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Current Atherosclerosis Reports

, Volume 7, Issue 1, pp 63–70 | Cite as

Fatty acid oxidation inhibitors in the management of chronic complications of atherosclerosis

  • Clifford D. L. Folmes
  • Alexander S. Clanachan
  • Gary D. Lopaschuk
Article

Abstract

Ischemic heart disease is characterized by a modification of the normal energy balance of the heart. During and following an ischemic event, circulating fatty acids are elevated, resulting in the acceleration of fatty acid oxidation at the expense of glucose oxidation. Despite the reduction in glucose oxidation, the rate of glycolysis increases, leading to an uncoupling of glucose metabolism. This results in the accumulation of metabolic byproducts, which leads to a decrease in cardiac efficiency. A novel therapeutic strategy involves improving the efficiency of oxygen utilization by the ischemic heart by the modulation of energy metabolism. This can be achieved by a reduction in the levels of circulating fatty acids using β-blockers, glucose-insulin-potassium infusions, and nicotinic acid. Alternatively, fatty acid oxidation can be directly inhibited using trimetazidine, ranolazine, or glucose oxidation directly activated using dichloroacetate, which significantly improves the efficiency of the heart.

Keywords

Fatty Acid Oxidation Glucose Oxidation Ranolazine Trimetazidine Dichloroacetate 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References and Recommended Reading

  1. 1.
    Opie LH: Heart Physiology, from Cell to Circulation. Philadelphia: Lippincott-Raven; 1998.Google Scholar
  2. 2.
    Neely JR, Morgan HE: Relationship between carbohydrate and lipid metabolism and the energy balance of heart muscle. Annu Rev Physiol 1974, 36:413–459.CrossRefGoogle Scholar
  3. 3.
    King LM, Opie LH: Glucose and Glycogen utilisation in myocardial ischemia—changes in metabolism and consequences for the myocyte. Mol Cell Biochem 1998, 180:3–26.PubMedCrossRefGoogle Scholar
  4. 4.
    Sambandam N, Lopaschuk GD: AMP-activated protein kinase (AMPK) control of fatty acid and glucose metabolism in the ischemic heart. Prog Lipid Res 2003, 42:238–256.PubMedCrossRefGoogle Scholar
  5. 5.
    Lopaschuk GD, Belke DD, Gamble J, et al.: Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994, 1213:263–276.PubMedGoogle Scholar
  6. 6.
    Stanley WC, Chandler MP: Energy metabolism in the normal and failing heart: potential for therapeutic interventions. Heart Fail Rev 2002, 7:115–130.PubMedCrossRefGoogle Scholar
  7. 7.
    Bonen A, Luiken JJ, Glatz JF: Regulation of fatty acid transport and membrane transporters in health and disease. Mol Cell Biochem 2002, 239:181–192.PubMedCrossRefGoogle Scholar
  8. 8.
    Takahashi S, Sakai J, Fujino T, et al.: The very low density lipoprotein (VLDL) receptor—a peripheral lipoprotein receptor for remnant lipoproteins into fatty acid active tissues. Mol Cell Biochem 2003, 248:121–127.PubMedCrossRefGoogle Scholar
  9. 9.
    Abel ED: Glucose transport in the heart. Front Biosci 2004, 9:201–215.PubMedCrossRefGoogle Scholar
  10. 10.
    Randle PJ, Garland PB, Hales CN, Newsholme EA: The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet 1963, 1:785–789.PubMedCrossRefGoogle Scholar
  11. 11.
    Liu B, Clanachan AS, Schulz R, Lopaschuk GD: Cardiac efficiency is improved after ischemia by altering both the source and fate of protons. Circ Res 1996, 79:940–948.PubMedGoogle Scholar
  12. 12.
    Liu B, el Alaoui-Talibi Z, Clanachan AS, et al.: Uncoupling of contractile function from mitochondrial TCA cycle activity and MVO2 during reperfusion of ischemic hearts. Am J Physiol 1996, 270(1 Pt 2):H72-H80.PubMedGoogle Scholar
  13. 13.
    Benzi RH, Lerch R: Dissociation between contractile function and oxidative metabolism in postischemic myocardium. Attenuation by ruthenium red administered during reperfusion. Circ Res 1992, 71:567–576.PubMedGoogle Scholar
  14. 14.
    Lopaschuk GD, Spafford MA, Davies NJ, Wall SR: Glucose and palmitate oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circ Res 1990, 66:546–553.PubMedGoogle Scholar
  15. 15.
    Saddik M, Lopaschuk GD: Myocardial triglyceride turnover and contribution to energy substrate utilization in isolated working rat hearts. J Biol Chem 1991, 266:8162–8170.PubMedGoogle Scholar
  16. 16.
    Oliver MF, Opie LH: Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias. Lancet 1994, 343:155–158.PubMedCrossRefGoogle Scholar
  17. 17.
    Lopaschuk GD, Collins-Nakai R, Olley PM, et al.: Plasma fatty acid levels in infants and adults after myocardial ischemia. Am Heart J 1994, 128:61–67.PubMedCrossRefGoogle Scholar
  18. 18.
    Kudo N, Barr AJ, Barr RL, et al.: High rates of fatty acid oxidation during reperfusion of ischemic hearts are associated with a decrease in malonyl-CoA levels due to an increase in 5′-AMP-activated protein kinase inhibition of acetyl-CoA carboxylase. J Biol Chem 1995, 270:17513–17520.PubMedCrossRefGoogle Scholar
  19. 19.
    Hardie DG: AMP-activated protein kinase: a master switch in glucose and lipid metabolism. Rev Endocr Metab Disord 2004, 5:119–125.PubMedCrossRefGoogle Scholar
  20. 20.
    Dyck JR, Kudo N, Barr AJ, et al.: Phosphorylation control of cardiac acetyl-CoA carboxylase by cAMP-dependent protein kinase and 5′-AMP activated protein kinase. Eur J Biochem 1999, 262:184–190.PubMedCrossRefGoogle Scholar
  21. 21.
    Musi N, Goodyear LJ: AMP-activated protein kinase and muscle glucose uptake. Acta Physiol Scand 2003, 178:337–345.PubMedCrossRefGoogle Scholar
  22. 22.
    Marsin AS, Bertrand L, Rider MH, et al.: Phosphorylation and activation of heart PFK-2 by AMPK has a role in the stimulation of glycolysis during ischaemia. Curr Biol 2000, 10:1247–1255.PubMedCrossRefGoogle Scholar
  23. 23.
    Karmazyn M: The role of the myocardial sodium-hydrogen exchanger in mediating ischemic and reperfusion injury. From amiloride to cariporide. Ann N Y Acad Sci 1999, 874:326–334.PubMedCrossRefGoogle Scholar
  24. 24.
    Sterling D, Casey JR: Bicarbonate transport proteins. Biochem Cell Biol 2002, 80:483–497.PubMedCrossRefGoogle Scholar
  25. 25.
    Karmazyn M, Moffat MP: Na+/H+ exchange and regulation of intracellular Ca2+. Cardiovasc Res 1993, 27:2079–2080.PubMedGoogle Scholar
  26. 26.
    Teo KK, Yusuf S, Furberg CD: Effects of prophylactic antiarrhythmic drug therapy in acute myocardial infarction. An overview of results from randomized controlled trials. JAMA 1993, 270:1589–1595.PubMedCrossRefGoogle Scholar
  27. 27.
    Sodi-Pallares D, Ponce de LJ, Bisteni A, Medrano GA: Potassium, glucose, and insulin in myocardial infarction. Lancet 1969, 1:1315–1316.PubMedCrossRefGoogle Scholar
  28. 28.
    Fath-Ordoubadi F, Beatt KJ: Glucose-insulin-potassium therapy for treatment of acute myocardial infarction: an overview of randomized placebo-controlled trials. Circulation 1997, 96:1152–1156.PubMedGoogle Scholar
  29. 29.
    Diaz R, Paolasso EA, Piegas LS, et al.: Metabolic modulation of acute myocardial infarction. The ECLA (Estudios Cardiologicos Latinoamerica) Collaborative Group. Circulation 1998, 98:2227–2234.PubMedGoogle Scholar
  30. 30.
    Rosenson RS: Antiatherothrombotic effects of nicotinic acid. Atherosclerosis 2003, 171:87–96.PubMedCrossRefGoogle Scholar
  31. 31.
    Brown WV: Review of clinical trials: proving the lipid hypothesis. Eur Heart J 1990, 11(Suppl H):15–20.PubMedGoogle Scholar
  32. 32.
    Datta S, Das DK, Engelman RM, et al.: Enhanced myocardial preservation by nicotinic acid, an antilipolytic compound: mechanism of action. Basic Res Cardiol 1989, 84:63–76.PubMedCrossRefGoogle Scholar
  33. 33.
    Trueblood NA, Ramasamy R, Wang LF, Schaefer S: Niacin protects the isolated heart from ischemia-reperfusion injury. Am J Physiol Heart Circ Physiol 2000, 279:H764-H771.PubMedGoogle Scholar
  34. 34.
    Kantor PF, Lucien A, Kozak R, Lopaschuk 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
  35. 35.
    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:e33-e37.PubMedCrossRefGoogle Scholar
  36. 36.
    d’Alche P, Clauser P, Morel M, Gauthier V: Assessment with potential mapping of the cardiac protective effect of a drug. Example of trimetazidine. J Pharmacol Methods 1991, 26:43–51.PubMedCrossRefGoogle Scholar
  37. 37.
    Libersa C, Honore E, Adamantidis M, et al.: Antiischemic effect of trimetazidine: enzymatic and electric response in a model of in-vitro myocardial ischemia. Cardiovasc Drugs Ther 1990, 4(Suppl 4):808–809.PubMedCrossRefGoogle Scholar
  38. 38.
    Boucher FR, Hearse DJ, Opie LH: Effects of trimetazidine on ischemic contracture in isolated perfused rat hearts. J Cardiovasc Pharmacol 1994, 24:45–49.PubMedCrossRefGoogle Scholar
  39. 39.
    El BH, Bernard M, Baetz D, et al.: Changes in intracellular sodium and pH during ischaemia-reperfusion are attenuated by trimetazidine. Comparison between low- and zero-flow ischaemia. Cardiovasc Res 2000, 47:688–696.CrossRefGoogle Scholar
  40. 40.
    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.PubMedGoogle Scholar
  41. 41.
    la-Volta S, Maraglino G, la-Valentina P, et al.: Comparison of trimetazidine with nifedipine in effort angiona: a double-blind, crossover study. Cardiovasc Drugs Ther 1990, 4(Suppl 4):853–859.CrossRefGoogle Scholar
  42. 42.
    Levy S: Combination therapy of trimetazidine with diltiazem in patients with coronary artery disease. Group of South of France Investigators. Am J Cardiol 1995, 76:12B-16B.PubMedCrossRefGoogle Scholar
  43. 43.
    Sellier P, Audouin P, Payen B, et al.: Acute effects of trimetazidine evaluated by exercise testing. Eur J Clin Pharmacol 1987, 33:205–207.PubMedCrossRefGoogle Scholar
  44. 44.
    Sellier P, Audouin P, Payen B, et al.: Ergometric effects of a single administration of trimetazidine. Presse Med 1986, 15:1771–1774.PubMedGoogle Scholar
  45. 45.
    Kober G, Buck T, Sievert H, Vallbracht C: Myocardial protection during percutaneous transluminal coronary angioplasty: effects of trimetazidine. Eur Heart J 1992, 13:1109–1115.PubMedGoogle Scholar
  46. 46.
    Clarke B, Wyatt KM, McCormack JG: Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hearts: evidence for an indirect mechanism. J Mol Cell Cardiol 1996, 28:341–350.PubMedCrossRefGoogle Scholar
  47. 47.
    McCormack JG, Barr RL, Wolff AA, Lopaschuk GD: Ranolazine stimulates glucose oxidation in normoxic, ischemic, and reperfused ischemic rat hearts. Circulation 1996, 93:135–142.PubMedGoogle Scholar
  48. 48.
    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
  49. 49.
    Gralinski MR, Black SC, Kilgore KS, et al.: Cardioprotective effects of ranolazine (RS-43285) in the isolated perfused rabbit heart. Cardiovasc Res 1994, 28:1231–1237.PubMedGoogle Scholar
  50. 50.
    Schofield RS, Hill JA: The use of ranolazine in cardiovascular disease. Expert Opin Investig Drugs 2002, 11:117–123.PubMedCrossRefGoogle Scholar
  51. 51.
    Chaitman BR, Skettino SL, Parker JO, et al.: Anti-ischemic effects and long-term survival during ranolazine monotherapy in patients with chronic severe angina. J Am Coll Cardiol 2004, 43:1375–1382.PubMedCrossRefGoogle Scholar
  52. 52.
    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
  53. 53.
    Stacpoole PW: The pharmacology of dichloroacetate. Metabolism 1989, 38:1124–1244.PubMedCrossRefGoogle Scholar
  54. 54.
    Lopaschuk GD, Wambolt RB, Barr RL: An imbalance between glycolysis and glucose oxidation is a possible explanation for the detrimental effects of high levels of fatty acids during aerobic reperfusion of ischemic hearts. J Pharmacol Exp Ther 1993, 264:135–144.PubMedGoogle Scholar
  55. 55.
    McVeigh JJ, Lopaschuk GD: Dichloroacetate stimulation of glucose oxidation improves recovery of ischemic rat hearts. Am J Physiol 1990, 259(4 Pt 2):H1079-H1085.PubMedGoogle Scholar
  56. 56.
    Mjos OD, Miller NE, Riemersma RA, Oliver MF: Effects of dichloroacetate on myocardial substrate extraction, epicardial ST-segment elevation, and ventricular blood flow following coronary occlusion in dogs. Cardiovasc Res 1976, 10:427–436.PubMedCrossRefGoogle Scholar
  57. 57.
    Wagovich TJ, MacDonald RG, Hill JA, et al.: Myocardial metabolic and hemodynamic effects of dichloroacetate in coronary artery disease. Am J Cardiol 1988, 61:65–70.CrossRefGoogle Scholar

Copyright information

© Current Science Inc 2005

Authors and Affiliations

  • Clifford D. L. Folmes
    • 1
  • Alexander S. Clanachan
    • 1
  • Gary D. Lopaschuk
    • 1
  1. 1.Cardiovascular Research GroupUniversity of AlbertaEdmontonCanada

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