetic failure, it is clear why the use of contractility-enhancing therapies such as inotropes is detrimental and will accelerate disease progression increasing mortality in heart failure [10–12].

In this review, we will summarize the evidence for using metabolic biomarkers to stage and prognosticate disease progression in heart failure. For background, we will summarize the metabolic adaptations alluded to above and focus on the evidence for endogenous ketone production (ketogenesis) and ketone utilization which has recently been discovered as a metabolic response to fuel deprivation. We identify opportunities for future investigation, encouraging research teams to discover the translational potential of ketones as biomarkers and therapeutic targets in human heart failure.

Role of Ketones in Myocardial Metabolism

The heart is an energy-intensive organ tasked with pumping thousands of liters of blood per day against pulmonary and systemic vascular resistance [13]. Carbohydrates and fatty acids are the primary metabolic substrates used by the heart to fulfill its steep energetic demands [3]. The heart can adapt to use other molecular sources of fuel based on varying conditions of substrate availability, including lactate, amino acids, and ketone bodies [14]. Under normal conditions, the heart does not significantly metabolize ketones due to the relative unavailability of ketones in a fed, physiological state [15]. Cardiac ketone utilization is typically limited to fasting or starvation conditions when glucose availability is low and ketones are readily formed [16].

Ketogenesis occurs in liver hepatocytes from fatty acids, which undergo β-oxidation to form acetyl-CoA, which is then converted to acetoacetate and β-hydroxybutyrate (BHB) through a series of intermediate enzyme-catalyzed reactions [17]. Ketone bodies are metabolized to produce acetyl-coenzyme A (CoA), the driver of the tricarboxylic acid cycle (TCA) [18]. Although glucose is more metabolically efficient than ketones due to its greater phosphate-to-oxygen (P/O) ratio, ketones are more efficient than fatty acids (FA), the primary fuel used by the myocardium. FA oxidation presents additional inefficiencies, namely increased mitochondrial uncoupling proteins and reactive oxygen species (ROS), which can diminish the ability of mitochondria to generate ATP [19]. The brain heavily relies on glucose for its energy supply [16]. Cardiac metabolism of ketones during fasting reduces the need for breaking down protein to fuel gluconeogenesis, preserving glucose for the brain [16]. Ketone metabolism is augmented in the heart when its capabilities for fatty acid and glucose oxidation are diminished as seen in the cardiac stress of advanced heart failure [20, 21].

There is evidence that sole ketone utilization is associated with myocardial complications. In a rat heart model, where ketones were the only metabolite available, mean cardiac output, diastolic, and systolic pressures were significantly reduced as compared to cardiac function with glucose present for utilization [22, 23]. Results revealed an accumulation of acetyl-CoA, citrate, and 2-oxoglutarate, indicating an inhibition of the TCA cycle at 2-oxoglutarate dehydrogenase [24]. Furthermore, this inhibition of 2-oxoglutarate dehydrogenase is associated with a drop in intramitochondrial concentrations of CoA. Since CoA is a required input in the reaction catalyzed by 2-oxoglutarate dehydrogenase, its sequestration effectively depletes TCA cycle intermediates, highlighting a key inefficiency of using ketone bodies as a fuel source [25]. When pyruvate, a glucose metabolite that forms TCA cycle intermediates, is present with acetoacetate, cardiac function and efficiency of the rat models no longer exhibit the decline observed during sole ketone utilization [26]. Evidently, a need exists for TCA cycle in optimal myocardial function.

There is conflicting evidence that ketones offer cardioprotective effects, notably in conditions of cardiac stress. Transgenic mice overexpressing D-β-hydroxybutyrate dehydrogenase 1, a key enzyme in ketone oxidation responsible for the interconversion of acetoacetate and β-hydroxybutyrate, demonstrated reduced ROS-mediated DNA damage and mitigated cardiac dysfunction when subjected to pressure overload-induced heart failure by aortic constriction [27]. Conversely, mice lacking succinyl-CoA:3-oxoacid CoA transferase, a key enzyme involved in ketone production, exhibited increased ROS activity in the myocardium, increased left ventricular volume, and diminished ejection fraction compared to control mice when subjected to pressure overload by aortic constriction. [28].

Metabolism in Heart Failure

Cardiac metabolism comprises three main components: substrate utilization, oxidative phosphorylation, and transport of energy (via ATP) to the myofibrils through the creatine kinase energy shuttle [13, 29]. In heart failure, all three of these components of metabolism are affected [29]. There is a reduction in substrate uptake, as fatty acid utilization is decreased in advanced heart failure, with rate of decrease correlating with progression of cardiac disease [30]. Glucose utilization is also decreased in cardiac failure, due to worsening insulin resistance in the myocardium and reduced expression of key factors involved in the transport and metabolism of pyruvate [30]. Oxidative phosphorylation is impaired due to cardiac mitochondrial abnormalities, resulting in decreased energy production [5, 29]. There is impairment in ATP synthase activity, as well as in electron transport chain complexes. When compared to normal cardiac function, ATP production can be reduced by at least 30% in advanced heart failure [5]. The level of uncoupling proteins is increased, which causes significant energy to be lost through heat rather than ATP production in the mitochondria [31].

Transport of energy to the cardiac myofibrils is also affected in heart failure. The decline in ATP transfer and utilization is due to a combination of decreased creatine kinase activity and depletion of high-energy phosphates [32]. This causes a decrease in energy delivery to the myofibrils by up to 71%, leading to loss of contractile function and loss of inotropic reserve with clinical manifestation of dyspnea on exertion [5]. Both the mitochondrial and myofibrillar creatine kinase activities are affected in heart failure [32]. Mitochondrial creatine kinase catalyzes the transfer of energy of high-energy phosphate from ATP to creatine, facilitating storage of energy in the form of phosphocreatine. Phosphocreatine can easily diffuse from mitochondria to myofibrils, where it is transformed back to ATP via the myofibrillar creatine kinase, but the failing heart displays lower levels of phosphocreatine than the normal heart [14, 33]. The assessment of cardiac energy metabolism is done using phosphorus-31 magnetic resonance spectroscopy that can detect levels of ATP and phosphocreatine [34]. Myocardial phosphocreatine/ATP ratio is reduced in cardiac failure and correlates with diastolic dysfunction, systolic dysfunction, and New York Heart Association classes [34].

At a molecular and genetic level, there are factors that affect the expression of genes that encode molecular regulators for energy metabolism. One of the main nuclear-receptor transcription factors is the peroxisome proliferator–activated receptor α (PPARα) that controls fatty acid oxidation. PPARα is reduced in heart failure, shifting cardiac energy utilization from fatty acid to glucose [35]. The deletion of PPARα gene resulted in decreased contractile reserve and depleted cardiac energy stores during inotropic challenge [36].

These intricate alterations in metabolism have been further studied to elucidate the role of various molecules in energy production and utilization during states of cardiac dysfunction. A study conducted by Bedi et al. (2016) aimed to further characterize the fatty acid utilization and carbohydrate metabolism in patients with non-ischemic heart failure. The results from this study indicate a reduction in concentrations of lipid intermediates, and instead a reliance on ketone utilization to fuel the failing heart [30]. This conclusion aligns with the above-discussed components of the compromised cardiac energy metabolism pathway in heart failure. More specifically, the reliance on ketone bodies as a source of energy stems from observed findings in heart failure regarding a decrease in fatty acid and glucose utilization, ATP synthase and respiratory chain complexes activities, PPARα, ATP synthase, phosphocreatine, creatine kinase activity, and ATP transfer [29–31, 34, 36].

Understanding how the three main components of energy metabolism are affected in patients with heart failure may have clinical and therapeutic implications, and metabolic therapy is a promising treatment of patients with heart failure: by modulation of substrate utilization, stimulation of oxidative phosphorylation, or manipulation of high-energy phosphate metabolites. Future studies are needed to explore possible therapeutic interventions to improve cardiac energy metabolism.

Evidence for Metabolic Biomarkers in Heart Failure

Metabolic biomarkers are of interest with heart failure as they can provide non-invasive data for both diagnosis and future prognosis. These can allow for earlier detection of the disease with the goal of improved morbidity and mortality. The main metabolic markers under study include nitric oxide, arginine, long-chain acylcarnitines, pentane, and ketones.

A study performed in 2011 by Janardhan et al. analyzed alterations in ketone body metabolism in advanced heart failure [37]. The study population consisted of 11 patients with advanced heart failure and 10 patients without heart failure undergoing electrophysiologic procedures. They evaluated ketone levels in both myocardial and skeletal muscle cells. Findings from the study indicate there is tissue-specific alteration in ketone utilization. There was noted impairment in ketone body metabolism in skeletal muscle cells. They posed the question of whether this dynamic alteration can be used as a biomarker for skeletal myopathy and progression of heart failure [37].

To further investigate this topic, Ho et al. (2019) utilized cardiac models in mice to study the contribution of this substrate in cardiac energy production and subsequent contractile efficiency [15]. Palmitate, glucose, and increasing concentrations of β-hydroxybutyrate were introduced to the cardiac models. Although ketones become the key source of energy for the failing heart, the increase in ketogenesis does not result in significant increase in cardiac work [15]. Thus, there was no increase in cardiac efficiency with sole reliance on ketones.

The reliance on ketone bodies as fuel, and the above conclusion that this substrate does not improve cardiac efficiency, points to a possible relationship between ketosis and heart failure progression. In a study examining the trend of blood ketones in 45 patients with chronic heart failure compared to 14 individuals without cardiac dysfunction, there were significantly elevated blood ketone bodies in heart failure (median 267 µmol/L) compared to normal subjects (median 150 µmol/L). There was found to be an association between ketone bodies and pulmonary artery wedge pressures, left ventricular ejection fraction, right atrial pressure, and circulating free fatty acids [20]. It was discovered that this metabolite was elevated in heart failure and that the degree of elevation was proportional to the severity of cardiac dysfunction [20]. These findings were re-demonstrated by Aubert et al. (2017); quantitative mitochondrial proteomics were used to study metabolic derangements in mouse models for heart failure [21]. Compared to the control group, the mice in the heart failure group had higher concentrations of ketone body utilization. This study demonstrated the reliance on this form of energy when cardiac function is compromised and the heart begins undergoing cardiac remodeling [21].

These studies help demonstrate the role of ketone bodies in the failing heart. As cardiac function worsens in the setting of pressure or volume overload, there is a reliance on generation of ketones as alternative fuel source. Unfortunately, this source of energy is not ideal, and it does not bode well for cardiac efficiency. Although not the most efficient pathway for the heart, the lack of ketone body generation at the same time can result in quicker onset of heart failure. Because of this intricate relationship, ketone bodies may potentially serve as metabolic biomarkers for heart failure. The degree of elevation in this substrate may be a marker of worsening cardiac function.

Regarding possible therapeutic approaches and targets, a study investigated TCA cycle intermediate levels in the failing hearts of mice. Investigators found not only that succinyl CoA levels were lower in the hearts of mice with ischemic cardiomyopathy, but dietary addition of 5-aminolevulinic acid can restore succinyl CoA levels and was shown to provide beneficial cardiac reverse remodeling [38]. Exercise tolerance and objective cardiac systolic function was improved with this dietary addition. It is reasonable to conclude that addition of dietary supplementation to the altered biochemistry of individuals with heart failure is a promising treatment avenue yet to be fully explored. But what about the ketones that the human body forms naturally?

Endogenous ketones, namely BHB that is formed in abundance during the very-low-carbohydrate intake diet (ketogenic diet [KD]), provide a different avenue for exploration with regards to heart failure treatment. Limitations to this form of treatment exist, including dietary adherence, increased LDL and triglyceride levels, transient endothelial dysfunction, and risk of lipotoxicity hinder KD as a viable, long-term, durable treatment for heart failure [39–41]. Additionally, the lipolysis that is characteristic of KD may worsen myocardial perfusion, which would be especially harmful for patients with ischemic cardiomyopathy or underlying microvascular dysfunction [41].

Exogenous ketones, supplemented to highlight the metabolic changes of heart failure, has yielded another area of scientific progress in this field. A small study analyzed cardiovascular changes in 16 patients admitted with HFrEF were administered an intravenous exogenous ketone ester, 3-hydroxybutyrate (3-OHB) or placebo. Increases in heart rate, stroke volume, and cardiac output were observed in the patients who received 3-OHB infusion [42]. Another study, recently published in Circulation, investigated dietary addition of an exogenous ketone ester, 3-hydroxybutyrate (3-OHB), in patients with chronic ambulatory heart failure with reduced ejection fraction (HFrEF). Subjects were given a 3-OHB supplement or isocaloric placebo drink with subsequent washout period, then sequence-controlled switched between treatment arms. It was found that 3-OHB supplementation resulted in mildly increased left ventricular ejection fraction, increased cardiac output, decreased ventricular filling pressure, and decreased NT pro-BNP levels when compared to the same subjects after placebo supplementation [43]. These new findings underscore the importance of understanding the role of ketone supplementation in HFrEF given that we have growing evidence of reverse remodeling among patients with chronic heart failure.

The role of sodium-glucose contransporter-1 and sodium-glucose cotransporter-2 (SGLT2) inhibitors provides another area for future study in the field of ketone metabolism in heart failure. There has been consistent data to support increased ketogenesis with multiple of the SGLT2-i’s; however, whether this increased ketosis is partially responsible for the reverse remodeling and mortality benefit seen with SGLT-2i use in patients with heart failure is yet to be elucidated [44–47].

Conclusion

Metabolic adaptations are critical in the ability of the human heart to provide a cardiac output, commensurate with the needs of the body under conditions of physiologic and pathologic stress. We know that the mammalian heart is capable of switching from utilization of one substrate to another, depending on conditions of physiologic demand with exercise, fasting, and abnormal management of fuel access. The failing human heart can rely on ketones in order to adapt to the known bioenergetic deficit in heart failure [30]. It is thus not surprising that ketone pathway elements can be invoked to understand, risk stratify, and treat cardiovascular disease.

Recent research has shown that acute nutritional ketosis via dietary supplementation of ketone esters can improve exercise tolerance and cardiac performance in performance athletes [48]. Given the reliance on ketone bodies for the failing heart, perhaps nutritional ketosis in patients with heart failure would provide necessary substrate to support the altered metabolism.

Or would it further the downward spiral of cardiac remodeling?

Research is needed to answer these questions and improve outcomes as heart failure is a devastating syndrome for patients, families, and society.

Author Contributions

M.F., J.R., P.K., A.A., A.E., and JER wrote the main manuscript text; M.F., J.R., and JER performed editing and formatting. All authors reviewed the manuscript before submission.

Funding

The authors have no sources of funding for this research to declare.

Data Availability

No datasets were generated or analysed during the current study.

Code Availability

Not applicable.

Declarations

Ethics Approval and Consent to Participate

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This study did not require institutional review board approval as it is a meta-analysis. This article does not contain any studies with animals performed by any of the authors.

Consent for Publication

Not applicable.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Competing Interests

The authors declare no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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References

1. Tanai E Frantz S Pathophysiology of heart failure Compr Physiol 2015 6 1 187 214 10.1002/cphy.c140055 26756631
Tanai E, Frantz S. Pathophysiology of heart failure. Compr Physiol. 2015;6(1):187–214.26756631
2. Malik A, Brito D, Vaqar S, Chhabra L. Congestive heart failure. StatPearls. Treasure Island (FL); 2024.
3. Taegtmeyer H Young ME Lopaschuk GD Assessing Cardiac Metabolism: A Scientific Statement from the American Heart Association Circ Res 2016 118 10 1659 701 10.1161/RES.0000000000000097 27012580
Taegtmeyer H, Young ME, Lopaschuk GD, et al. Assessing Cardiac Metabolism: A Scientific Statement from the American Heart Association. Circ Res. 2016;118(10):1659–701.27012580
4. Tsao CW Aday AW Almarzooq ZI Heart Disease and Stroke Statistics-2023 update: a Report from the American Heart Association Circulation 2023 147 8 e93 621 10.1161/CIR.0000000000001123 36695182
Tsao CW, Aday AW, Almarzooq ZI, et al. Heart Disease and Stroke Statistics-2023 update: a Report from the American Heart Association. Circulation. 2023;147(8):e93–621.36695182
5. Neubauer S The failing heart–an engine out of fuel N Engl J Med 2007 356 11 1140 51 10.1056/NEJMra063052 17360992
Neubauer S. The failing heart–an engine out of fuel. N Engl J Med. 2007;356(11):1140–51.17360992
6. Siranart N Chokesuwattanaskul R Prasitlumkum N Reverse of left ventricular remodeling in heart failure patients with left bundle branch area pacing: systematic review and meta-analysis Pacing Clin Electrophysiol 2023 46 6 459 66 10.1111/pace.14661 36633357
Siranart N, Chokesuwattanaskul R, Prasitlumkum N, et al. Reverse of left ventricular remodeling in heart failure patients with left bundle branch area pacing: systematic review and meta-analysis. Pacing Clin Electrophysiol. 2023;46(6):459–66.36633357
7. Ha J Lee CJ Oh J Park S Lee SH Kang SM The Association between On-treatment Ambulatory Central Blood pressure and left ventricular reverse remodeling in heart failure with reduced ejection fraction Int J Heart Fail 2023 5 3 150 8 10.36628/ijhf.2023.0004 37554693
Ha J, Lee CJ, Oh J, Park S, Lee SH, Kang SM. The Association between On-treatment Ambulatory Central Blood pressure and left ventricular reverse remodeling in heart failure with reduced ejection fraction. Int J Heart Fail. 2023;5(3):150–8.37554693
8. Nishihara Y Nishimori M Sawa T Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure Heart Vessels 2024 39 2 95 104 10.1007/s00380-023-02311-3 37733071
Nishihara Y, Nishimori M, Sawa T, et al. Left ventricular reverse remodeling following initiation of sacubitril/valsartan for heart failure with reduced ejection fraction and low blood pressure. Heart Vessels. 2024;39(2):95–104.37733071
9. Rame JE Chronic heart failure: a reversible metabolic syndrome? Circulation 2012 125 23 2809 11 10.1161/CIRCULATIONAHA.112.108316 22586280
Rame JE. Chronic heart failure: a reversible metabolic syndrome? Circulation. 2012;125(23):2809–11.22586280
10. Arfaras-Melainis A Ventoulis I Polyzogopoulou E Boultadakis A Parissis J The current and future status of inotropes in heart failure management Expert Rev Cardiovasc Ther 2023 21 8 573 85 10.1080/14779072.2023.2237869 37458248
Arfaras-Melainis A, Ventoulis I, Polyzogopoulou E, Boultadakis A, Parissis J. The current and future status of inotropes in heart failure management. Expert Rev Cardiovasc Ther. 2023;21(8):573–85.37458248
11. Heidenreich PA Bozkurt B Aguilar D 2022 AHA/ACC/HFSA Guideline for the management of Heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice guidelines J Am Coll Cardiol 2022 79 17 1757 80 10.1016/j.jacc.2021.12.011 35379504
Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the management of Heart failure: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice guidelines. J Am Coll Cardiol. 2022;79(17):1757–80.35379504
12. Packer M Carver JR Rodeheffer RJ Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group N Engl J Med 1991 325 21 1468 75 10.1056/NEJM199111213252103 1944425
Packer M, Carver JR, Rodeheffer RJ, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325(21):1468–75.1944425
13. Berne RM Cardiovascular Physiology Annu Rev Physiol 1981 43 1 357 8 10.1146/annurev.ph.43.030181.002041
Berne RM. Cardiovascular Physiology. Annu Rev Physiol. 1981;43(1):357–8.
14. Glatz JFC Nabben M Young ME Schulze PC Taegtmeyer H Luiken J Re-balancing cellular energy substrate metabolism to mend the failing heart Biochim Biophys Acta Mol Basis Dis 2020 1866 5 165579 10.1016/j.bbadis.2019.165579 31678200
Glatz JFC, Nabben M, Young ME, Schulze PC, Taegtmeyer H, Luiken J. Re-balancing cellular energy substrate metabolism to mend the failing heart. Biochim Biophys Acta Mol Basis Dis. 2020;1866(5):165579.31678200
15. Ho KL Zhang L Wagg C Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency Cardiovasc Res 2019 115 11 1606 16 10.1093/cvr/cvz045 30778524
Ho KL, Zhang L, Wagg C, et al. Increased ketone body oxidation provides additional energy for the failing heart without improving cardiac efficiency. Cardiovasc Res. 2019;115(11):1606–16.30778524
16. Cahill GF Jr. Starvation in man Clin Endocrinol Metab 1976 5 2 397 415 10.1016/S0300-595X(76)80028-X 182420
Cahill GF. Jr. Starvation in man. Clin Endocrinol Metab. 1976;5(2):397–415.182420
17. 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 70 3 243 51 10.1016/j.plefa.2003.11.001
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;70(3):243–51.
18. Puchalska P Crawford PA Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics Cell Metab 2017 25 2 262 84 10.1016/j.cmet.2016.12.022 28178565
Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 2017;25(2):262–84.28178565
19. Abdul Kadir A Clarke K Evans RD Cardiac ketone body metabolism Biochim Biophys Acta Mol Basis Dis 2020 1866 6 165739 10.1016/j.bbadis.2020.165739 32084511
Abdul Kadir A, Clarke K, Evans RD. Cardiac ketone body metabolism. Biochim Biophys Acta Mol Basis Dis. 2020;1866(6):165739.32084511
20. Lommi J Koskinen P Naveri H Harkonen M Kupari M Heart failure ketosis J Intern Med 1997 242 3 231 8 10.1046/j.1365-2796.1997.00187.x 9350168
Lommi J, Koskinen P, Naveri H, Harkonen M, Kupari M. Heart failure ketosis. J Intern Med. 1997;242(3):231–8.9350168
21. Aubert G Martin OJ Horton JL The failing heart relies on Ketone bodies as a fuel Circulation 2016 133 8 698 705 10.1161/CIRCULATIONAHA.115.017355 26819376
Aubert G, Martin OJ, Horton JL, et al. The failing heart relies on Ketone bodies as a fuel. Circulation. 2016;133(8):698–705. This benchtop research confirmed the use of ketones by failing cardiac tissue. This spurred on the recent trend in researching possible therapeutic applications of ketones in heart failure.26819376
22. Taegtmeyer H Hems R Krebs HA Utilization of energy-providing substrates in the isolated working rat heart Biochem J 1980 186 3 701 11 10.1042/bj1860701 6994712
Taegtmeyer H, Hems R, Krebs HA. Utilization of energy-providing substrates in the isolated working rat heart. Biochem J. 1980;186(3):701–11.6994712
23. 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 2 384 90 10.1172/JCI115008 1671390
Russell RR 3rd, 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(2):384–90.1671390
24. Taegtmeyer H 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 4 435 50 10.1007/BF02070167 6626122
Taegtmeyer H. 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(4):435–50.6626122
25. Russell RR Taegtmeyer H Coenzyme A sequestration in rat hearts oxidizing ketone bodies J Clin Invest 1992 89 3 968 73 10.1172/JCI115679 1541685
Russell RR 3rd, Taegtmeyer H. Coenzyme A sequestration in rat hearts oxidizing ketone bodies. J Clin Invest. 1992;89(3):968–73.1541685
26. Russell RR Taegtmeyer H Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate Am J Physiol 1991 261 6 Pt 2 H1756 62 1750532
Russell RR 3rd, Taegtmeyer H. Pyruvate carboxylation prevents the decline in contractile function of rat hearts oxidizing acetoacetate. Am J Physiol. 1991;261(6 Pt 2):H1756–62.1750532
27. Uchihashi M, Hoshino A, Okawa Y et al. Cardiac-specific Bdh1 overexpression ameliorates oxidative stress and Cardiac Remodeling in pressure overload-Induced Heart failure. Circ Heart Fail 2017; 10(12).
28. Schugar RC Moll AR Andre d’Avignon D Weinheimer CJ Kovacs A Crawford PA Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling Mol Metab 2014 3 7 754 69 10.1016/j.molmet.2014.07.010 25353003
Schugar RC, Moll AR, Andre d’Avignon D, Weinheimer CJ, Kovacs A, Crawford PA. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol Metab. 2014;3(7):754–69.25353003
29. Doenst T Nguyen TD Abel ED Cardiac metabolism in heart failure: implications beyond ATP production Circ Res 2013 113 6 709 24 10.1161/CIRCRESAHA.113.300376 23989714
Doenst T, Nguyen TD, Abel ED. Cardiac metabolism in heart failure: implications beyond ATP production. Circ Res. 2013;113(6):709–24.23989714
30. Bedi KC Jr Snyder NW Brandimarto J Evidence for Intramyocardial Disruption of Lipid Metabolism and increased myocardial ketone utilization in Advanced Human Heart failure Circulation 2016 133 8 706 16 10.1161/CIRCULATIONAHA.115.017545 26819374
Bedi KC Jr., Snyder NW, Brandimarto J, et al. Evidence for Intramyocardial Disruption of Lipid Metabolism and increased myocardial ketone utilization in Advanced Human Heart failure. Circulation. 2016;133(8):706–16.26819374
31. Busiello RA Savarese S Lombardi A Mitochondrial uncoupling proteins and energy metabolism Front Physiol 2015 6 36 10.3389/fphys.2015.00036 25713540
Busiello RA, Savarese S, Lombardi A. Mitochondrial uncoupling proteins and energy metabolism. Front Physiol. 2015;6:36.25713540
32. Del Franco A Ambrosio G Baroncelli L Creatine deficiency and heart failure Heart Fail Rev 2022 27 5 1605 16 10.1007/s10741-021-10173-y 34618287
Del Franco A, Ambrosio G, Baroncelli L, et al. Creatine deficiency and heart failure. Heart Fail Rev. 2022;27(5):1605–16.34618287
33. Guzun R Timohhina N Tepp K Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function Amino Acids 2011 40 5 1333 48 10.1007/s00726-011-0854-x 21390528
Guzun R, Timohhina N, Tepp K, et al. Systems bioenergetics of creatine kinase networks: physiological roles of creatine and phosphocreatine in regulation of cardiac cell function. Amino Acids. 2011;40(5):1333–48.21390528
34. Neubauer S Horn M Cramer M Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy Circulation 1997 96 7 2190 6 10.1161/01.CIR.96.7.2190 9337189
Neubauer S, Horn M, Cramer M, et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation. 1997;96(7):2190–6.9337189
35. Oka S Zhai P Yamamoto T Peroxisome Proliferator Activated Receptor-Alpha Association with Silent Information Regulator 1 suppresses cardiac fatty acid metabolism in the failing heart Circ Heart Fail 2015 8 6 1123 32 10.1161/CIRCHEARTFAILURE.115.002216 26443578
Oka S, Zhai P, Yamamoto T, et al. Peroxisome Proliferator Activated Receptor-Alpha Association with Silent Information Regulator 1 suppresses cardiac fatty acid metabolism in the failing heart. Circ Heart Fail. 2015;8(6):1123–32.26443578
36. Luptak I Balschi JA Xing Y Leone TC Kelly DP Tian R Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization Circulation 2005 112 15 2339 46 10.1161/CIRCULATIONAHA.105.534594 16203912
Luptak I, Balschi JA, Xing Y, Leone TC, Kelly DP, Tian R. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation. 2005;112(15):2339–46.16203912
37. Janardhan A Chen J Crawford PA Altered systemic ketone body metabolism in advanced heart failure Tex Heart Inst J 2011 38 5 533 8 22163128
Janardhan A, Chen J, Crawford PA. Altered systemic ketone body metabolism in advanced heart failure. Tex Heart Inst J. 2011;38(5):533–8.22163128
38. Takada S Maekawa S Furihata T Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure Proc Natl Acad Sci U S A 2022 119 41 e2203628119 10.1073/pnas.2203628119 36201541
Takada S, Maekawa S, Furihata T, et al. Succinyl-CoA-based energy metabolism dysfunction in chronic heart failure. Proc Natl Acad Sci U S A. 2022;119(41):e2203628119.36201541
39. Foster GD Wyatt HR Hill JO Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial Ann Intern Med 2010 153 3 147 57 10.7326/0003-4819-153-3-201008030-00005 20679559
Foster GD, Wyatt HR, Hill JO, et al. Weight and metabolic outcomes after 2 years on a low-carbohydrate versus low-fat diet: a randomized trial. Ann Intern Med. 2010;153(3):147–57.20679559
40. Buscemi S Verga S Tranchina MR Cottone S Cerasola G Effects of hypocaloric very-low-carbohydrate diet vs. Mediterranean diet on endothelial function in obese women* Eur J Clin Invest 2009 39 5 339 47 10.1111/j.1365-2362.2009.02091.x 19302563
Buscemi S, Verga S, Tranchina MR, Cottone S, Cerasola G. Effects of hypocaloric very-low-carbohydrate diet vs. Mediterranean diet on endothelial function in obese women*. Eur J Clin Invest. 2009;39(5):339–47.19302563
41. Karwi QG Biswas D Pulinilkunnil T Lopaschuk GD Myocardial ketones Metabolism in Heart failure J Card Fail 2020 26 11 998 1005 10.1016/j.cardfail.2020.04.005 32442517
Karwi QG, Biswas D, Pulinilkunnil T, Lopaschuk GD. Myocardial ketones Metabolism in Heart failure. J Card Fail. 2020;26(11):998–1005.32442517
42. Nielsen R, Møller N, Gormsen LC et al. Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients. Circulation. 2019;139(18):2129–2141. This was the original, small-scale research study that analyzed the possible impact of intravenous ketone supplementation in patients with heart failure. This study demonstrated possible benefits in multiple areas of cardiovascular function.
43. Berg-Hansen K, Gopalasingam N, Christensen KH et al. Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial. Circulation 2024; 149(19): 1474-89. This is a recent, seminal randomized control trial that analyzed whether dietary supplementation ketones has benefits to cardiovascular function in heart failure. The results of this study will encourage more research in the developing field of myocardial metabolism.
44. Daniele G Xiong J Solis-Herrera C Merovci A Eldor R Tripathy D Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes Diabetes Care 2016 39 2036 41 10.2337/dc15-2688 27561923
Daniele G, Xiong J, Solis-Herrera C, Merovci A, Eldor R, Tripathy D, et al. Dapagliflozin enhances fat oxidation and ketone production in patients with type 2 diabetes. Diabetes Care. 2016;39:2036–41.27561923
45. Polidori D Iijima H Goda M Maruyama N Inagaki N Crawford PA Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin Diabetes Obes Metab 2018 20 1321 6 10.1111/dom.13224 29341404
Polidori D, Iijima H, Goda M, Maruyama N, Inagaki N, Crawford PA. Intra- and inter-subject variability for increases in serum ketone bodies in patients with type 2 diabetes treated with the sodium glucose co-transporter 2 inhibitor canagliflozin. Diabetes Obes Metab. 2018;20:1321–6.29341404
46. Santos-Gallego CG Requena-Ibanez JA San Antonio R Ishikawa K Watanabe S Picatoste B Flores E Garcia-Ropero A Sanz J Hajjar RJ Fuster V Badimon JJ Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics J Am Coll Cardiol 2019 73 15 1931 44 10.1016/j.jacc.2019.01.056 30999996
Santos-Gallego CG, Requena-Ibanez JA, San Antonio R, Ishikawa K, Watanabe S, Picatoste B, Flores E, Garcia-Ropero A, Sanz J, Hajjar RJ, Fuster V, Badimon JJ. Empagliflozin ameliorates adverse left ventricular remodeling in nondiabetic heart failure by enhancing myocardial energetics. J Am Coll Cardiol. 2019;73(15):1931–44.30999996
47. Saucedo-Orozco H Voorrips SN Yurista SR de Boer RA Westenbrink BD SGLT2 inhibitors and Ketone Metabolism in Heart failure J Lipid Atheroscler 2022 11 1 1 19 10.12997/jla.2022.11.1.1 35118019
Saucedo-Orozco H, Voorrips SN, Yurista SR, de Boer RA, Westenbrink BD. SGLT2 inhibitors and Ketone Metabolism in Heart failure. J Lipid Atheroscler. 2022;11(1):1–19.35118019
48. Cox PJ Clarke K Acute nutritional ketosis: implications for exercise performance and metabolism Extrem Physiol Med 2014 3 17 10.1186/2046-7648-3-17 25379174
Cox PJ, Clarke K. Acute nutritional ketosis: implications for exercise performance and metabolism. Extrem Physiol Med. 2014;3:17.25379174
Key References

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(8):698–705.
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(18):2129–41.
Berg-Hansen K, Gopalasingam N, Christensen KH, Ladefoged B, Andersen MJ, Poulsen SH, et al. Cardiovascular Effects of oral Ketone Ester treatment in patients with heart failure with reduced ejection fraction: A randomized, controlled, double-blind trial. Circulation. 2024;149(19):1474–89.
