New directions in the treatment of heart failure: Targeting free fatty acid oxidation

  • Gabriele Fragasso
  • Roberto Spoladore
  • Giorgio Bassanelli
  • Amarild Cuko
  • Chiara Montano
  • Anna Salerno
  • Alberto Margonato
Article

Abstract

The possibility of modifying cardiac metabolism by switching the fuel used by the myocardium could become increasingly important. Inhibitors of free fatty acid (FFA) oxidation could have an important role in therapeutic strategy for patients with heart failure, and shifting the energy substrate preference away from FFA metabolism and toward glucose metabolism may be an effective adjunctive treatment. Additionally, abnormalities of glucose homeostasis in patients with heart failure contribute to the progression of the primary disease. If not adequately treated, these abnormalities can contribute to the occurrence of complications, including severe left ventricular dysfunction. Apart from meticulous metabolic control of frank diabetes, special attention should be paid to insulin resistance, a distinct clinical entity. The observed combined beneficial effects of FFA inhibitors on left ventricular function and glucose metabolism represent an additional advantage of these drugs, especially when abnormalities of myocardial and glucose metabolism coexist.

References and Recommended Reading

  1. 1.
    Lommi J, Kupari M, Koskinen P, et al.: Blood ketone bodies in congestive heart failure. J Am Coll Cardiol 1996, 28:665–672.PubMedGoogle Scholar
  2. 2.
    Riley M, Bell N, Elborn JS, et al.: Metabolic response to graded exercise in chronic heart failure: Eur Heart J 1993, 14:1484–1488.PubMedGoogle Scholar
  3. 3.
    Paolisso G, De Riu S, Marrazzo G, et al.: Insulin resistance and hyperinsulinemia in patients with chronic heart failure. Metabolism 1991, 40:972–977.PubMedCrossRefGoogle Scholar
  4. 4.
    Lopaschuck GD, Stanley WC: Glucose metabolism in the ischemic heart. Circulation 1997, 95:313–315.Google Scholar
  5. 5.
    Nuutila P, Knuuti MJ, Raitakari M, et al.: Effect of antilipolysis on heart and skeletal muscle glucose uptake in overnight fasted humans. Am J Physiol 1994, 267:E941–E946.PubMedGoogle Scholar
  6. 6.
    Lewis GF, Carpentier A, Adeli K, Giacca A: Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev 2002, 23:201–229.PubMedCrossRefGoogle Scholar
  7. 7.
    Steinberg HO, Baron AD: Vascular function, insulin resistance and fatty acids. Diabetologia 2002, 45:623–634.PubMedCrossRefGoogle Scholar
  8. 8.
    Kantor PF, Lucien A, Kozak R, Lopashuck GD: 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.PubMedGoogle Scholar
  9. 9.
    Fantini E, Demaison L, Sentex E, et al.: Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell Cardiol 1994, 26:949–958.PubMedCrossRefGoogle Scholar
  10. 10.
    Lopaschuk GD, Barr R, Thomas PD, Dyck JR: Beneficial effects of trimetazidine in ex vivo working ischemic hearts are due to a stimulation of glucose oxidation secondary to inhibition of long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2003, 93:e26–e32.CrossRefGoogle Scholar
  11. 11.
    MacInnes A, Fairman DA, Binding P, et al.: The antianginal trimetazidine does not exert its functional benefit via inhibition of mithocondrial long-chain 3-ketoacyl coenzyme A thiolase. Circ Res 2003, 93:e33–e37.CrossRefGoogle Scholar
  12. 12.
    Brottier L, Barat JL, Combe C, et al.: Therapeutic value of a cardioprotective agent in patients with severe ischemic cardiomyopathy. Eur Heart J 1990, 11:207–212.PubMedGoogle Scholar
  13. 13.
    Lu C, Dabrowski P, Fragasso G, Chierchia SL: Effects of trimetazidine on ischemic left ventricular dysfunction in patients with coronary artery disease. Am J Cardiol 1998, 82:898–901.PubMedCrossRefGoogle Scholar
  14. 14.
    Belardinelli R, Purcaro A: Effects of trimetazidine on the contractile response of chronically dysfunctional myocardium to low-dose dobutamine in ischaemic cardiomyopathy. Eur Heart J 2001, 22:2164–2170.PubMedCrossRefGoogle Scholar
  15. 15.
    Fragasso G, Piatti PM, Monti L, et al.: Short and long term beneficial effects of partial free fatty acid inhibition in diabetic patients with ischemic dilated cardiomyopathy. Am Heart J 2003, 146:E1–E8.CrossRefGoogle Scholar
  16. 16.
    Rosano GM, Vitale C, Sposato B, et al.: Trimetazidine improves left ventricular function in diabetic patients with coronary artery disease: a double-blind placebo-controlled study. Cardiovasc Diabetol 2003, 2:16.PubMedCrossRefGoogle Scholar
  17. 17.
    Vitale C, Wajngaten M, Sposato B, et al.: Trimetazidine improves left ventricular function and quality of life in elderly patients with coronary artery disease. Eur Heart J 2004, 25:1814–1821.PubMedCrossRefGoogle Scholar
  18. 18.
    Di Napoli P, Taccardi AA, Barsotti A: Long term cardioprotective action of trimetazidine and potential effect on the inflammatory process in patients with ischaemic dilated cardiomyopathy. Heart 2005, 91:161–165.PubMedCrossRefGoogle Scholar
  19. 19.
    Lavanchy N, Martin J, Rossi A: Anti-ischemia effects of trimetazidine: 31P-NMR spectroscopy in the isolated rat heart. Arch Int Pharmacodyn Ther 1987, 286:97–110.PubMedGoogle Scholar
  20. 20.
    Conway MA, Allis J, Ouwerkerk R, et al.: Detection of low PCr to ATP ratio in failing hypertrophied myocardium by 31P magnetic resonance spectroscopy. Lancet 1991, 338:973–976.PubMedCrossRefGoogle Scholar
  21. 21.
    Yabe T, Mitsunami K, Inubushi T, Kinoshita M: Quantitative measurements of cardiac phosphorus metabolites in coronary artery disease by 31P magnetic resonance spectroscopy. Circulation 1995, 92:15–23.PubMedGoogle Scholar
  22. 22.
    Nascimben L, Ingwall JS, Pauletto P, et al.: The creatine kinase system in failing and nonfailing human myocardium. Circulation 1996, 94:1894–1901.PubMedGoogle Scholar
  23. 23.
    Fragasso G, De Cobelli F, Perseghin 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 2006, 27:942–948.PubMedCrossRefGoogle Scholar
  24. 24.
    Neubauer S, Horn M, Cramer M, et al.: Myocardial phosphocreatine-to-ATP ratio is a predictor of mortality in patients with dilated cardiomyopathy. Circulation 1997, 96:2190–2196.PubMedGoogle Scholar
  25. 25.
    Fragasso G, Palloshi A, Puccetti P, et al.: A randomized clinical trial of trimetazidine, a partial free fatty acid oxidation inhibitor, in patients with heart failure. J Am Coll Cardiol 2006, 48:992–998.PubMedCrossRefGoogle Scholar
  26. 26.
    Sabbah HN, Chandler MP, Mishima T, et al.: Ranolazine, a partial fatty acid oxidation (pFOX) inhibitor, improves left ventricular function in dogs with chronic heart failure. J Card Fail 2002, 8:416–422.PubMedCrossRefGoogle Scholar
  27. 27.
    Chandler MP, Stanley WC, Morita H, et al.: Short-term treatment with ranolazine improves mechanical efficacy in dogs with chronic heart failure. Circ Res 2002, 91:278–280.PubMedCrossRefGoogle Scholar
  28. 28.
    Hayashida W, van Eyll C, Rousseau MF, Pouleur H: Effects of ranolazine on left ventricular regional diastolic function in patients with ischemic heart disease. Cardiovasc Drugs Ther 1994, 5:741–747.CrossRefGoogle Scholar
  29. 29.
    Aaker A, McCormack JG, Hirai T, Musch TI: Effects of ranolazine on the exercise capacity of rats with chronic heart failure induced by myocardial infarction. J Cardiovasc Pharmacol 1996, 28:353–362.PubMedCrossRefGoogle Scholar
  30. 30.
    McCormack JG, Baracos VE, Barr R, Lopaschuk GD: Effects of ranolazine on oxidative substrate preference in epitrochlearis muscle. J Appl Physiol 1996, 81:905–910.PubMedGoogle Scholar
  31. 31.
    Murray AJ, Anderson RE, Watson GC, et al.: Uncoupling proteins in human heart. Lancet 2004 364:1786–1788.PubMedCrossRefGoogle Scholar
  32. 32.
    Opie LH: The metabolic vicious cycle in heart failure. Lancet 2004, 364:1733–1734.PubMedCrossRefGoogle Scholar
  33. 33.
    Metra M, Ponikowski O, Dickstein K, et al.: Advanced chronic heart failure: a position statement from the Study Group on Advanced Heart Failure of the Heart Failure Association of the European Society of Cardiology. Eur J Heart Fail 2007, 9:684–694.PubMedCrossRefGoogle Scholar
  34. 34.
    Piatti PM, Monti LD, Galli L, et al.: Relationship between endothelin-1 concentrations and the metabolic alterations typical of the insulin resistance syndrome. Metabolism 2000, 49:748–752.PubMedCrossRefGoogle Scholar
  35. 35.
    Piatti PM, Monti LD, Zavaroni I, et al.: Alterations in nitric oxide/cyclic-GMP pathway in nondiabetic siblings of patients with type 2 diabetes. J Clin Endocrinol Metab 2000, 85:2416–2420.PubMedCrossRefGoogle Scholar
  36. 36.
    Crettaz M, Zaninetti D, Jeanrenaud B: Insulin-resistance in heart and skeletal muscles of genetically obese Zucker rats. Biochem Soc Trans 1981, 9:524–525.PubMedGoogle Scholar
  37. 37.
    Natali A, Taddei S, Quiñones Galvan A, et al.: Insulin sensitivity, vascular reactivity, and clamp-induced vasodilatation in essential hypertension. Circulation 1997, 96:725–726.Google Scholar
  38. 38.
    Despres JP, Lamarche B, Mauriege P, et al.: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996, 334:952–957.PubMedCrossRefGoogle Scholar
  39. 39.
    Yoshimura T, Hisatomi A, Kajihara S, et al.: The relationship between insulin resistance and polymorphisms of the endothelial nitric oxide synthase gene in patients with coronary artery disease. J Atheroscler Thromb 2003, 10:43–47.PubMedGoogle Scholar
  40. 40.
    Piatti PM, Fragasso G, Monti LD, et al.: Endothelial and metabolic characteristics of patients with angina and angiographically normal coronary arteries. J Am Coll Cardiol 1999, 34:1452–1460.PubMedCrossRefGoogle Scholar
  41. 41.
    Piatti P, Di Mario C, Monti LD, et al.: Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation 2003, 108:2074–2081.PubMedCrossRefGoogle Scholar
  42. 42.
    Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria. The DECODE study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative analysis Of Diagnostic criteria in Europe. Lancet 1999, 354:617–621.Google Scholar
  43. 43.
    Wallhaus TR, Taylor M, DeGrado TR, Russell DC: Myocardial free fatty acid and glucose use after carvedilol treatment in patients with congestive heart failure. Circulation 2001, 103:2441–2446.PubMedGoogle Scholar
  44. 44.
    Podbregar M, Voga G: Effect of selective and nonselective beta-blockers on resting energy production rate and total body substrate utilization in chronic heart failure. J Card Fail 2002, 8:369–378.PubMedCrossRefGoogle Scholar
  45. 45.
    Poole-Wilson PA, Swedberg K, Cleland JG, et al.: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003, 362:7–13.PubMedCrossRefGoogle Scholar
  46. 46.
    Cohn JN, Pfeffer MA, Rouleau J, et al.: Adverse mortality effect of central sympathetic inhibition with sustained-release moxonidine in patients with heart failure (MOXCON). Eur J Heart Fail 2003, 5:659–667.PubMedCrossRefGoogle Scholar
  47. 47.
    Mobini R, Fu M, Jansson PA, et al.: Influence of central inhibition of sympathetic nervous activity on myocardial metabolism in chronic heart failure: acute effects of the inidazoline I1-receptor agonist moxonidine. Clin Sci (Lond) 2006, 110:329–336.CrossRefGoogle Scholar
  48. 48.
    Cano C, Bermúdez VJ, Medina MT, et al.: Trimetazidine diminishes fasting glucose in rats with fasting hyperglycemia: a preliminary study. Am J Ther 2003, 10:444–446.PubMedCrossRefGoogle Scholar
  49. 49.
    Monti LD, Setola E, Fragasso G, et al.: Metabolic and endothelial effects of trimetazidine on forearm muscle in patients with type 2 diabetes and ischemic cardiomyopathy. Am J Physiol Endocrinol Metab 2006, 290:E54–E59.PubMedCrossRefGoogle Scholar
  50. 50.
    Ryden L, Standl E, Bartnik M: Guidelines on diabetes, prediabetes, and cardiovascular diseases: executive summary. The Task Force on Diabetes and Cardiovascular Diseases of the European Society of Cardiology (ESC) and of the European Association for the Study of Diabetes (EASD). Eur Heart J 2007, 2:88–136.Google Scholar
  51. 51.
    Fragasso G, Piatti P, Monti L, et al.: Acute effects of heparin administration on the ischemic threshold of patients with coronary artery disease: evaluation of the protective role of the metabolic modulator trimetazidine. J Am Coll Cardiol 2002, 39:413–419.PubMedCrossRefGoogle Scholar
  52. 52.
    Yamauchi-Kohno R, Miyauchi T, Hoshino T, et al.: Role of endothelin in deterioration of heart failure due to cardiomyopathy in hamsters: increase in endothelin production in the heart and beneficial effect of endothelin A antagonist on survival and cardiac function. Circulation 1999, 99:2171–2176.PubMedGoogle Scholar
  53. 53.
    Maridonneau-Parini I, Harpey C: Effects of trimetazidine on membrane damage induced by oxygen free radicals in human red cells. Br J Clin Pharmacol 1985, 20:148–151.PubMedGoogle Scholar
  54. 54.
    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.PubMedCrossRefGoogle Scholar
  55. 55.
    Timmis AD, Chaitman BR, Crager M: Effects of ranolazine on exercise tolerance and HbA1c in patients with chronic angina and diabetes. Eur Heart J 2006, 27:42–48.PubMedCrossRefGoogle Scholar
  56. 56.
    Lopashuck GD, Wall SR, Olley PM, Davies NJ: Etomoxir, a carnitine palmitoyltransferase I inhibitor, protects hearts from fatty acid-induced ischemic injury independent of changes in long chain acylcarnitine. Circ Res 1988, 63:1036–1043.Google Scholar
  57. 57.
    Ratheiser K, Schneeweiss B, Waldhausl W, et al.: Inhibition by etomoxir of carnitine palmitoyltransferase I reduces hepatic glucose production and plasma lipids in noninsulin-dependent diabetes mellitus. Metabolism 1991, 40:1185–1190.PubMedCrossRefGoogle Scholar
  58. 58.
    Turcani M, Rupp H: Etomoxir improves left ventricular performance of pressure-overloaded rat heart. Circulation 1997, 96:3681–3686.PubMedGoogle Scholar
  59. 59.
    Zarain-Herzberg A, Rupp H: Therapeutic potential of CPT I inhibitors: cardiac gene transcription as a target. Expert Opin Investig Drugs 2002, 11:345–356.PubMedCrossRefGoogle Scholar
  60. 60.
    Schmidt-Schweda S, Holubarsch C: First clinical trial with etomoxir in patients with chronic congestive heart failure. Clin Sci 2000, 99:27–35.PubMedCrossRefGoogle Scholar
  61. 61.
    Schmitz FJ, Rösen P, Reinauer H: Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl transferase inhibitor etomoxir. Horm Metab Res 1995, 27:515–522.PubMedCrossRefGoogle Scholar
  62. 62.
    Cabreros A, Merlos M, Laguna JC, Carrera MV: Downregulation of acyl-CoA oxidase gene expression and increased NF-kappaB activity in etomoxir-induced cardiac hypertrophy. J Lipid Res 2003, 44:388–398.CrossRefGoogle Scholar
  63. 63.
    Merril CL, Ni H, Yoon LW, et al.: Etomoxir-induced oxidative stress in HepG2 cells detected by differential gene expression is confirmed biochemically. Toxicol Sci 2002, 68:93–101.CrossRefGoogle Scholar
  64. 64.
    Kennedy JA, Kiosoglous AJ, Murphy GA, et al.: Effect of perhexiline and oxfenicine on myocardial function and metabolism during low-flow ischemia/reperfusion in the isolated rat heart. J Cardiovasc Pharmacol 2000, 36:794–801.PubMedCrossRefGoogle Scholar
  65. 65.
    Jeffrey FM, Alvarez L, Diczku V, et al.: Direct evidence that perhexiline modifies myocardial substrate utilization from fatty acids to lactate. J Cardiovasc Pharmacol 1995, 25:469–472.PubMedCrossRefGoogle Scholar
  66. 66.
    Stephens TW, Higgins AJ, Cook GA, Harris RA: Two mechanisms produce tissue-specific inhibition of fatty acid oxidation by oxfenicine. Biochem J 1985, 227:651–660.PubMedGoogle Scholar
  67. 67.
    Bergman G, Atkinson L, Metcalfe J, et al.: Beneficial effect of enhanced myocardial carbohydrate utilisation after oxfenicine (L-hydroxyphenylglycine) in angina pectoris. Eur Heart J 1980, 1:247–253.PubMedGoogle Scholar
  68. 68.
    Cole PL, Beamer AD, McGowan N, et al.: Efficacy and safety of perhexiline maleate in refractory angina: a double-blind placebo-controlled clinical trial of a novel antianginal agent. Circulation 1990, 81:1260–1270.PubMedGoogle Scholar
  69. 69.
    Lee L, Campbell R, Scheuermann-Freestone M, et al.: Metabolic modulation with perhexiline in chronic heart failure. A randomized, controlled trial of short-term use of a novel treatment. Circulation 2005, 112:3280–3288.PubMedCrossRefGoogle Scholar
  70. 70.
    Meier C, Wahllaender A, Hess CW, Preisig R: Perhexiline-induced lipidosis in the dark Agouti (DA) rat. An animal model of genetically determined neurotoxicity. Brain 1986, 109:649–660.PubMedCrossRefGoogle Scholar
  71. 71.
    Killalea SM, Krum H: Systematic review of the efficacy and safety of perhexiline in the treatment of ischemic heart disease. Am J Cardiovasc Drugs 2001, 1:193–204.PubMedCrossRefGoogle Scholar
  72. 72.
    Steg PG, Grollier G, Gallay P, et al.: A randomized double-blind trial of intravenous trimetazidine as adjunctive therapy to primary angioplasty for acute myocardial infarction. Int J Cardiol 2001, 77:263–273.PubMedCrossRefGoogle Scholar
  73. 73.
    Papadopoulos CL, Kanonidis IE, Kotridis PS, et al.: The effect of trimetazidine on reperfusion arrhythmia in acute myocardial infarction. Int J Cardiol 1996, 55:137–142.PubMedCrossRefGoogle Scholar
  74. 74.
    Di Pasquale P, Lo Verso P, Bucca V, et al.: Effects of trimetazidine administration before thrombolysis in patients with anterior myocardial infarction: short-term and long term results. Cardiovasc Drug Ther 1999, 13:423–428.CrossRefGoogle Scholar
  75. 75.
    Fabiani JN, Ponzio O, Emerit I, et al.: Cardioprotective effect of trimetazidine during coronary artery graft surgery. J Cardiovasc Surg 1992, 33:486–491.Google Scholar
  76. 76.
    Kober G, Buck T, Sievert H, et al.: Myocardial protection during percutaneous transluminal angioplasty: effects of trimetazidine. Eur Heart J 1992, 13:1109–1115.PubMedGoogle Scholar
  77. 77.
    Bonello L, Sbragia P, Amabile N, et al.: Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention. Heart 2007, 93:703–707.PubMedCrossRefGoogle Scholar
  78. 78.
    Weiss JN, Korge P, Honda HM, et al.: Role of the mitochondrial permeability transition in myocardial disease. Circ Res 2003, 93:292–301.PubMedCrossRefGoogle Scholar
  79. 79.
    Argaud L, Gomez L, Gateau-Roesch O, et al.: Trimetazidine inhibits mitochondrial permeability transition pore opening and prevents lethal ischemia-reperfusion injury. J Mol Cell Cardiol 2005, 39:893–899.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Gabriele Fragasso
    • 1
  • Roberto Spoladore
  • Giorgio Bassanelli
  • Amarild Cuko
  • Chiara Montano
  • Anna Salerno
  • Alberto Margonato
  1. 1.Heart Failure ClinicIstituto Scientifico San RaffaeleMilanoItaly

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