Abstract
The heart consumes large amounts of energy in the form of ATP that is continuously replenished by oxidative phosphorylation in mitochondria and, to a lesser extent, by glycolysis. To adapt the ATP supply efficiently to the constantly varying demand of cardiac myocytes, a complex network of enzymatic and signalling pathways controls the metabolic flux of substrates towards their oxidation in mitochondria. In patients with heart failure, derangements of substrate utilization and intermediate metabolism, an energetic deficit, and oxidative stress are thought to underlie contractile dysfunction and the progression of the disease. In this Review, we give an overview of the physiological processes of cardiac energy metabolism and their pathological alterations in heart failure and diabetes mellitus. Although the energetic deficit in failing hearts — discovered >2 decades ago — might account for contractile dysfunction during maximal exertion, we suggest that the alterations of intermediate substrate metabolism and oxidative stress rather than an ATP deficit per se account for maladaptive cardiac remodelling and dysfunction under resting conditions. Treatments targeting substrate utilization and/or oxidative stress in mitochondria are currently being tested in patients with heart failure and might be promising tools to improve cardiac function beyond that achieved with neuroendocrine inhibition.
Key points
-
The healthy heart is metabolically flexible and can derive energy from various circulating substrates.
-
Heart failure (HF) and diabetes mellitus are characterized by an increased reliance on ketone bodies and fatty acid oxidation, respectively, for cardiac ATP production.
-
Metabolic inflexibility and accumulation of toxic intermediates, rather than unbalanced substrate utilization, might detrimentally affect cardiac function.
-
Metabolic intermediates can operate as signalling factors, inducing post-translational and epigenetic modifications or activating intracellular signalling cascades, which ultimately affect several cellular functions.
-
In the failing heart, derangements in metabolism and excitation–contraction coupling contribute to mitochondrial dysfunction and oxidative stress.
-
Targeting metabolic alterations and/or oxidative stress in mitochondria ameliorates HF development in animal models, and translation of these approaches to patients with HF is ongoing.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Ponikowski, P. et al. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. Heart J. 18, 891–975 (2016).
Neubauer, S. The failing heart—an engine out of fuel. N. Engl. J. Med. 356, 1140–1151 (2007).
Stanley, W. C., Recchia, F. A. & Lopaschuk, G. D. Myocardial substrate metabolism in the normal and failing heart. Physiol. Rev. 85, 1093–1129 (2005).
Münzel, T. et al. Impact of oxidative stress on the heart and vasculature: part 2 of a 3-part series. J. Am. Coll. Cardiol. 70, 212–229 (2017).
Bers, D. M. Altered cardiac myocyte Ca regulation in heart failure. Physiology 21, 380–387 (2006).
Ingwall, J. S. ATP and the Heart (Kluwer Academic Publishers, Dordrecht, The Netherlands, 2002).
Bers, D. M. Excitation-Contraction Coupling and Cardiac Contractile Force 2nd Edition (Kluwer Academic Publishers, Dordrecht, The Netherlands, 2001).
Goodwin, G. W., Taylor, C. S. & Taegtmeyer, H. Regulation of energy metabolism of the heart during acute increase in heart work. J. Biol. Chem. 273, 29530–29539 (1998).
Taegtmeyer, H., Golfman, L., Sharma, S., Razeghi, P. & van Arsdall, M. Linking gene expression to function: metabolic flexibility in the normal and diseased heart. Ann. NY Acad. Sci. 1015, 202–213 (2004).
Randle, P. J., Garland, P. B., Hales, C. N. & Newsholme, E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1, 785–789 (1963).
Hardie, D. G. & Carling, D. The AMP-activated protein kinase—fuel gauge of the mammalian cell? Eur. J. Biochem. 246, 259–273 (1997).
Zaha, V. G. & Young, L. H. AMP-activated protein kinase regulation and biological actions in the heart. Circ. Res. 111, 800–814 (2012).
Dufour, C. R. et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma. Cell Metab. 5, 345–356 (2007).
Lehman, J. J. et al. Peroxisome proliferator-activated receptor gamma coactivator-1 promotes cardiac mitochondrial biogenesis. J. Clin. Invest. 106, 847–856 (2000).
Rowe, G. C., Jiang, A. & Arany, Z. PGC-1 coactivators in cardiac development and disease. Circ. Res. 107, 825–838 (2010).
Haemmerle, G. et al. ATGL-mediated fat catabolism regulates cardiac mitochondrial function via PPAR-alpha and PGC-1. Nat. Med. 17, 1076–1085 (2011).
Balaban, R. S. Domestication of the cardiac mitochondrion for energy conversion. J. Mol. Cell. Cardiol. 46, 832–841 (2009).
Balaban, R. S. Cardiac energy metabolism homeostasis: role of cytosolic calcium. J. Mol. Cell. Cardiol. 34, 1259–1271 (2002).
Balaban, R., Kantor, H., Katz, L. & Briggs, R. Relation between work and phosphate metabolite in the in vivo paced mammalian heart. Science 232, 1121–1123 (1986).
Conway, M. A. et al. Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy. Lancet 338, 973–976 (1991).
Neubauer, S. et al. 31P magnetic resonance spectroscopy in dilated cardiomyopathy and coronary artery disease. Altered cardiac high-energy phosphate metabolism in heart failure. Circulation 86, 1810–1818 (1992).
Hardy, C. J., Weiss, R. G., Bottomley, P. A. & Gerstenblith, G. Altered myocardial high-energy phosphate metabolites in patients with dilated cardiomyopathy. Am. Heart J. 122, 795–801 (1991).
Neubauer, S. et al. Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 96, 2190–2196 (1997).
Beer, M. et al. Absolute concentrations of high-energy phosphate metabolites in normal, hypertrophied, and failing human myocardium measured noninvasively with (31)P-SLOOP magnetic resonance spectroscopy. J. Am. Coll. Cardiol. 40, 1267–1274 (2002).
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).
Gupta, A. et al. Creatine kinase-mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved. J. Clin. Invest. 122, 291–302 (2012).
Lygate, C. A. et al. Living without creatine: unchanged exercise capacity and response to chronic myocardial infarction in creatine-deficient mice. Circ. Res. 112, 945–955 (2013).
Nahrendorf, M. et al. Creatine kinase knockout mice show left ventricular hypertrophy and dilatation, but unaltered remodeling post-myocardial infarction. Cardiovasc. Res. 65, 419–427 (2005).
Nicholls, D. G. & Ferguson, S. J. Bioenergetics. 4th Edition (Academic Press, Cambridge, MA, 2013).
Gupta, A., Chacko, V. P., Schar, M., Akki, A. & Weiss, R. G. Impaired ATP kinetics in failing in vivo mouse heart. Circ. Cardiovasc. Imaging 4, 42–50 (2011).
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).
Bottomley, P. A. et al. Metabolic rates of ATP transfer through creatine kinase (CK Flux) predict clinical heart failure events and death. Sci. Transl. Med. 5, 215re3 (2013).
Nickel, A., Loffler, J. & Maack, C. Myocardial energetics in heart failure. Basic Res. Cardiol. 108, 358 (2013).
Doenst, T. et al. Decreased rates of substrate oxidation ex vivo predict the onset of heart failure and contractile dysfunction in rats with pressure overload. Cardiovasc. Res. 86, 461–470 (2010).
Christe, M. E. & Rodgers, R. L. Altered glucose and fatty acid oxidation in hearts of the spontaneously hypertensive rat. J. Mol. Cell. Cardiol. 26, 1371–1375 (1994).
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).
Degens, H. et al. Cardiac fatty acid metabolism is preserved in the compensated hypertrophic rat heart. Basic Res. Cardiol. 101, 17–26 (2006).
Kato, T. et al. Analysis of metabolic remodeling in compensated left ventricular hypertrophy and heart failure. Circ. Heart Fail. 3, 420–430 (2010).
Doenst, T., Nguyen, T. D. & Abel, E. D. Cardiac metabolism in heart failure: implications beyond ATP production. Circ. Res. 113, 709–724 (2013).
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).
Heather, L. C. et al. Fatty acid transporter levels and palmitate oxidation rate correlate with ejection fraction in the infarcted rat heart. Cardiovasc. Res. 72, 430–437 (2006).
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).
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).
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).
Barger, P. M., Brandt, J. M., Leone, T. C., Weinheimer, C. J. & Kelly, D. P. Deactivation of peroxisome proliferator-activated receptor-alpha during cardiac hypertrophic growth. J. Clin. Invest. 105, 1723–1730 (2000).
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).
Krishnan, J. et al. Activation of a HIF1α-PPARγ axis underlies the integration of glycolytic and lipid anabolic pathways in pathologic cardiac hypertrophy. Cell Metab. 9, 512–524 (2009).
Sack, M. N. et al. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 94, 2837–2842 (1996).
Opie, L. H. & Knuuti, J. The adrenergic-fatty acid load in heart failure. J. Am. Coll. Cardiol. 54, 1637–1646 (2009).
Sharma, S. et al. Intramyocardial lipid accumulation in the failing human heart resembles the lipotoxic rat heart. FASEB J. 18, 1692–1700 (2004).
Wende, A. R. & Abel, E. D. Lipotoxicity in the heart. Biochim. Biophys. Acta 1801, 311–319 (2010).
Goldberg, I. J., Trent, C. M. & Schulze, P. C. Lipid metabolism and toxicity in the heart. Cell Metab. 15, 805–812 (2012).
Kim, J. K. et al. PKC-theta knockout mice are protected from fat-induced insulin resistance. J. Clin. Invest. 114, 823–827 (2004).
Yuan, M. et al. Reversal of obesity- and diet-induced insulin resistance with salicylates or targeted disruption of Ikkβ. Science 293, 1673–1677 (2001).
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).
Taegtmeyer, H., Beauloye, C., Harmancey, R. & Hue, L. Insulin resistance protects the heart from fuel overload in dysregulated metabolic states. Am. J. Physiol. Heart Circ. Physiol. 305, H1693–H1697 (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).
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).
Nascimben, L. et al. Mechanisms for increased glycolysis in the hypertrophied rat heart. Hypertension 44, 662–667 (2004).
Atherton, H. J. et al. Role of pyruvate dehydrogenase inhibition in the development of hypertrophy in the hyperthyroid rat heart: a combined magnetic resonance imaging and hyperpolarized magnetic resonance spectroscopy study. Circulation 123, 2552–2561 (2011).
Mori, J. et al. 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. 5, 493–503 (2012).
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).
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).
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).
Fukushima, A. & Lopaschuk, G. D. Cardiac fatty acid oxidation in heart failure associated with obesity and diabetes. Biochim. Biophys. Acta 1861, 1525–1534 (2016).
Swan, J. W. et al. Insulin resistance in chronic heart failure: relation to severity and etiology of heart failure. J. Am. Coll. Cardiol. 30, 527–532 (1997).
Lydell, C. P. et al. Pyruvate dehydrogenase and the regulation of glucose oxidation in hypertrophied rat hearts. Cardiovasc. Res. 53, 841–851 (2002).
Aubert, G. et al. The failing heart relies on ketone bodies as a fuel. Circulation 133, 698–705 (2016).
Cahill, G. F. Jr Fuel metabolism in starvation. Annu. Rev. Nutr. 26, 1–22 (2006).
Seferovic, P. M. & Paulus, W. J. Clinical diabetic cardiomyopathy: a two-faced disease with restrictive and dilated phenotypes. Eur. Heart J. 36, 1718–1727, 1727a-1727c (2015).
Bayeva, M., Sawicki, K. T. & Ardehali, H. Taking diabetes to heart—deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J. Am. Heart Assoc. 2, e000433 (2013).
Herrero, P. et al. Increased myocardial fatty acid metabolism in patients with type 1 diabetes mellitus. J. Am. Coll. Cardiol. 47, 598–604 (2006).
Paternostro, G. et al. Cardiac and skeletal muscle insulin resistance in patients with coronary heart disease. A study with positron emission tomography. J. Clin. Invest. 98, 2094–2099 (1996).
Scheuermann-Freestone, M. et al. Abnormal cardiac and skeletal muscle energy metabolism in patients with type 2 diabetes. Circulation 107, 3040–3046 (2003).
Buchanan, J. et al. Reduced cardiac efficiency and altered substrate metabolism precedes the onset of hyperglycemia and contractile dysfunction in two mouse models of insulin resistance and obesity. Endocrinology 146, 5341–5349 (2005).
Razeghi, P., Young, M. E., Cockrill, T. C., Frazier, O. H. & Taegtmeyer, H. Downregulation of myocardial myocyte enhancer factor 2C and myocyte enhancer factor 2C-regulated gene expression in diabetic patients with nonischemic heart failure. Circulation 106, 407–411 (2002).
Anderson, E. J. et al. Substrate-specific derangements in mitochondrial metabolism and redox balance in the atrium of the type 2 diabetic human heart. J. Am. Coll. Cardiol. 54, 1891–1898 (2009).
Sankaralingam, S. et al. Lowering body weight in obese mice with diastolic heart failure improves cardiac insulin sensitivity and function: implications for the obesity paradox. Diabetes 64, 1643–1657 (2015).
Alrob, O. A. et al. Obesity-induced lysine acetylation increases cardiac fatty acid oxidation and impairs insulin signalling. Cardiovasc. Res. 103, 485–497 (2014).
Murray, A. J., Anderson, R. E., Watson, G. C., Radda, G. K. & Clarke, K. Uncoupling proteins in human heart. Lancet 364, 1786–1788 (2004).
Hesselink, M. K. et al. Increased uncoupling protein 3 content does not affect mitochondrial function in human skeletal muscle in vivo. J. Clin. Invest. 111, 479–486 (2003).
Hesselink, M. K. & Schrauwen, P. Uncoupling proteins in the failing human heart: friend or foe? Lancet 365, 385–386 (2005).
Turner, J. D., Gaspers, L. D., Wang, G. & Thomas, A. P. Uncoupling protein-2 modulates myocardial excitation-contraction coupling. Circ. Res. 106, 730–738 (2010).
How, O. J. et al. Increased myocardial oxygen consumption reduces cardiac efficiency in diabetic mice. Diabetes 55, 466–473 (2006).
Mather, K. J. et al. Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer. Am. J. Physiol. Endocrinol. Metab. 310, E452–E460 (2016).
McGavock, J. M. et al. Cardiac steatosis in diabetes mellitus: a 1H-magnetic resonance spectroscopy study. Circulation 116, 1170–1175 (2007).
Balteau, M. et al. NADPH oxidase activation by hyperglycaemia in cardiomyocytes is independent of glucose metabolism but requires SGLT1. Cardiovasc. Res. 92, 237–246 (2011).
Serpillon, S. et al. Superoxide production by NAD(P)H oxidase and mitochondria is increased in genetically obese and hyperglycemic rat heart and aorta before the development of cardiac dysfunction. The role of glucose-6-phosphate dehydrogenase-derived NADPH. Am. J. Physiol. Heart Circ. Physiol. 297, H153–H162 (2009).
Shah, M. S. & Brownlee, M. Molecular and cellular mechanisms of cardiovascular disorders in diabetes. Circ. Res. 118, 1808–1829 (2016).
Bodiga, V. L., Eda, S. R. & Bodiga, S. Advanced glycation end products: role in pathology of diabetic cardiomyopathy. Heart Fail. Rev. 19, 49–63 (2014).
Ramasamy, R. & Goldberg, I. J. Aldose reductase and cardiovascular diseases, creating human-like diabetic complications in an experimental model. Circ. Res. 106, 1449–1458 (2010).
Ritterhoff, J. & Tian, R. Metabolism in cardiomyopathy: every substrate matters. Cardiovasc. Res. 113, 411–421 (2017).
Peterzan, M. A., Lygate, C. A., Neubauer, S. & Rider, O. J. Metabolic remodeling in hypertrophied and failing myocardium: a review. Am. J. Physiol. Heart Circ. Physiol. 313, H597–H616 (2017).
Pereira, R. O. et al. GLUT1 deficiency in cardiomyocytes does not accelerate the transition from compensated hypertrophy to heart failure. J. Mol. Cell. Cardiol. 72, 95–103 (2014).
Abel, E. D. et al. Cardiac hypertrophy with preserved contractile function after selective deletion of GLUT4 from the heart. J. Clin. Invest. 104, 1703–1714 (1999).
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).
Finck, B. N. et al. The cardiac phenotype induced by PPARα overexpression mimics that caused by diabetes mellitus. J. Clin. Invest. 109, 121–130 (2002).
Nagendran, J. et al. Cardiomyocyte-specific ablation of CD36 improves post-ischemic functional recovery. J. Mol. Cell. Cardiol. 63, 180–188 (2013).
Kienesberger, P. C. et al. Myocardial ATGL overexpression decreases the reliance on fatty acid oxidation and protects against pressure overload-induced cardiac dysfunction. Mol. Cell. Biol. 32, 740–750 (2012).
Luptak, I. et al. Decreased contractile and metabolic reserve in peroxisome proliferator-activated receptor-alpha-null hearts can be rescued by increasing glucose transport and utilization. Circulation 112, 2339–2346 (2005).
Cheng, L. et al. Cardiomyocyte-restricted peroxisome proliferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat. Med. 10, 1245–1250 (2004).
He, L. et al. Carnitine palmitoyltransferase-1b deficiency aggravates pressure overload-induced cardiac hypertrophy caused by lipotoxicity. Circulation 126, 1705–1716 (2012).
Luptak, I. et al. Long-term effects of increased glucose entry on mouse hearts during normal aging and ischemic stress. Circulation 116, 901–909 (2007).
McCommis, K. S., Douglas, D. L., Krenz, M. & Baines, C. P. Cardiac-specific hexokinase 2 overexpression attenuates hypertrophy by increasing pentose phosphate pathway flux. J. Am. Heart Assoc. 2, e000355 (2013).
Yan, J. et al. Increased glucose uptake and oxidation in mouse hearts prevent high fatty acid oxidation but cause cardiac dysfunction in diet-induced obesity. Circulation 119, 2818–2828 (2009).
McKnight, S. L. On getting there from here. Science 330, 1338–1339 (2010).
Gibb, A. A. et al. Exercise-induced changes in glucose metabolism promote physiological cardiac growth. Circulation 136, 2144–2157 (2017).
Riquelme, C. A. et al. Fatty acids identified in the Burmese python promote beneficial cardiac growth. Science 334, 528–531 (2011).
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).
Facundo, H. T. et al. O-GlcNAc signaling is essential for NFAT-mediated transcriptional reprogramming during cardiomyocyte hypertrophy. Am. J. Physiol. Heart Circ. Physiol. 302, H2122–H2130 (2012).
Erickson, J. R. et al. Diabetic hyperglycaemia activates CaMKII and arrhythmias by O-linked glycosylation. Nature 502, 372 (2013).
Gelinas, R. et al. AMPK activation counteracts cardiac hypertrophy by reducing O-GlcNAcylation. Nat. Commun. 9, 374 (2018).
Lehmann, L. H. et al. A proteolytic fragment of histone deacetylase 4 protects the heart from failure by regulating the hexosamine biosynthetic pathway. Nat. Med. 24, 62–72 (2018).
Matsuhashi, T. et al. Activation of pyruvate dehydrogenase by dichloroacetate has the potential to induce epigenetic remodeling in the heart. J. Mol. Cell. Cardiol. 82, 116–124 (2015).
Dunn, W. B. et al. Serum metabolomics reveals many novel metabolic markers of heart failure, including pseudouridine and 2- oxoglutarate. Metabolomics 3, e426 (2007).
Nulton-Persson, A. C. & Szweda, L. I. Modulation of mitochondrial function by hydrogen peroxide. J. Biol. Chem. 276, 23357–23361 (2001).
He, W. et al. Citric acid cycle intermediates as ligands for orphan G-protein-coupled receptors. Nature 429, 188–193 (2004).
Omede, A. et al. The oxoglutarate receptor 1 (OXGR1) modulates pressure overload-induced cardiac hypertrophy in mice. Biochem. Biophys. Res. Commun. 479, 708–714 (2016).
Karlstaedt, A. et al. Oncometabolite d-2-hydroxyglutarate impairs alpha-ketoglutarate dehydrogenase and contractile function in rodent heart. Proc. Natl Acad. Sci. USA 113, 10436–10441 (2016).
Tsukada, Y. et al. Histone demethylation by a family of JmjC domain-containing proteins. Nature 439, 811–816 (2006).
Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).
Fukushima, A. & Lopaschuk, G. D. Acetylation control of cardiac fatty acid beta-oxidation and energy metabolism in obesity, diabetes, and heart failure. Biochim. Biophys. Acta 1862, 2211–2220 (2016).
Zhao, S. et al. Regulation of cellular metabolism by protein lysine acetylation. Science 327, 1000–1004 (2010).
Rardin, M. J. et al. Label-free quantitative proteomics of the lysine acetylome in mitochondria identifies substrates of SIRT3 in metabolic pathways. Proc. Natl Acad. Sci. USA 110, 6601–6606 (2013).
Horton, J. L. et al. Mitochondrial protein hyperacetylation in the failing heart. JCI Insight 1, e84897 (2016).
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).
Lee, C. F. et al. Normalization of NAD+ redox balance as a therapy for heart failure. Circulation 134, 883–894 (2016).
Brookes, P. S. & Taegtmeyer, H. Metabolism: a direct link between cardiac structure and function. Circulation 136, 2158–2161 (2017).
Nickel, A., Kohlhaas, M. & Maack, C. Mitochondrial reactive oxygen species production and elimination. J. Mol. Cell. Cardiol. 73, 26–33 (2014).
Kohlhaas, M., Nickel, A. G. & Maack, C. Mitochondrial energetics and calcium coupling in the heart. J. Physiol. 595, 3753–3763 (2017).
Murphy, E. et al. Mitochondrial function, biology, and role in disease: a scientific statement from the American Heart Association. Circ. Res. 118, 1960–1991 (2016).
Shirihai, O. S., Song, M. & Dorn, G. W. How mitochondrial dynamism orchestrates mitophagy. Circ. Res. 116, 1835–1849 (2015).
Tsushima, K. et al. Mitochondrial reactive oxygen species in lipotoxic hearts induce post-translational modifications of AKAP121, DRP1, and OPA1 that promote mitochondrial fission. Circ. Res. 122, 58–73 (2018).
Coronado, M. et al. Physiological mitochondrial fragmentation is a normal cardiac adaptation to increased energy demand. Circ. Res. 122, 282–295 (2018).
Goikoetxea, M. J. et al. Altered cardiac expression of peroxisome proliferator-activated receptor-isoforms in patients with hypertensive heart disease. Cardiovasc. Res. 69, 899–907 (2006).
Sihag, S., Cresci, S., Li, A. Y., Sucharov, C. C. & Lehman, J. J. PGC-1alpha and ERRalpha target gene downregulation is a signature of the failing human heart. J. Mol. Cell. Cardiol. 46, 201–212 (2009).
Baughman, J. M. et al. Integrative genomics identifies MCU as an essential component of the mitochondrial calcium uniporter. Nature 476, 341–345 (2011).
De Stefani, D., Raffaello, A., Teardo, E., Szabo, I. & Rizzuto, R. A forty-kilodalton protein of the inner membrane is the mitochondrial calcium uniporter. Nature 476, 336–340 (2011).
Palty, R. et al. NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc. Natl Acad. Sci. USA 107, 436–441 (2010).
Kirichok, Y., Krapivinsky, G. & Clapham, D. E. The mitochondrial calcium uniporter is a highly selective ion channel. Nature 427, 360–364 (2004).
Giacomello, M. et al. Ca2+ hot spots on the mitochondrial surface are generated by Ca2+ mobilization from stores, but not by activation of store-operated Ca2+ channels. Mol. Cell 38, 280–290 (2010).
de Brito, O. M. & Scorrano, L. Mitofusin 2 tethers endoplasmic reticulum to mitochondria. Nature 456, 605–610 (2008).
Chen, Y. et al. Mitofusin 2-containing mitochondrial-reticular microdomains direct rapid cardiomyocyte bioenergetic responses via interorganelle Ca2+ crosstalk. Circ. Res. 111, 863–875 (2012).
Wu, S. et al. Binding of FUN14 domain containing 1 with Inositol 1,4,5-Trisphosphate receptor in mitochondria-associated endoplasmic reticulum membranes maintains mitochondrial dynamics and function in hearts in vivo. Circulation 136, 2248–2266 (2017).
Pinali, C., Bennett, H., Davenport, J. B., Trafford, A. W. & Kitmitto, A. Three-dimensional reconstruction of cardiac sarcoplasmic reticulum reveals a continuous network linking transverse-tubules: this organization is perturbed in heart failure. Circ. Res. 113, 1219–1230 (2013).
Kohlhaas, M. & Maack, C. Adverse bioenergetic consequences of Na+-Ca2+ exchanger-mediated Ca2+ influx in cardiac myocytes. Circulation 122, 2273–2280 (2010).
Despa, S., Islam, M. A., Weber, C. R., Pogwizd, S. M. & Bers, D. M. Intracellular Na+ concentration is elevated in heart failure but Na/K pump function is unchanged. Circulation 105, 2543–2548 (2002).
Kohlhaas, M. et al. Elevated cytosolic Na+ increases mitochondrial formation of reactive oxygen species in failing cardiac myocytes. Circulation 121, 1606–1613 (2010).
Liu, T. & O’Rourke, B. Enhancing mitochondrial Ca2+ uptake in myocytes from failing hearts restores energy supply and demand matching. Circ. Res. 103, 279–288 (2008).
Valdivia, C. R. et al. Increased late sodium current in myocytes from a canine heart failure model and from failing human heart. J. Mol. Cell. Cardiol. 38, 475–483 (2005).
Baartscheer, A. et al. Increased Na+/H+-exchange activity is the cause of increased [Na+]i and underlies disturbed calcium handling in the rabbit pressure and volume overload heart failure model. Cardiovasc. Res. 57, 1015–1024 (2003).
Schwinger, R. H. et al. Reduced sodium pump α1, α3, and β1-isoform protein levels and Na+,K+-ATPase activity but unchanged Na+-Ca2+ exchanger protein levels in human heart failure. Circulation 99, 2105–2112 (1999).
Swift, F. et al. Altered Na+/Ca2+-exchanger activity due to downregulation of Na+/K+-ATPase α2-isoform in heart failure. Cardiovasc. Res. 78, 71–78 (2008).
Lambert, R. et al. Intracellular Na+ concentration ([Na+]i) is elevated in diabetic hearts due to enhanced Na+-glucose cotransport. J. Am. Heart Assoc. 4, e002183 (2015).
Bay, J., Kohlhaas, M. & Maack, C. Intracellular Na+ and cardiac metabolism. J. Mol. Cell. Cardiol. 61, 20–27 (2013).
Nickel, A. G. et al. Reversal of mitochondrial transhydrogenase causes oxidative stress in heart failure. Cell Metab. 22, 472–484 (2015).
Ide, T. et al. Mitochondrial electron transport complex I is a potential source of oxygen free radicals in the failing myocardium. Circ. Res. 85, 357–363 (1999).
Beadle, R. M. et al. Improvement in cardiac energetics by perhexiline in heart failure due to dilated cardiomyopathy. JACC Heart Fail. 3, 202–211 (2015).
Abozguia, K. et al. Metabolic modulator perhexiline corrects energy deficiency and improves exercise capacity in symptomatic hypertrophic cardiomyopathy. Circulation 122, 1562–1569 (2010).
Fragasso, G. et al. Effects of metabolic modulation by trimetazidine on left ventricular function and phosphocreatine/adenosine triphosphate ratio in patients with heart failure. Eur. Heart J. 27, 942–948 (2006).
Fragasso, G. et al. Short- and long-term beneficial effects of trimetazidine in patients with diabetes and ischemic cardiomyopathy. Am. Heart J. 146, E18 (2003).
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).
Winter, J. L. et al. Effects of trimetazidine in nonischemic heart failure: a randomized study. J. Card. Fail. 20, 149–154 (2014).
Tuunanen, H. et al. Trimetazidine, a metabolic modulator, has cardiac and extracardiac benefits in idiopathic dilated cardiomyopathy. Circulation 118, 1250–1258 (2008).
Cook, W. S., Yeldandi, A. V., Rao, M. S., Hashimoto, T. & Reddy, J. K. Less extrahepatic induction of fatty acid beta-oxidation enzymes by PPAR alpha. Biochem. Biophys. Res. Commun. 278, 250–257 (2000).
Yue, T. L. et al. Activation of peroxisome proliferator-activated receptor-alpha protects the heart from ischemia/reperfusion injury. Circulation 108, 2393–2399 (2003).
Jun, M. et al. Effects of fibrates on cardiovascular outcomes: a systematic review and meta-analysis. Lancet 375, 1875–1884 (2010).
Tuunanen, H. et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation 114, 2130–2137 (2006).
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).
Lewis, J. F., DaCosta, M., Wargowich, T. & Stacpoole, P. Effects of dichloroacetate in patients with congestive heart failure. Clin. Cardiol. 21, 888–892 (1998).
Zinman, B. et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N. Engl. J. Med. 373, 2117–2128 (2015).
Neal, B. et al. Canagliflozin and cardiovascular and renal events in type 2 diabetes. N. Engl. J. Med. 377, 644–657 (2017).
Ferrannini, E., Mark, M. & Mayoux, E. CV protection in the EMPA-REG OUTCOME Trial: a “Thrifty Substrate” hypothesis. Diabetes Care 39, 1108–1114 (2016).
Mudaliar, S., Alloju, S. & Henry, R. R. Can a shift in fuel energetics explain the beneficial cardiorenal outcomes in the EMPA-REG OUTCOME study? A unify. hypothesis. Diabetes Care 39, 1115–1122 (2016).
Lopaschuk, Gary, D. & Verma, S. Empagliflozin’s fuel hypothesis: not so soon. Cell Metab. 24, 200–202 (2016).
Baartscheer, A. et al. Empagliflozin decreases myocardial cytoplasmic Na+ through inhibition of the cardiac Na+/H+ exchanger in rats and rabbits. Diabetologia 60, 568–573 (2017).
Packer, M., Anker, S. D., Butler, J., Filippatos, G. & Zannad, F. Effects of sodium-glucose cotransporter 2 inhibitors for the treatment of patients with heart failure: proposal of a novel mechanism of action. JAMA Cardiol. 2, 1025–1029 (2017).
Bertero, E., Prates Roma, L., Ameri, P. & Maack, C. Cardiac effects of SGLT2 inhibitors: the sodium hypothesis. Cardiovasc. Res. 114, 12–18 (2018).
Folkers, K., Wolaniuk, J., Simonsen, R., Morishita, M. & Vadhanavikit, S. Biochemical rationale and the cardiac response of patients with muscle disease to therapy with coenzyme Q10. Proc. Natl Acad. Sci. USA 82, 4513–4516 (1985).
Mortensen, S. A. et al. The effect of coenzyme Q10 on morbidity and mortality in chronic heart failure: results from Q-SYMBIO: a randomized double-blind trial. JACC Heart Fail. 2, 641–649 (2014).
Smith, R. A., Hartley, R. C., Cocheme, H. M. & Murphy, M. P. Mitochondrial pharmacology. Trends Pharmacol. Sci. 33, 341–352 (2012).
Szeto, H. H. First-in-class cardiolipin-protective compound as a therapeutic agent to restore mitochondrial bioenergetics. Br. J. Pharmacol. 171, 2029–2050 (2014).
Daubert, M. A. et al. Novel mitochondria-targeting peptide in heart failure treatment: a randomized, placebo-controlled trial of elamipretide. Circ. Heart Fail. 10, e004389 (2017).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02814097 (2017).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02914665 (2018).
US National Library of Medicine. ClinicalTrials.gov http://www.clinicaltrials.gov/ct2/show/NCT02788747 (2018).
Burgoyne, J. R., Mongue-Din, H., Eaton, P. & Shah, A. M. Redox signaling in cardiac physiology and pathology. Circ. Res. 111, 1091–1106 (2012).
Liu, T. et al. Inhibiting mitochondrial Na+/Ca2+ exchange prevents sudden death in a Guinea pig model of heart failure. Circ. Res. 115, 44–54 (2014).
Twig, G. et al. Fission and selective fusion govern mitochondrial segregation and elimination by autophagy. EMBO J. 27, 433–446 (2008).
Dorn, G. W. 2nd. Mitochondrial dynamics in heart disease. Biochim. Biophys. Acta 1833, 233–241 (2013).
Chambers, K. T. et al. Chronic inhibition of pyruvate dehydrogenase in heart triggers an adaptive metabolic response. J. Biol. Chem. 286, 11155–11162 (2011).
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).
Liang, Q., Donthi, R. V., Kralik, P. M. & Epstein, P. N. Elevated hexokinase increases cardiac glycolysis in transgenic mice. Cardiovasc. Res. 53, 423–430 (2002).
Liao, R. et al. Cardiac-specific overexpression of GLUT1 prevents the development of heart failure attributable to pressure overload in mice. Circulation 106, 2125–2131 (2002).
Pereira, R. O. et al. Inducible overexpression of GLUT1 prevents mitochondrial dysfunction and attenuates structural remodeling in pressure overload but does not prevent left ventricular dysfunction. J. Am. Heart Assoc. 2, e000301 (2013).
Acknowledgements
C.M.’s research is currently supported by the Deutsche Forschungsgemeinschaft (DFG; SFB 894, TRR-219, and Ma 2528/7-1) and the Bundesministerium für Bildung und Forschung (BMBF; 01EO1504).
Reviewer information
Nature Reviews Cardiology thanks C. Lygate, H. Taegtmeyer, and the other anonymous reviewer for their contribution to the peer review of this work.
Author information
Authors and Affiliations
Contributions
Both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission.
Corresponding author
Ethics declarations
Competing interests
C.M. serves as an adviser to Boehringer Ingelheim and Servier, and has received speaker honoraria from Berlin Chemie. E.B. declares no competing interests.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Bertero, E., Maack, C. Metabolic remodelling in heart failure. Nat Rev Cardiol 15, 457–470 (2018). https://doi.org/10.1038/s41569-018-0044-6
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41569-018-0044-6
This article is cited by
-
Serum metabolite signatures of cardiac function and morphology in individuals from a population-based cohort
Biomarker Research (2024)
-
HNF4α ubiquitination mediated by Peli1 impairs FAO and accelerates pressure overload-induced myocardial hypertrophy
Cell Death & Disease (2024)
-
Thiamine-modified metabolic reprogramming of human pluripotent stem cell-derived cardiomyocyte under space microgravity
Signal Transduction and Targeted Therapy (2024)
-
From Energy Metabolic Change to Precision Therapy: a Holistic View of Energy Metabolism in Heart Failure
Journal of Cardiovascular Translational Research (2024)
-
Advances in Metabolic Remodeling and Intervention Strategies in Heart Failure
Journal of Cardiovascular Translational Research (2024)
