Cardiac Metabolism as a Target for the Treatment of Heart Failure
2004; Lippincott Williams & Wilkins; Volume: 110; Issue: 8 Linguagem: Inglês
10.1161/01.cir.0000139340.88769.d5
ISSN1524-4539
Autores Tópico(s)Adipose Tissue and Metabolism
ResumoHomeCirculationVol. 110, No. 8Cardiac Metabolism as a Target for the Treatment of Heart Failure Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBCardiac Metabolism as a Target for the Treatment of Heart Failure Heinrich Taegtmeyer, MD, DPhil Heinrich TaegtmeyerHeinrich Taegtmeyer From the Department of Internal Medicine, Division of Cardiology, University of Texas Health Science Center at Houston. Originally published24 Aug 2004https://doi.org/10.1161/01.CIR.0000139340.88769.D5Circulation. 2004;110:894–896Few things in life are more irritating than failing to recognize the obvious. A case in point is energy substrate metabolism as a potential target of pharmacological agents for improving function of the failing heart. The complexities of hemodynamics, coronary flow, and cardiac structure obscure the simple fact that the heart is an efficient converter of energy. The reasoning is straightforward: In a series of highly regulated, enzyme-catalyzed reactions, heart muscle converts chemical energy into mechanical energy.1 Although metabolism and function in the heart are inextricably linked (Figure), few investigators have considered energy substrate metabolism and the first law of thermodynamics (which states that all energy is conserved) as paradigms for the treatment of heart failure. However, interest in this area is growing. Download figureDownload PowerPointHypothesis of inextricable link between metabolism and function of heart. See text for further discussion.See p 955The Present Study in PerspectiveA report in this issue of Circulation2 joins a canon of papers from Richard Shannon's laboratory in Pittsburgh describing metabolic derangements3,4 and interventions5 in heart failure. In the present study, the authors show that recombinant glucagon-like peptide 1 (rGLP-1) dramatically improves left ventricular, systemic, and coronary flow hemodynamics in dogs with advanced dilated cardiomyopathy. The basis for this functional improvement appears to be related to the restoration of insulin sensitivity in the failing heart, but these are difficult studies to perform and the mechanism is unclear. The authors were unable to prove that direct metabolic effects on the heart were the cause for the improvement in myocardial contractile performance, because such proof can only be provided by an isolated, perfused-heart preparation. However, the effects of GLP-1 on contractile performance, myocardial oxygen consumption, and myocardial uptake of glucose and fatty acids strongly suggest a direct metabolic action of GLP-1, including a tighter coupling of oxidative metabolism and contraction of the heart.Cardiac Metabolism in Heart FailureThe mammalian heart has been described as a "metabolic omnivore" because of its capacity to oxidize fat and carbohydrates, either simultaneously or vicariously. The dominance of fatty-acid metabolism by the heart in the fasted state gave rise to the concept of the "glucose–fatty-acid cycle."6 When the heart is acutely stressed, it readily switches from fat to carbohydrate as fuel for oxidative energy production.7 When the heart is exposed to sustained changes in ventricular pressures, it reactivates the fetal gene program.8 Reactivation of these fetal genes includes a switch from fat to glucose oxidation,9 which though initially adaptive, ultimately results in a loss of insulin sensitivity and hence, a loss of metabolic flexibility. This loss of flexibility then becomes an early feature of metabolic dysregulation in the failing heart,10 which also exhibits all the features of insulin resistance, as Dr Shannon and his laboratory staff have elegantly shown.3,4Possible Modes of Action of GLP-1What is GLP-1, and how can this hormone achieve such a feat? At this time, one can only speculate and refer to the substantial literature that already exists on the hemodynamic actions of glucagon, which was amassed during the "golden age" of cardiovascular pharmacology.11 GLP-1, like glucagon, is one of the 5 separately processed domains of pre-proglucagon. It is tempting to speculate that the cellular and hemodynamic actions of GLP-1 are similar to those of glucagon. Indeed, inotropic effects of glucagon are well documented in experimental (pentobarbital-induced) heart failure,12 as are the G-protein–coupled receptor activation and effect of glucagon on heart adenylate cyclase.13 For a "classic" pharmacologist, a side-by-side comparison of GLP-1, glucagon, glucose-insulin-potassium, and a β-adrenergic receptor agonist would determine whether administration of GLP-1 represents a new principle for the treatment of heart failure.The half-life of glucagon is ≈5 minutes. The need for continuous infusion of GLP-1 suggests that it has a similar short half-life. What happens when the GLP-1 infusion is turned off? GLP-1 would be an ideal agent for the treatment of heart failure if it were able to induce both short-term and sustained (ie, transcriptional) effects on heart muscle. However, the ill-fated experience with "dobutamine holidays" for patients with advanced heart failure serves as a reminder that there are no quick fixes for the failing heart. In brief, the "short-term" results presented here are not totally unexpected, but much more work is needed before the metabolic principle can be accepted as a therapeutic principle for the long-term treatment of heart failure.Metabolic Targets for Improved Cardiac FunctionDespite these concerns, the work from Shannon's group is a step in the right direction. The human heart uses several kilograms of ATP per day. Not surprisingly, one third of the cardiac myocyte consists of mitochondria.1 Given these facts, it is difficult to understand why myocardial energy substrate metabolism has thus far largely eluded the attention of the pharmaceutical industry. An exception, perhaps, is the group of drugs that are supposed to shift the heart's energy supply from oxidation of fatty acids to the energetically more efficient oxidation of glucose and lactate in the postischemic heart. This shift can be brought about by restoring insulin sensitivity of the heart, by inhibiting fatty-acid oxidation at various levels, or by activating the pyruvate dehydrogenase complex. A case in point is the success of glucose-insulin-potassium in the treatment of cardiogenic shock after hypothermic ischemic arrest of the heart.14 Other examples include (1) etomoxir, ethyl-2-tetradecyl glycidate, and oxfenicine, drugs that inhibit long-chain fatty-acid oxidation by inhibiting the entry of long-chain fatty acids into the mitochondria at the level of carnitine palmitoyl transferase I (CPT I).15,16 CPT I has become a target for pharmacological intervention in the postischemic, reperfused heart in which rates of fatty-acid oxidation are relatively high and contractile function is (reversibly) impaired. Etomoxir has also generated interest as a drug that may improve energy efficiency in heart failure.17 However, the therapeutic window of etomoxir seems narrow, because in skeletal muscle, CPT I inhibition leads to excess triglyceride accumulation and lipotoxicity.18 (2) The piperazine compound trimetazidine belongs to the group of "partial fatty-acid oxidation" (PFox) inhibitors and is widely used in France as an antianginal drug.19 Trimetazidine is thought to inhibit long-chain fatty-acid oxidation by inhibiting one of the terminal steps in the β-oxidation pathway,20 resulting in a switch of energy substrate preference and improved coupling between glycolysis and glucose oxidation. (3) Ranolazine is another piperazine derivative in the group of PFox inhibitors. In a recent randomized, controlled trial, ranolazine reduced the frequency and severity of chest pain and improved exercise duration in patients with chronic, stable angina who were already receiving other antianginal therapy.21 Ranolazine decreases fatty-acid oxidation, promotes glucose oxidation, and acts indirectly by increasing pyruvate dehydrogenase complex activity.22 The exact mechanism of action of PFox inhibitors is, however, still unknown.The list of drugs targeting intermediary metabolism for the treatment of cardiac dysfunction also includes insulin-sensitizing agents such as thiazolidinediones, lipid-lowering agents such as fibrates and statins, as well as propionyl l-carnitine, an anaplerotic agent that raises the level of free coenzyme A. The opportunities for regeneration of normal cardiac myocyte function through metabolic interventions seem unlimited.OutlookWho knows what comes next? Given the complexity of metabolic pathways and the multitude of potential targets, pharmacological research has much to explore. It is also clear that investigators have only just begun to understand the importance of modulating metabolic pathways to influence cardiac efficiency. The work presented by Nikolaidis et al2 holds the promise of introducing a whole new class of drugs for the treatment of heart failure. On the clinical level, we may witness a long-awaited breakthrough akin to the spectacular results already available in animal models of heart failure subjected to manipulations of metabolic gene expression.Lastly, a word of caution: One must not underestimate the complexities of intermediary metabolism in the heart. Although the myocardium has certain distinctive biochemical features, many of its basic reaction patterns are similar to those of other tissues. Metabolism is not limited to energy transfer. Its pleiotropic actions include the generation of signals for cardiac growth, programmed cell death and programmed cell survival, the formation of reactive oxygen species, and the regulation of transcription factors.23,24 This list further increases our awareness as we begin to identify new metabolic targets for the treatment of heart failure. A reasonable starting point would be to distinguish between drugs that act on one specific enzyme or protein and drugs that, like hormones, act on entire metabolic pathways.25 Once again, we are reminded of a piece of ancient wisdom: "All is in flux" (παντα ρει), as Heraclitus (540 to 480 bce) taught his students in Ephesus 2500 years ago.The opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Work in my laboratory is supported by grants from the US Public Health Service. I thank Stacey Vigil for help with the preparation of this manuscript.FootnotesCorrespondence to Heinrich Taegtmeyer, MD, DPhil, Division of Cardiology, University of Texas Health Science Center at Houston, 6431 Fannin, MSB 1.246, Houston TX 77030. E-mail [email protected] References 1 Taegtmeyer H. Energy metabolism of the heart: from basic concepts to clinical applications. Curr Prob Cardiol. 1994; 19: 57–116.CrossrefGoogle Scholar2 Nikolaidis LA, Elahi D, Hentosz T, et al. Recombinant glucagon-like peptide-1 increases myocardial glucose uptake and improves left ventricular performance in conscious dogs with pacing-induced dilated cardiomyopathy. Circulation. 2004; 110: 955–961.LinkGoogle Scholar3 Shah A, Shannon RP. Insulin resistance in dilated cardiomyopathy. Rev Cardiovasc Med. 2003; 4 (suppl 6): S50–S57.MedlineGoogle Scholar4 Nikolaidis LA, Sturzu A, Stolarski C, et al. The development of myocardial insulin resistance in conscious dogs with advanced dilated cardiomyopathy. Cardiovasc Res. 2004; 61: 297–306.CrossrefMedlineGoogle Scholar5 Nikolaidis LA, Mankad S, Sokos GG, et al. Effects of glucagon-like peptide-1 in patients with acute myocardial infarction and left ventricular dysfunction after successful reperfusion. Circulation. 2004; 109: 962–965.LinkGoogle Scholar6 Randle PJ, Garland PB, Hales CN, et al. The glucose fatty-acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963; 1: 785–789.CrossrefMedlineGoogle Scholar7 Goodwin GW, Taylor CS, Taegtmeyer H. Regulation of energy metabolism of the heart during acute increase in heart work. J Biol Chem. 1998; 273: 29530–29539.CrossrefMedlineGoogle Scholar8 Depre C, Shipley GL, Chen W, et al. Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nat Med. 1998; 4: 1269–1275.CrossrefMedlineGoogle Scholar9 Doenst T, Goodwin GW, Cedars AM, et al. Load-induced changes in vivo alter substrate fluxes and insulin responsiveness of rat heart in vitro. Metabolism. 2001; 50: 1083–1090.CrossrefMedlineGoogle Scholar10 Taegtmeyer H, Sharma S, Golfman L, et al. Linking gene expression to function: metabolic flexibility in normal and diseased heart. Ann N Y Acad Sci. 2004; 1015: 1–12.CrossrefMedlineGoogle Scholar11 Farah AE. Glucagon and the circulation. Pharmacol Rev. 1983; 35: 181–217.MedlineGoogle Scholar12 Gold HK, Prindle KH, Levey GS, et al. Effects of experimental heart failure on the capacity of glucagon to augment myocardial contractility and activate adenyl cyclase. J Clin Invest. 1970; 49: 999–1006.CrossrefMedlineGoogle Scholar13 Murad F, Vaughan M. Effect of glucagon on rat heart adenyl cyclase. Biochem Pharmacol. 1969; 18: 1053–1059.CrossrefMedlineGoogle Scholar14 Gradinak S, Coleman GM, Taegtmeyer H, et al. Improved cardiac function with glucose-insulin-potassium after coronary bypass surgery. Ann Thorac Surg. 1989; 48: 484–489.CrossrefMedlineGoogle Scholar15 Rupp H, Jacob R. Metabolically modulated growth and phenotype of the rat heart. Eur Heart J. 1992; 13 (suppl D): 56–61.CrossrefMedlineGoogle Scholar16 Tutwiler GF, Brentzel HJ, Kiorpes TC. Inhibition of mitochondrial carnitine palmitoyl transferase A in vivo with methyl 2-tetradecylglycidate (methyl palmoxirate) and its relationship to ketonemia and glycemia. Proc Soc Exp Biol Med. 1985; 178: 288–296.CrossrefMedlineGoogle Scholar17 Bristow M. Etomoxir: a new approach to treatment of chronic heart failure. Lancet. 2000; 356: 1621–1622.CrossrefMedlineGoogle Scholar18 Dobbins RL, Szczepaniak LS, Bentley B, et al. Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats. Diabetes. 2001; 50: 123–130.CrossrefMedlineGoogle Scholar19 Detry JM, Sellier P, Pennaforte S, et al. Trimetazidine: a new concept in the treatment of angina: comparison with propranolol in patients with stable angina. Trimetazidine European Multicenter Study Group. Br J Clin Pharmacol. 1994; 37: 279–288.CrossrefMedlineGoogle Scholar20 Kantor PF, Lucien A, Kozak R, et al. The antianginal drug trimetazidine shifts cardiac energy metabolism from fatty acid oxidation to glucose oxidation by inhibiting mitochondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res. 2000; 86: 580–588.CrossrefMedlineGoogle Scholar21 Chaitman BR, Pepine CJ, Parker JO, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: a randomized controlled trial. JAMA. 2004; 291: 309–316.CrossrefMedlineGoogle Scholar22 McCormack JG, Barr RL, Wolff AA, et al. Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation. 1996; 93: 135–142.CrossrefMedlineGoogle Scholar23 Taegtmeyer H. Genetics of energetics: transcriptional responses in cardiac metabolism. Ann Biomed Eng. 2000; 28: 871–876.CrossrefMedlineGoogle Scholar24 Barger PM, Kelly DP. PPAR signaling in the control of cardiac energy metabolism. Trends Cardiovasc Med. 2000; 10: 238–245.CrossrefMedlineGoogle Scholar25 Taegtmeyer H. Switching metabolic genes to build a better heart. Circulation. 2002; 106: 2043–2045.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Tougaard R, Laustsen C, Lassen T, Qi H, Lindhardt J, Schroeder M, Jespersen N, Hansen E, Ringgaard S, Bøtker H, Kim W, Stødkilde‐Jørgensen H and Wiggers H (2021) Remodeling after myocardial infarction and effects of heart failure treatment investigated by hyperpolarized [1‐ 13 C]pyruvate magnetic resonance spectroscopy , Magnetic Resonance in Medicine, 10.1002/mrm.28964, 87:1, (57-69), Online publication date: 1-Jan-2022. 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