Cardiac metabolism is vital for heart function. Given that cardiac contraction requires a continuous supply of ATP in large quantities, the role of fuel metabolism in the heart has been mostly considered from the perspective of energy production. However, the consequence of metabolic remodelling in the failing heart is not limited to a compromised energy supply. The rewired metabolic network generates metabolites that can directly regulate signalling cascades, protein function, gene transcription and epigenetic modifications, thereby affecting the overall stress response of the heart. In addition, metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to the development of cardiac pathologies. In this Review, we first summarize how energy metabolism is altered in cardiac hypertrophy and heart failure of different aetiologies, followed by a discussion of emerging concepts in cardiac metabolic remodelling, that is, the non-energy-generating function of metabolism. We highlight challenges and open questions in these areas and finish with a brief perspective on how mechanistic research can be translated into therapies for heart failure.
Substrate preference in the heart changes in response to environmental stress and occurs in physiological and pathological hypertrophy.
Metabolic remodelling coupled with mitochondrial dysfunction leads to energy starvation in the failing heart.
Rewiring of substrate metabolism contributes to the cardiac stress response via epigenomic and signalling mechanisms.
Metabolic changes in both cardiomyocytes and non-cardiomyocytes contribute to pathological remodelling of the heart.
The new paradigm for studying metabolic remodelling in heart failure faces challenges but also offers opportunities to develop novel therapies to treat heart failure.
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Barth, E., Stämmler, G., Speiser, B. & Schaper, J. Ultrastructural quantitation of mitochondria and myofilaments in cardiac muscle from 10 different animal species including man. J. Mol. Cell Cardiol. 24, 669–681 (1992).
Lopaschuk, G. D., Ussher, J. R., Folmes, C. D., Jaswal, J. S. & Stanley, W. C. Myocardial fatty acid metabolism in health and disease. Physiol. Rev. 90, 207–258 (2010).
Ritterhoff, J. & Tian, R. Metabolism in cardiomyopathy: every substrate matters. Cardiovasc. Res. 113, 411–421 (2017).
Lopaschuk, G. D., Karwi, Q. G., Tian, R., Wende, A. R. & Abel, E. D. Cardiac energy metabolism in heart failure. Circ. Res. 128, 1487–1513 (2021).
Keating, S. T. & El-Osta, A. Epigenetics and metabolism. Circ. Res. 116, 715–736 (2015).
Zhou, B. & Tian, R. Mitochondrial dysfunction in pathophysiology of heart failure. J. Clin. Invest. 128, 3716–3726 (2018).
Spinelli, J. B. & Haigis, M. C. The multifaceted contributions of mitochondria to cellular metabolism. Nat. Cell Biol. 20, 745–754 (2018).
Kolwicz, S. C. Jr, Purohit, S. & Tian, R. Cardiac metabolism and its interactions with contraction, growth, and survival of cardiomyocytes. Circ. Res. 113, 603–616 (2013).
Shao, D. & Tian, R. Glucose transporters in cardiac metabolism and hypertrophy. Compr. Physiol. 6, 331–351 (2015).
Gibb, A. A. & Hill, B. G. Metabolic coordination of physiological and pathological cardiac remodeling. Circ. Res. 123, 107–128 (2018).
Cotter, D. G., Schugar, R. C. & Crawford, P. A. Ketone body metabolism and cardiovascular disease. Am. J. Physiol. Heart Circ. Physiol. 304, H1060–H1076 (2013).
Ho, K. L. et al. Ketones can become the major fuel source for the heart but do not increase cardiac efficiency. Cardiovasc. Res. 117, 1178–1187 (2021).
Murashige, D. et al. Comprehensive quantification of fuel use by the failing and nonfailing human heart. Science 370, 364–368 (2020).
Mizuno, Y. et al. The diabetic heart utilizes ketone bodies as an energy source. Metabolism 77, 65–72 (2017).
Puchalska, P. & Crawford, P. A. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. Cell Metab. 25, 262–284 (2017).
Canto, C., Menzies, K. J. & Auwerx, J. NAD+ metabolism and the control of energy homeostasis: a balancing act between mitochondria and the nucleus. Cell Metab. 22, 31–53 (2015).
Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).
Neubauer, S. The failing heart — an engine out of fuel. N. Engl. J. Med. 356, 1140–1151 (2007).
Ingwall, J. S. ATP and the Heart (Kluwer AcademicPublishers, 2002).
Qiu, Y., Pan, X., Chen, Y. & Xiao, J. Hallmarks of exercised heart. J. Mol. Cell Cardiol. 164, 126–135 (2022).
Abel, E. D. & Doenst, T. Mitochondrial adaptations to physiological vs. pathological cardiac hypertrophy. Cardiovasc. Res. 90, 234–242 (2011).
Schannwell, C. M. et al. Left ventricular hypertrophy and diastolic dysfunction in healthy pregnant women. Cardiology 97, 73–78 (2002).
Fulghum, K. L. et al. Metabolic signatures of pregnancy-induced cardiac growth. Am. J. Physiol. Heart Circ. Physiol. 323, H146–H164 (2022).
Menendez-Montes, I. et al. Myocardial VHL-HIF signaling controls an embryonic metabolic switch essential for cardiac maturation. Dev. Cell 39, 724–739 (2016).
Holness, M. J., Changani, K. K. & Sugden, M. C. Progressive suppression of muscle glucose utilization during pregnancy. Biochem. J. 280, 549–552 (1991).
Sugden, M. C. & Holness, M. J. Control of muscle pyruvate oxidation during late pregnancy. FEBS Lett. 321, 121–126 (1993).
Sugden, M. C., Changani, K. K., Bentley, J. & Holness, M. J. Cardiac glucose metabolism during pregnancy. Biochem. Soc. Trans. 20, 195S (1992).
Liu, L. X. et al. PDK4 inhibits cardiac pyruvate oxidation in late pregnancy. Circ. Res. 121, 1370–1378 (2017).
Pinto, J. et al. Following healthy pregnancy by NMR metabolomics of plasma and correlation to urine. J. Proteome Res. 14, 1263–1274 (2015).
Gibb, A. A. et al. Exercise-induced changes in glucose metabolism promote physiological cardiac growth. Circulation 136, 2144–2157 (2017).
Li, F. H. et al. Cardiac basal autophagic activity and increased exercise capacity. J. Physiol. Sci. 68, 729–742 (2018).
White, F. C. et al. Adaptation of the left ventricle to exercise-induced hypertrophy. J. Appl. Physiol. 62, 1097–1110 (1987).
Riehle, C. et al. Insulin receptor substrates are essential for the bioenergetic and hypertrophic response of the heart to exercise training. Mol. Cell Biol. 34, 3450–3460 (2014).
Burelle, Y. et al. Regular exercise is associated with a protective metabolic phenotype in the rat heart. Am. J. Physiol. Heart Circ. Physiol. 287, H1055–H1063 (2004).
Lai, L. et al. Energy metabolic reprogramming in the hypertrophied and early stage failing heart: a multisystems approach. Circ. Heart Fail. 7, 1022–1031 (2014).
Regitz-Zagrosek, V. & Kararigas, G. Mechanistic pathways of sex differences in cardiovascular disease. Physiol. Rev. 97, 1–37 (2017).
Dunlay, S. M., Roger, V. L. & Redfield, M. M. Epidemiology of heart failure with preserved ejection fraction. Nat. Rev. Cardiol. 14, 591–602 (2017).
Walker, C. J., Schroeder, M. E., Aguado, B. A., Anseth, K. S. & Leinwand, L. A. Matters of the heart: cellular sex differences. J. Mol. Cell Cardiol. 160, 42–55 (2021).
Ritterhoff, J. et al. Increasing fatty acid oxidation elicits a sex-dependent response in failing mouse hearts. J. Mol. Cell Cardiol. 158, 1–10 (2021).
Kararigas, G. et al. Comparative proteomic analysis reveals sex and estrogen receptor beta effects in the pressure overloaded heart. J. Proteome Res. 13, 5829–5836 (2014).
Fliegner, D. et al. Female sex and estrogen receptor-beta attenuate cardiac remodeling and apoptosis in pressure overload. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R1597–R1606 (2010).
Naumenko, N. et al. PGC-1alpha deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice. Cardiovasc. Res. 118, 1520–1534 (2022).
Cao, Y. et al. Sex differences in heart mitochondria regulate diastolic dysfunction. Nat. Commun. 13, 3850 (2022).
Bloom, M. W. et al. Heart failure with reduced ejection fraction. Nat. Rev. Dis. Prim. 3, 17058 (2017).
Nagueh, S. F. et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J. Am. Soc. Echocardiogr. 29, 277–314 (2016).
Mishra, S. & Kass, D. A. Cellular and molecular pathobiology of heart failure with preserved ejection fraction. Nat. Rev. Cardiol. 18, 400–423 (2021).
Kitzman, D. W. & Shah, S. J. The HFpEF obesity phenotype: the elephant in the room. J. Am. Coll. Cardiol. 68, 200–203 (2016).
Gibb, A. A. et al. Molecular signature of HFpEF: systems biology in a cardiac-centric large animal model. JACC Basic Transl. Sci. 6, 650–672 (2021).
Deng, Y. et al. Targeting mitochondria-inflammation circuit by beta-hydroxybutyrate mitigates HFpEF. Circ. Res. 128, 232–245 (2021).
Tong, D. et al. NAD+ repletion reverses heart failure with preserved ejection fraction. Circ. Res. 128, 1629–1641 (2021).
Yoshii, A. & Tian, R. Remodeling of cardiac metabolism in heart failure with preserved ejection fraction. Curr. Opin. Physiol. 27, 100559 (2022).
Neglia, D. et al. Impaired myocardial metabolic reserve and substrate selection flexibility during stress in patients with idiopathic dilated cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 293, H3270–H3278 (2007).
Rosenblatt-Velin, N., Montessuit, C., Papageorgiou, I., Terrand, J. & Lerch, R. Postinfarction heart failure in rats is associated with upregulation of GLUT-1 and downregulation of genes of fatty acid metabolism. Cardiovasc. Res. 52, 407–416 (2001).
Sack, M. N. et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94, 2837–2842 (1996).
Osorio, J. C. et al. Impaired myocardial fatty acid oxidation and reduced protein expression of retinoid X receptor-alpha in pacing-induced heart failure. Circulation 106, 606–612 (2002).
Grover-McKay, M. et al. Regional myocardial blood flow and metabolism at rest in mildly symptomatic patients with hypertrophic cardiomyopathy. J. Am. Coll. Cardiol. 13, 317–324 (1989).
Kato, T. et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ. Heart Fail. 3, 420–430 (2010).
Taylor, M. et al. 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. 42, 55–62 (2001).
Funada, J. et al. Substrate utilization by the failing human heart by direct quantification using arterio-venous blood sampling. PLoS ONE 4, e7533 (2009).
Voros, G. et al. Increased cardiac uptake of ketone bodies and free fatty acids in human heart failure and hypertrophic left ventricular remodeling. Circ. Heart Fail. 11, e004953 (2018).
Davila-Roman, V. G. et al. Altered myocardial fatty acid and glucose metabolism in idiopathic dilated cardiomyopathy. J. Am. Coll. Cardiol. 40, 271–277 (2002).
Tuunanen, H. et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 114, 2130–2137 (2006).
O’Donnell, J. M., Fields, A. D., Sorokina, N. & Lewandowski, E. D. The absence of endogenous lipid oxidation in early stage heart failure exposes limits in lipid storage and turnover. J. Mol. Cell Cardiol. 44, 315–322 (2008).
Lahey, R., Wang, X., Carley, A. N. & Lewandowski, E. D. Dietary fat supply to failing hearts determines dynamic lipid signaling for nuclear receptor activation and oxidation of stored triglyceride. Circulation 130, 1790–1799 (2014).
Flam, E. et al. Integrated landscape of cardiac metabolism in end-stage human nonischemic dilated cardiomyopathy. Nat. Cardiovasc. Res. 1, 817–829 (2022).
Allard, M. F., Schonekess, B. O., Henning, S. L., English, D. R. & Lopaschuk, G. D. Contribution of oxidative metabolism and glycolysis to ATP production in hypertrophied hearts. Am. J. Physiol. 267, H742–H750 (1994).
Ritterhoff, J. et al. Metabolic remodeling promotes cardiac hypertrophy by directing glucose to aspartate biosynthesis. Circ. Res. 126, 182–196 (2020).
Shao, D. et al. Glucose promotes cell growth by suppressing branched-chain amino acid degradation. Nat. Commun. 9, 2935 (2018).
Zhou, B. et al. Upregulation of mitochondrial ATPase inhibitory factor 1 (ATPIF1) mediates increased glycolysis in mouse hearts. J. Clin. Invest. 132, e155333 (2022).
Recchia, F. A. et al. Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ. Res. 83, 969–979 (1998).
Zhang, L. et al. Cardiac insulin-resistance and decreased mitochondrial energy production precede the development of systolic heart failure after pressure-overload hypertrophy. Circ. Heart Fail. 6, 1039–1048 (2013).
Mori, J. et al. ANG II causes insulin resistance and induces cardiac metabolic switch and inefficiency: a critical role of PDK4. Am. J. Physiol. Heart Circ. Physiol. 304, H1103–H1113 (2013).
Zhabyeyev, P. et al. Pressure-overload-induced heart failure induces a selective reduction in glucose oxidation at physiological afterload. Cardiovasc. Res. 97, 676–685 (2013).
Schroeder, M. A. et al. Hyperpolarized 13C magnetic resonance reveals early- and late-onset changes to in vivo pyruvate metabolism in the failing heart. Eur. J. Heart Fail. 15, 130–140 (2013).
Sorokina, N. et al. Recruitment of compensatory pathways to sustain oxidative flux with reduced carnitine palmitoyltransferase I activity characterizes inefficiency in energy metabolism in hypertrophied hearts. Circulation 115, 2033–2041 (2007).
Pound, K. M. et al. Substrate-enzyme competition attenuates upregulated anaplerotic flux through malic enzyme in hypertrophied rat heart and restores triacylglyceride content: attenuating upregulated anaplerosis in hypertrophy. Circ. Res. 104, 805–812 (2009).
Lahey, R. et al. Enhanced redox state and efficiency of glucose oxidation with miR based suppression of maladaptive NADPH-dependent malic enzyme 1 expression in hypertrophied hearts. Circ. Res. 122, 836–845 (2018).
Ruiz-Canela, M. et al. Plasma branched-chain amino acids and incident cardiovascular disease in the PREDIMED trial. Clin. Chem. 62, 582–592 (2016).
Magnusson, M. et al. A diabetes-predictive amino acid score and future cardiovascular disease. Eur. Heart J. 34, 1982–1989 (2013).
Bhattacharya, S. et al. Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. Atherosclerosis 232, 191–196 (2014).
Venturini, A. et al. The importance of myocardial amino acids during ischemia and reperfusion in dilated left ventricle of patients with degenerative mitral valve disease. Mol. Cell Biochem. 330, 63–70 (2009).
Murashige, D. et al. Extra-cardiac BCAA catabolism lowers blood pressure and protects from heart failure. Cell Metab. 34, 1749–1764.e1747 (2022).
Sun, H. et al. Catabolic defect of branched-chain amino acids promotes heart failure. Circulation 133, 2038–2049 (2016).
Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 133, 698–705 (2016).
Bedi, K. C. Jr et al. Evidence for intramyocardial disruption of lipid metabolism and increased myocardial ketone utilization in advanced human heart failure. Circulation 133, 706–716 (2016).
Herrero, P. et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J. Am. Coll. Cardiol. 47, 598–604 (2006).
Lopaschuk, G. D., Folmes, C. D. & Stanley, W. C. Cardiac energy metabolism in obesity. Circ. Res. 101, 335–347 (2007).
McGavock, J. M. et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116, 1170–1175 (2007).
Shao, D. et al. Increasing fatty acid oxidation prevents high-fat diet-induced cardiomyopathy through regulating parkin-mediated mitophagy. Circulation 142, 983–997 (2020).
Kolwicz, S. C. Jr. et al. Cardiac-specific deletion of acetyl CoA carboxylase 2 prevents metabolic remodeling during pressure-overload hypertrophy. Circ. Res. 111, 728–738 (2012).
Qian, N. & Wang, Y. Ketone body metabolism in diabetic and non-diabetic heart failure. Heart Fail. Rev. 25, 817–822 (2020).
Abdurrachim, D. et al. Empagliflozin reduces myocardial ketone utilization while preserving glucose utilization in diabetic hypertensive heart disease: a hyperpolarized 13C magnetic resonance spectroscopy study. Diabetes Obes. Metab. 21, 357–365 (2019).
Verma, S. et al. Empagliflozin increases cardiac energy production in diabetes: novel translational insights into the heart failure benefits of SGLT2 inhibitors. JACC Basic Transl. Sci. 3, 575–587 (2018).
Fillmore, N. et al. Uncoupling of glycolysis from glucose oxidation accompanies the development of heart failure with preserved ejection fraction. Mol. Med. 24, 3 (2018).
Phan, T. T. et al. Heart failure with preserved ejection fraction is characterized by dynamic impairment of active relaxation and contraction of the left ventricle on exercise and associated with myocardial energy deficiency. J. Am. Coll. Cardiol. 54, 402–409 (2009).
Mahmod, M. et al. The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction: a cardiovascular magnetic resonance study. J. Cardiovasc. Magn. Reson. 20, 88 (2018).
Burrage, M. K. et al. Energetic basis for exercise-induced pulmonary congestion in heart failure with preserved ejection fraction. Circulation 144, 1664–1678 (2021).
Doenst, T., Nguyen, T. D. & Abel, E. D. Cardiac metabolism in heart failure: implications beyond ATP production. Circ. Res. 113, 709–724 (2013).
Ingwall, J. S. & Weiss, R. G. Is the failing heart energy starved? On using chemical energy to support cardiac function. Circ. Res. 95, 135–145 (2004).
Tian, R., Nascimben, L., Ingwall, J. S. & Lorell, B. H. Failure to maintain a low ADP concentration impairs diastolic function in hypertrophied rat hearts. Circulation 96, 1313–1319 (1997).
Weiss, R. G., Gerstenblith, G. & Bottomley, P. A. ATP flux through creatine kinase in the normal, stressed, and failing human heart. Proc. Natl Acad. Sci. USA 102, 808–813 (2005).
Smith, C. S., Bottomley, P. A., Schulman, S. P., Gerstenblith, G. & Weiss, R. G. Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium. Circulation 114, 1151–1158 (2006).
DeBerardinis, R. J. & Keshari, K. R. Metabolic analysis as a driver for discovery, diagnosis, and therapy. Cell 185, 2678–2689 (2022).
Yoshii, A. & Tian, R. Deciphering metabolic remodeling of the failing hearts. Nat. Cardiovasc. Res. 1, 800–801 (2022).
Diakos, N. A. 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 Transl. Sci. 1, 432–444 (2016).
Lei, B. et al. Paradoxical downregulation of the glucose oxidation pathway despite enhanced flux in severe heart failure. J. Mol. Cell Cardiol. 36, 567–576 (2004).
Fernandez-Caggiano, M. et al. Mitochondrial pyruvate carrier abundance mediates pathological cardiac hypertrophy. Nat. Metab. 2, 1223–1231 (2020).
McCommis, K. S. et al. Nutritional modulation of heart failure in mitochondrial pyruvate carrier-deficient mice. Nat. Metab. 2, 1232–1247 (2020).
Cluntun, A. A. et al. The pyruvate–lactate axis modulates cardiac hypertrophy and heart failure. Cell Metab. 33, 629–648 e610 (2021).
Scarpulla, R. C., Vega, R. B. & Kelly, D. P. Transcriptional integration of mitochondrial biogenesis. Trends Endocrinol. Metab. 23, 459–466 (2012).
Previs, M. J. et al. Defects in the proteome and metabolome in human hypertrophic cardiomyopathy. Circ. Heart Fail. 15, e009521 (2022).
Djousse, L. et al. Plasma free fatty acids and risk of heart failure: the cardiovascular health study. Circ. Heart Fail. 6, 964–969 (2013).
Sharma, S. et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 18, 1692–1700 (2004).
Chokshi, A. et al. Ventricular assist device implantation corrects myocardial lipotoxicity, reverses insulin resistance, and normalizes cardiac metabolism in patients with advanced heart failure. Circulation 125, 2844–2853 (2012).
Haemmerle, G. et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat. Med. 17, 1076–1085 (2011).
Hahn, V. S. et al. Myocardial gene expression signatures in human heart failure with preserved ejection fraction. Circulation 143, 120–134 (2021).
Redondo-Angulo, I. et al. Fgf21 is required for cardiac remodeling in pregnancy. Cardiovasc. Res. 113, 1574–1584 (2017).
Cuevas-Ramos, D. et al. Exercise increases serum fibroblast growth factor 21 (FGF21) levels. PLoS ONE 7, e38022 (2012).
Obokata, M., Reddy, Y. N. V., Pislaru, S. V., Melenovsky, V. & Borlaug, B. A. Evidence supporting the existence of a distinct obese phenotype of heart failure with preserved ejection fraction. Circulation 136, 6–19 (2017).
Jin, L. et al. FGF21–sirtuin 3 axis confers the protective effects of exercise against diabetic cardiomyopathy by governing mitochondrial integrity. Circulation 146, 1537–1557 (2022).
Kolwicz, S. C. Jr., Airhart, S. & Tian, R. Ketones step to the plate: a game changer for metabolic remodeling in heart failure. Circulation 133, 689–691 (2016).
Paterson, P., Sheath, J., Taft, P. & Wood, C. Maternal and foetal ketone concentrations in plasma and urine. Lancet 1, 862–865 (1967).
Li, X. et al. Circulating metabolite homeostasis achieved through mass action. Nat. Metab. 4, 141–152 (2022).
Cook, G. A., Lavrentyev, E. N., Pham, K. & Park, E. A. Streptozotocin diabetes increases mRNA expression of ketogenic enzymes in the rat heart. Biochim. Biophys. Acta Gen. Subj. 1861, 307–312 (2017).
Caudal, A. et al. Mitochondrial interactome quantitation reveals structural changes in metabolic machinery in the failing murine heart. Nat. Cardiovasc. Res. 1, 855–866 (2022).
Horton, J. L. et al. The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense. JCI Insight 4, e12479 (2019).
Schugar, R. C. et al. Cardiomyocyte-specific deficiency of ketone body metabolism promotes accelerated pathological remodeling. Mol. Metab. 3, 754–769 (2014).
Sun, H., Lu, G., Ren, S., Chen, J. & Wang, Y. Catabolism of branched-chain amino acids in heart failure: insights from genetic models. Pediatr. Cardiol. 32, 305–310 (2011).
Backs, J. & Olson, E. N. Control of cardiac growth by histone acetylation/deacetylation. Circ. Res. 98, 15–24 (2006).
Keating, S. T. & El-Osta, A. Metaboloepigenetics in cancer, immunity and cardiovascular disease. Cardiovasc. Res. 119, 357–370 (2023).
McKinsey, T. A. Therapeutic potential for HDAC inhibitors in the heart. Annu. Rev. Pharmacol. Toxicol. 52, 303–319 (2012).
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).
Abdul Kadir, A., Clarke, K. & Evans, R. D. Cardiac ketone body metabolism. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165739 (2020).
Deb, D. K., Chen, Y., Sun, J., Wang, Y. & Li, Y. C. ATP-citrate lyase is essential for high glucose-induced histone hyperacetylation and fibrogenic gene upregulation in mesangial cells. Am. J. Physiol. Ren. Physiol. 313, F423–F429 (2017).
Kronlage, M. et al. O-GlcNAcylation of histone deacetylase 4 protects the diabetic heart from failure. Circulation 140, 580–594 (2019).
Martinez-Reyes, I. & Chandel, N. S. Mitochondrial TCA cycle metabolites control physiology and disease. Nat. Commun. 11, 102 (2020).
Lombardi, A. A. et al. Mitochondrial calcium exchange links metabolism with the epigenome to control cellular differentiation. Nat. Commun. 10, 4509 (2019).
Gibb, A. A. et al. Glutamine uptake and catabolism is required for myofibroblast formation and persistence. J. Mol. Cell Cardiol. 172, 78–89 (2022).
Khoury, G. A., Baliban, R. C. & Floudas, C. A. Proteome-wide post-translational modification statistics: frequency analysis and curation of the swiss-prot database. Sci. Rep. 1, 90 (2011).
Pietrocola, F., Galluzzi, L., Bravo-San Pedro, J. M., Madeo, F. & Kroemer, G. Acetyl coenzyme A: a central metabolite and second messenger. Cell Metab. 21, 805–821 (2015).
Campbell, S. L. & Wellen, K. E. Metabolic signaling to the nucleus in cancer. Mol. Cell 71, 398–408 (2018).
Karamanlidis, G. et al. Mitochondrial complex I deficiency increases protein acetylation and accelerates heart failure. Cell Metab. 18, 239–250 (2013).
Lee, C. F. et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883–894 (2016).
Walker, M. A. et al. Acetylation of muscle creatine kinase negatively impacts high-energy phosphotransfer in heart failure. JCI Insight 6, e144301 (2021).
Liu, X. et al. Mitochondrial protein hyperacetylation underpins heart failure with preserved ejection fraction in mice. J. Mol. Cell Cardiol. 165, 76–85 (2022).
Horton, J. L. et al. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 2, e84897 (2016).
Zhang, X. et al. MicroRNA-195 regulates metabolism in failing myocardium via alterations in sirtuin 3 expression and mitochondrial protein acetylation. Circulation 137, 2052–2067 (2018).
Wallner, M. et al. HDAC inhibition improves cardiopulmonary function in a feline model of diastolic dysfunction. Sci. Transl. Med. 12, eaay7205 (2020).
Davidson, M. T. et al. Extreme acetylation of the cardiac mitochondrial proteome does not promote heart failure. Circ. Res. 127, 1094–1108 (2020).
Yang, L. et al. The fasted/fed mouse metabolic acetylome: N6-acetylation differences suggest acetylation coordinates organ-specific fuel switching. J. Proteome Res. 10, 4134–4149 (2011).
Ketema, E. B. & Lopaschuk, G. D. Post-translational acetylation control of cardiac energy metabolism. Front. Cardiovasc. Med. 8, 723996 (2021).
Thapa, D. et al. Acetylation of mitochondrial proteins by GCN5L1 promotes enhanced fatty acid oxidation in the heart. Am. J. Physiol. Heart Circ. Physiol. 313, H265–H274 (2017).
Alrob, O. A. et al. Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc. Res. 103, 485–497 (2014).
Keceli, G. et al. Mitochondrial creatine kinase attenuates pathologic remodeling in heart failure. Circ. Res. 130, 741–759 (2022).
Hu, Y. et al. Adenovirus-mediated overexpression of O-GlcNAcase improves contractile function in the diabetic heart. Circ. Res. 96, 1006–1013 (2005).
Mailleux, F., Gelinas, R., Beauloye, C., Horman, S. & Bertrand, L. O-GlcNAcylation, enemy or ally during cardiac hypertrophy development? Biochim. Biophys. Acta 1862, 2232–2243 (2016).
Collins, H. E. & Chatham, J. C. Regulation of cardiac O-GlcNAcylation: more than just nutrient availability. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165712 (2020).
Lunde, I. G. et al. Cardiac O-GlcNAc signaling is increased in hypertrophy and heart failure. Physiol. Genomics 44, 162–172 (2012).
Watson, L. J. et al. O-linked beta-N-acetylglucosamine transferase is indispensable in the failing heart. Proc. Natl Acad. Sci. USA 107, 17797–17802 (2010).
Umapathi, P. et al. Excessive O-GlcNAcylation causes heart failure and sudden death. Circulation 143, 1687–1703 (2021).
Jensen, R. V., Andreadou, I., Hausenloy, D. J. & Bøtker, H. E. The role of O-GlcNAcylation for protection against ischemia-reperfusion injury. Int. J. Mol. Sci. 2, 404 (2019).
Hirschey, M. D. & Zhao, Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell Proteom. 14, 2308–2315 (2015).
Xin, Q. et al. Lactylation: a passing fad or the future of posttranslational modification. Inflammation 45, 1419–1429 (2022).
Ali, H. R. et al. Defining decreased protein succinylation of failing human cardiac myofibrils in ischemic cardiomyopathy. J. Mol. Cell Cardiol. 138, 304–317 (2020).
Wu, L. F. et al. Global profiling of protein lysine malonylation in mouse cardiac hypertrophy. J. Proteom. 266, 104667 (2022).
Kim, M. & Tian, R. Targeting AMPK for cardiac protection: opportunities and challenges. J. Mol. Cell Cardiol. 51, 548–553 (2011).
Li, J. et al. Activation of AMPK alpha- and gamma-isoform complexes in the intact ischemic rat heart. Am. J. Physiol. Heart Circ. Physiol. 291, H1927–H1934 (2006).
Musi, N. et al. Functional role of AMP-activated protein kinase in the heart during exercise. FEBS Lett. 579, 2045–2050 (2005).
Tian, R., Musi, N., D’Agostino, J., Hirshman, M. F. & Goodyear, L. J. Increased adenosine monophosphate-activated protein kinase activity in rat hearts with pressure-overload hypertrophy. Circulation 104, 1664–1669 (2001).
Cieslik, K. A. et al. AICAR-dependent AMPK activation improves scar formation in the aged heart in a murine model of reperfused myocardial infarction. J. Mol. Cell Cardiol. 63, 26–36 (2013).
Li, Y. et al. AMPK blunts chronic heart failure by inhibiting autophagy. Biosci. Rep. 38, BSR20170982 (2018).
Sen, S. et al. Glucose regulation of load-induced mTOR signaling and ER stress in mammalian heart. J. Am. Heart Assoc. 2, e004796 (2013).
Roberts, D. J., Tan-Sah, V. P., Ding, E. Y., Smith, J. M. & Miyamoto, S. Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition. Mol. Cell 53, 521–533 (2014).
Neishabouri, S. H., Hutson, S. M. & Davoodi, J. Chronic activation of mTOR complex 1 by branched chain amino acids and organ hypertrophy. Amino Acids 47, 1167–1182 (2015).
Foryst-Ludwig, A. et al. Adipose tissue lipolysis promotes exercise-induced cardiac hypertrophy involving the lipokine C16:1n7-palmitoleate. J. Biol. Chem. 290, 23603–23615 (2015).
Husted, A. S., Trauelsen, M., Rudenko, O., Hjorth, S. A. & Schwartz, T. W. GPCR-mediated signaling of metabolites. Cell Metab. 25, 777–796 (2017).
Hu, Q. et al. Genetically encoded biosensors for evaluating NAD+/NADH ratio in cytosolic and mitochondrial compartments. Cell Rep. Methods 1, 100116 (2021).
Pinto, A. R. et al. Revisiting cardiac cellular composition. Circ. Res. 118, 400–409 (2016).
Litvinukova, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020).
Zhou, P. & Pu, W. T. Recounting cardiac cellular composition. Circ. Res. 118, 368–370 (2016).
Gibb, A. A., Lazaropoulos, M. P. & Elrod, J. W. Myofibroblasts and fibrosis: mitochondrial and metabolic control of cellular differentiation. Circ. Res. 127, 427–447 (2020).
Travers, J. G., Kamal, F. A., Robbins, J., Yutzey, K. E. & Blaxall, B. C. Cardiac fibrosis: the fibroblast awakens. Circ. Res. 118, 1021–1040 (2016).
Negmadjanov, U. et al. TGF-beta1-mediated differentiation of fibroblasts is associated with increased mitochondrial content and cellular respiration. PLoS ONE 10, e0123046 (2015).
Jain, M. et al. Mitochondrial reactive oxygen species regulate transforming growth factor-beta signaling. J. Biol. Chem. 288, 770–777 (2013).
Chen, Z. T. et al. Glycolysis inhibition alleviates cardiac fibrosis after myocardial infarction by suppressing cardiac fibroblast activation. Front. Cardiovasc. Med. 8, 701745 (2021).
Ding, H. et al. Inhibiting aerobic glycolysis suppresses renal interstitial fibroblast activation and renal fibrosis. Am. J. Physiol. Ren. Physiol. 313, F561–F575 (2017).
Gibb, A. A. et al. Glutaminolysis is essential for myofibroblast persistence and in vivo targeting reverses fibrosis and cardiac dysfunction in heart failure. Circulation 145, 1625–1628 (2022).
Mathis, D. & Shoelson, S. E. Immunometabolism: an emerging frontier. Nat. Rev. Immunol. 11, 81 (2011).
Swirski, F. K. & Nahrendorf, M. Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat. Rev. Immunol. 18, 733–744 (2018).
Kelly, B. & O’Neill, L. A. Metabolic reprogramming in macrophages and dendritic cells in innate immunity. Cell Res. 25, 771–784 (2015).
Zhao, M., Wang, D. D., Liu, X. & Tian, R. Metabolic modulation of macrophage function post myocardial infarction. Front. Physiol. 11, 674 (2020).
Mouton, A. J. et al. Mapping macrophage polarization over the myocardial infarction time continuum. Basic Res. Cardiol. 113, 26 (2018).
Rodriguez-Prados, J. C. et al. Substrate fate in activated macrophages: a comparison between innate, classic, and alternative activation. J. Immunol. 185, 605–614 (2010).
Jha, A. K. et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity 42, 419–430 (2015).
Ryan, D. G. & O’Neill, L. A. J. Krebs cycle reborn in macrophage immunometabolism. Annu. Rev. Immunol. 38, 289–313 (2020).
Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).
Zhang, S. et al. Immunometabolism of phagocytes and relationships to cardiac repair. Front. Cardiovasc. Med. 6, 42 (2019).
Liu, P. S. et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).
Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nat. Immunol. 6, 1191–1197 (2005).
Park, D. et al. Continued clearance of apoptotic cells critically depends on the phagocyte Ucp2 protein. Nature 477, 220–224 (2011).
Cai, S. et al. Mitochondrial dysfunction in macrophages promotes inflammation and suppresses repair after myocardial infarction. J. Clin. Invest. 133, e159498 (2023).
Zhang, S. et al. Efferocytosis fuels requirements of fatty acid oxidation and the electron transport chain to polarize macrophages for tissue repair. Cell Metab. 29, 443–456.e445 (2019).
Weinberg, S. E. et al. Mitochondrial complex III is essential for suppressive function of regulatory T cells. Nature 565, 495–499 (2019).
Wu, J. et al. Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice. J. Mol. Cell Cardiol. 135, 134–148 (2019).
Li, X., Sun, X. & Carmeliet, P. Hallmarks of endothelial cell metabolism in health and disease. Cell Metab. 30, 414–433 (2019).
Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis. Cell 146, 873–887 (2011).
Mouton, A. J. et al. Fibroblast polarization over the myocardial infarction time continuum shifts roles from inflammation to angiogenesis. Basic Res. Cardiol. 114, 6 (2019).
Gogiraju, R., Bochenek, M. L. & Schafer, K. Angiogenic endothelial cell signaling in cardiac hypertrophy and heart failure. Front. Cardiovasc. Med. 6, 20 (2019).
De Bock, K. et al. Role of PFKFB3-driven glycolysis in vessel sprouting. Cell 154, 651–663 (2013).
Kim, B., Li, J., Jang, C. & Arany, Z. Glutamine fuels proliferation but not migration of endothelial cells. EMBO J. 36, 2321–2333 (2017).
Weis, E. M. et al. Ketone body oxidation increases cardiac endothelial cell proliferation. EMBO Mol. Med. 14, e14753 (2022).
Schoors, S. et al. Fatty acid carbon is essential for dNTP synthesis in endothelial cells. Nature 520, 192–197 (2015).
Trenson, S. et al. Cardiac microvascular endothelial cells in pressure overload–induced heart disease. Circ. Heart Fail. 14, e006979 (2021).
Lau, A. N. & Heiden, M. G. V. Metabolism in the tumor microenvironment. Annu. Rev. Cancer Biol. 4, 17–40 (2020).
Matejuk, A. & Ransohoff, R. M. Crosstalk between astrocytes and microglia: an overview. Front. Immunol. 11, 1416 (2020).
Bisbach, C. M. et al. Succinate can shuttle reducing power from the hypoxic retina to the O2-rich pigment epithelium. Cell Rep. 31, 107606 (2020).
Mehrotra, D., Wu, J., Papangeli, I. & Chun, H. J. Endothelium as a gatekeeper of fatty acid transport. Trends Endocrinol. Metab. 25, 99–106 (2014).
Coppiello, G. et al. Meox2/Tcf15 heterodimers program the heart capillary endothelium for cardiac fatty acid uptake. Circulation 131, 815–826 (2015).
Son, N. H. et al. Endothelial cell CD36 optimizes tissue fatty acid uptake. J. Clin. Invest. 128, 4329–4342 (2018).
Jang, C. et al. A branched-chain amino acid metabolite drives vascular fatty acid transport and causes insulin resistance. Nat. Med. 22, 421–426 (2016).
Cohen, D. M., Guthrie, P. H., Gao, X., Sakai, R. & Taegtmeyer, H. Glutamine cycling in isolated working rat heart. Am. J. Physiol. Endocrinol. Metab. 285, E1312–E1316 (2003).
Lauzier, B. et al. Metabolic effects of glutamine on the heart: anaplerosis versus the hexosamine biosynthetic pathway. J. Mol. Cell. Cardiol. 55, 92–100 (2013).
Yoo, H. C., Yu, Y. C., Sung, Y. & Han, J. M. Glutamine reliance in cell metabolism. Exp. Mol. Med. 52, 1496–1516 (2020).
Kuppe, C. et al. Spatial multi-omic map of human myocardial infarction. Nature 608, 766–777 (2022).
Pinckard, K. M. et al. A novel endocrine role for the BAT-released lipokine 12,13-diHOME to mediate cardiac function. Circulation 143, 145–159 (2021).
Lydell, C. P. et al. Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts. Cardiovasc. Res. 53, 841–851 (2002).
Bogh, N. et al. Increasing carbohydrate oxidation improves contractile reserves and prevents hypertrophy in porcine right heart failure. Sci. Rep. 10, 8158 (2020).
Wargovich, T. J. et al. Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am. J. Cardiol. 61, 65–70 (1988).
Lewis, J. F., DaCosta, M., Wargowich, T. & Stacpoole, P. Effects of dichloroacetate in patients with congestive heart failure. Clin. Cardiol. 21, 888–892 (1998).
Bersin, R. M. et al. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J. Am. Coll. Cardiol. 23, 1617–1624 (1994).
Abdelmalak, M. et al. Long-term safety of dichloroacetate in congenital lactic acidosis. Mol. Genet. Metab. 109, 139–143 (2013).
Tataranni, T. & Piccoli, C. Dichloroacetate (DCA) and cancer: an overview towards clinical applications. Oxid. Med. Cell Longev. 2019, 8201079 (2019).
Hayashida, W., van Eyll, C., Rousseau, M. F. & Pouleur, H. Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc. Drugs Ther. 8, 741–747 (1994).
Fragasso, G. et al. A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J. Am. Coll. Cardiol. 48, 992–998 (2006).
Fragasso, G. et al. Effect of partial fatty acid oxidation inhibition with trimetazidine on mortality and morbidity in heart failure: results from an international multicentre retrospective cohort study. Int. J. Cardiol. 163, 320–325 (2013).
Di Napoli, P., Di Giovanni, P., Gaeta, M. A., 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. 154, 602 e601–602 e605 (2007).
Tuunanen, H. et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation 118, 1250–1258 (2008).
Milinkovic, I., Rosano, G., Lopatin, Y. & Seferovic, P. M. The role of ivabradine and trimetazidine in the new ESC HF Guidelines. Card. Fail. Rev. 2, 123–129 (2016).
Lee, L. et al. Metabolic modulation with perhexiline in chronic heart failure: a randomized, controlled trial of short-term use of a novel treatment. Circulation 112, 3280–3288 (2005).
Gao, D., Ning, N., Niu, X., Hao, G. & Meng, Z. Trimetazidine: a meta-analysis of randomised controlled trials in heart failure. Heart 97, 278–286 (2011).
Schmidt-Schweda, S. & Holubarsch, C. First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin. Sci. 99, 27–35 (2000).
Holubarsch, C. J. et al. A double-blind randomized multicentre clinical trial to evaluate the efficacy and safety of two doses of etomoxir in comparison with placebo in patients with moderate congestive heart failure: the ERGO (etomoxir for the recovery of glucose oxidation) study. Clin. Sci. 113, 205–212 (2007).
Peng, S. et al. The efficacy of trimetazidine on stable angina pectoris: a meta-analysis of randomized clinical trials. Int. J. Cardiol. 177, 780–785 (2014).
Coats, C. J. et al. Effect of trimetazidine dihydrochloride therapy on exercise capacity in patients with nonobstructive hypertrophic cardiomyopathy: a randomized clinical trial. JAMA Cardiol. 4, 230–235 (2019).
Killalea, S. M. & Krum, H. Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease. Am. J. Cardiovasc. Drugs 1, 193–204 (2001).
Choi, Y. S. et al. Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion. J. Mol. Cell Cardiol. 100, 64–71 (2016).
Yurista, S. R. et al. Ketone ester treatment improves cardiac function and reduces pathologic remodeling in preclinical models of heart failure. Circ. Heart Fail. 14, e007684 (2021).
Takahara, S. et al. Chronic exogenous ketone supplementation blunts the decline of cardiac function in the failing heart. Esc. Heart Fail. 8, 5606–5612 (2021).
Gershuni, V. M., Yan, S. L. & Medici, V. Nutritional ketosis for weight management and reversal of metabolic syndrome. Curr. Nutr. Rep. 7, 97–106 (2018).
Monzo, L. et al. Myocardial ketone body utilization in patients with heart failure: the impact of oral ketone ester. Metabolism 115, 154452 (2021).
Nielsen, R. et al. Cardiovascular effects of treatment with the ketone body 3-hydroxybutyrate in chronic heart failure patients. Circulation 139, 2129–2141 (2019).
Saucedo-Orozco, H., Voorrips, S. N., Yurista, S. R., de Boer, R. A. & Westenbrink, B. D. SGLT2 Inhibitors and ketone metabolism in heart failure. J. Lipid Atheroscler. 11, 1–19 (2022).
van der Pol, A., van Gilst, W. H., Voors, A. A. & van der Meer, P. Treating oxidative stress in heart failure: past, present and future. Eur. J. Heart Fail. 21, 425–435 (2019).
Dey, S., DeMazumder, D., Sidor, A., Foster, D. B. & O’Rourke, B. Mitochondrial ROS drive sudden cardiac death and chronic proteome remodeling in heart failure. Circ. Res. 123, 356–371 (2018).
Graham, D. et al. Mitochondria-targeted antioxidant MitoQ10 improves endothelial function and attenuates cardiac hypertrophy. Hypertension 54, 322–328 (2009).
Manskikh, V. N. et al. Age-associated murine cardiac lesions are attenuated by the mitochondria-targeted antioxidant SkQ1. Histol. Histopathol. 30, 353–360 (2015).
US National Library of Medicine. ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT03960073 (2022).
US National Library of Medicine. ClinicalTrials.gov, https://www.clinicaltrials.gov/ct2/show/NCT05410873 (2022).
Chiao, Y. A. et al. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. eLife 9, e55513 (2020).
Szeto, H. H. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171, 2029–2050 (2014).
Butler, J. et al. Effects of elamipretide on left ventricular function in patients with heart failure with reduced ejection fraction: the PROGRESS-HF phase 2 trial. J. Card. Fail. 26, 429–437 (2020).
Diguet, N. et al. Nicotinamide riboside preserves cardiac function in a mouse model of dilated cardiomyopathy. Circulation 137, 2256–2273 (2018).
Airhart, S. E. et al. An open-label, non-randomized study of the pharmacokinetics of the nutritional supplement nicotinamide riboside (NR) and its effects on blood NAD+ levels in healthy volunteers. PLoS ONE 12, e0186459 (2017).
Martens, C. R. et al. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat. Commun. 9, 1286 (2018).
Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021).
Zhou, B. et al. Boosting NAD level suppresses inflammatory activation of PBMCs in heart failure. J. Clin. Invest. 130, 6054–6063 (2020).
Wang, D. D. et al. Safety and tolerability of nicotinamide riboside in heart failure with reduced ejection fraction. JACC Basic Transl. Sci. 7, 1183–1196 (2022).
Uddin, G. M. et al. Impaired branched chain amino acid oxidation contributes to cardiac insulin resistance in heart failure. Cardiovasc. Diabetol. 18, 86 (2019).
Wang, W. et al. Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction. Am. J. Physiol. Heart Circ. Physiol. 311, H1160–H1169 (2016).
Chellappa, K. et al. NAD precursors cycle between host tissues and the gut microbiome. Cell Metab. 34, 1947–1959 e1945 (2022).
Zhang, L., Liu, C., Jiang, Q. & Yin, Y. Butyrate in energy metabolism: there is still more to learn. Trends Endocrinol. Metab. 32, 159–169 (2021).
Carley, A. N. et al. Short-chain fatty acids outpace ketone oxidation in the failing heart. Circulation 143, 1797–1808 (2021).
Herrmann, G. & Decherd, G. M. The chemical nature of heart failure. Ann. Intern. Med. 12, 1233–1244 (1939).
James, M. O. et al. Therapeutic applications of dichloroacetate and the role of glutathione transferase zeta-1. Pharmacol. Ther. 170, 166–180 (2017).
Packer, M. et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N. Engl. J. Med. 383, 1413–1424 (2020).
Bhatt, D. L. et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N. Engl. J. Med. 384, 117–128 (2021).
Anker, S. D. et al. Empagliflozin in heart failure with a preserved ejection fraction. N. Engl. J. Med. 385, 1451–1461 (2021).
Anker, S. D., Usman, M. S. & Butler, J. SGLT2 inhibitors: from antihyperglycemic agents to all-around heart failure therapy. Circulation 146, 299–302 (2022).
McMurray, J. J. V. et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N. Engl. J. Med. 381, 1995–2008 (2019).
Zannad, F. et al. SGLT2 inhibitors in patients with heart failure with reduced ejection fraction: a meta-analysis of the EMPEROR-Reduced and DAPA-HF trials. Lancet 396, 819–829 (2020).
Yu, Z. et al. Oral supplementation with butyrate improves myocardial ischemia/reperfusion injury via a gut–brain neural circuit. Front. Cardiovasc. Med. 8, 718674 (2021).
Liao, R., Nascimben, L., Friedrich, J., Gwathmey, J. K. & Ingwall, J. S. Decreased energy reserve in an animal model of dilated cardiomyopathy. Relationship to contractile performance. Circ. Res. 78, 893–902 (1996).
Neubauer, S. et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96, 2190–2196 (1997).
Starling, R. C., Hammer, D. F. & Altschuld, R. A. Human myocardial ATP content and in vivo contractile function. Mol. Cell Biochem. 180, 171–177 (1998).
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. 1188, 191–198 (2010).
Rajabi, M., Kassiotis, C., Razeghi, P. & Taegtmeyer, H. Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail. Rev. 12, 331–343 (2007).
Karbowska, J., Kochan, Z. & Smoleński, R. T. Peroxisome proliferator-activated receptor alpha is downregulated in the failing human heart. Cell Mol. Biol. Lett. 8, 49–53 (2003).
The authors are supported in part by the US NIH (grants HL142628, HL149695, HL144778, HL110349 and HL144937) to R.T.
R.T. is listed as a co-inventor on a patent application submitted by the University of Washington, USA, regarding the targeting of NAD+ metabolism to treat inflammation in heart failure, and is a member of the Scientific Advisory Board of Cytokinetics, USA. J.R. declares no competing interests.
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Metabolic pathway that replenishes intermediates of the tricarboxylic acid cycle.
Metabolic pathways that break down molecules into smaller units, which can be oxidized to generate energy.
The process by which apoptotic cells are removed by phagocytic cells, primarily macrophages.
- Insulin resistance
Impairment of proper insulin and glucose absorption by cells, which results in excessive glucose levels in the blood.
Deleterious effects of lipid accumulation in non-adipose tissues that can lead to cellular dysfunction or cell death.
- Oxidative phosphorylation
The production of ATP by the mitochondrial respiratory chain.
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Ritterhoff, J., Tian, R. Metabolic mechanisms in physiological and pathological cardiac hypertrophy: new paradigms and challenges. Nat Rev Cardiol (2023). https://doi.org/10.1038/s41569-023-00887-x