Heart Failure Reviews

, Volume 7, Issue 2, pp 115–130

Energy Metabolism in the Normal and Failing Heart: Potential for Therapeutic Interventions

  • William C. Stanley
  • Margaret P. Chandler
Article

Abstract

The chronically failing heart has been shown to be metabolically abnormal, in both animal models and in patients. Little data are available on the rate of myocardial glucose, lactate and fatty acid metabolism and oxidation in heart failure patients, thus at present, it is not possible to draw definitive conclusions about cardiac substrate preference in the various stages and manifestations of the disease. Normal cardiac function is dependent on a constant resynthesis of ATP by oxidative phosphorylation in the mitochondria. The healthy heart gets 60–90% of its energy for oxidative phosphorylation from fatty acid oxidation, with the balance from lactate and glucose. There is some indication that compensated NYHA Class III heart failure patients have a significantly greater rate of lipid oxidation, and decreased glucose uptake and carbohydrate oxidation compared to healthy age-matched individuals, and that therapies that acutely switch the substrate of the heart away from fatty acids result in improvement in left ventricular function. Clinical studies using long-term therapy with beta-adrenergic receptor antagonists show improved left ventricular function that corresponds with a switch away from fatty acid oxidation towards more carbohydrate oxidation by the heart. These findings suggest that chronic manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less fatty acid oxidation may improve ventricular performance and slow the progression of left ventricular dysfunction in heart failure patients. At present, this intriguing hypothesis requires further evaluation.

cardiac heart glucose lactate myocardial metabolism pyruvate dehydrogenase 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    American Heart Association 1998. Heart and Stroke Statistical Update. Dallas, Texas.Google Scholar
  2. 2.
    Rich MW, Nease RF. Cost effectiveness analysis in clinical practice: the case of heart failure. Arch Intern Med 1999;159:1690–1700.Google Scholar
  3. 3.
    From AHL. Should manipulation of myocardial substrate utilization patterns be a component of the congestive heart failure therapeutic paradigm? J Cardiac Failure 1998;4:127–129.Google Scholar
  4. 4.
    Stanley WC, Hoppel CL. Mitochondrial dysfunction in heart failure: potential for therapeutic interventions? Cardiovasc Res 2000;45:805–806.Google Scholar
  5. 5.
    Stanley WC, Lopaschuk GD, Hall JL, McCormack JG. Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions: potential for pharmacological interventions. Cardiovasc Res 1997;33:243–257.Google Scholar
  6. 6.
    McCormack JG, Stanley WC, Wolff AA. Pharmacology of ranolazine: a novel metabolic modulator for the treatment of angina. Gen Pharmacol 1998;30:639–645.Google Scholar
  7. 7.
    Opie LH. The Heart: Physiology and Metabolism, 2nd ed. New York: Raven Press, 1991;208–276.Google Scholar
  8. 8.
    Taegtmeyer H. Energy metabolism in the heart. Curr Prob Cardiol 1994;19:59–113.Google Scholar
  9. 9.
    Suga H. Ventricular energetics. Physiol Rev 1990; 70:247–277.Google Scholar
  10. 10.
    Lopaschuk GD, Belke DD, Gamble J, Itoi T, Schönekess BO. Regulation of fatty acid oxidation in the mammalian heart in health and disease. Biochim Biophys Acta 1994;1213:263–276.Google Scholar
  11. 11.
    Wisneski JA, Gertz EW, Neese RA, Mayr M. Myocardial metabolism of free fatty acids: studies with 14Clabeled substrates in humans. J Clin Invest 1987; 79:359–366.Google Scholar
  12. 12.
    van der Vusse GJ, van Bilsen M, Glatz JF. Cardiac fatty acid uptake and transport in health and disease. Cardiovasc Res 2000;45:279–293.Google Scholar
  13. 13.
    Awan AA, Saggerson ED. Malonyl-CoA metabolism in cardiac myocytes and its relevance to the control of fatty acid oxidation. Biochem J 1993;295:61–66.Google Scholar
  14. 14.
    Kerner J, Bieber LL. Isolation of a malonyl-CoA sensitive CPT/beta-oxidation complex from heart mitochondria. Biochem 1990;29:4326–4334.Google Scholar
  15. 15.
    McGarry JD, Mills SE, Long CS, Foster DW. Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Biochem J 1983;214: 21–28.Google Scholar
  16. 16.
    McGarry JD. The mitochondrial carnitine palmitoyltransferase system: its broadening role in fuel homoestasis and new insights into its molecular features. Biochem Soc Trans 1995;23:321–324.Google Scholar
  17. 17.
    Brand MD, Chien LF, Ainscow EK, Rolfe DF, Porter RK. The causes and functions of mitochondrial proton leak. Biochim Biophys Acta 1994;1187:132–139.Google Scholar
  18. 18.
    Borst P, Loos JA, Christ EJ, Slater EC. Uncoupling activity of long-chain fatty acids. Biochim Biophy Acta 1962;62:509–518.Google Scholar
  19. 19.
    Pressman BC, Lardy HA. Effects of surface active agents on the latent ATPase of mitochondria. Biochim Biophys Acta 1956;21:458-466.Google Scholar
  20. 20.
    Burkhoff D, Weiss RG, Schulman SP, Kalil-Filho R, Wannenburg T, Gerstenblith G. Influence of metabolic substrate on rat heart function and metabolism at different coronary flows. Am J Physiol 1991; 261:H741–H750.Google Scholar
  21. 21.
    Mjøs OD. Effect of free fatty acids on myocardial function and oxygen consumption in intact dogs. J Clin Invest 1971;50:1386–1389.Google Scholar
  22. 22.
    Kjekshus JK, Mjøs OD. Effect of free fatty acids on myocardial function and metabolism in the ischemic dog heart. J Clin Invest 1972;51:1767–1776.Google Scholar
  23. 23.
    Liedtke AJ. Alterations of carbohydrate and lipid metabolism in the acutely ischemic heart. Prog Cardiovas Dis 1981;23:321–326.Google Scholar
  24. 24.
    Liedtke AJ, DeMaison L, Eggleston AM, Cohen LM, Nellis SH. Changes in substrate metabolism and effects of excess fatty acids in reperfused myocardium. Circ Res 1988;62:535–542.Google Scholar
  25. 25.
    Lopaschuk GD, Spafford MA, Davies NJ, Walls SR. Glucose and palmite oxidation in isolated working rat hearts reperfused after a period of transient global ischemia. Circ Res 1990;66:546–553.Google Scholar
  26. 26.
    Hutter JF, Schweickhardt C, Piper HM, Spieckermann PG. Inhibition of fatty acid oxidation and decrease of oxygen consumption of working rat heart by 4-bromochrotonic acid. J Mol Cell Cardiol 1984;16:105–108.Google Scholar
  27. 27.
    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.Google Scholar
  28. 28.
    Young LH, Renfu Y, Russell R, Hu X, Caplan M, Ren J, Shulman GI, Sinusas AJ. Low-flow ischemia leads to translocation of canine heart GLUT-4 and GLUT-1 glucose transporters to the sarcolemma in vivo [see comments]. Circulation 1997;5:415–422.Google Scholar
  29. 29.
    Russell RR, III, Yin R, Caplan MJ, Hu X, Ren J, Shulman GI, Sinusas AJ, Young LH. Additive effects of hyperinsulinemia and ischemia on myocardial GLUT1 and GLUT4 translocation in vivo. Circulation 1998;98:2180–2186.Google Scholar
  30. 30.
    Kashiway Y, Sato K, Tsuchiya N, Thomas S, Fell DA, Veech RL, Passonneau JV. Control of glucose utilization in working perfused rat heart. J Biol Chem 1994;269:25502–25514.Google Scholar
  31. 31.
    Depre C, Rider MH, Veitch K, Hue L. Role of fructose 2,6-bisphosphate in the control of heart glycolysis. J Biol Chem 1993;268:13274–13279.Google Scholar
  32. 32.
    Hue L, Depre C, Lefebvre V, Rider MH, Veitch K. Regulation of glucose metabolism in cardiac muscle. Biochem Soc Trans 1995;23:311–314.Google Scholar
  33. 33.
    Kobayashi K, Neely JR. Control of maximum rates of glycolysis in rat cardiac muscle. Circ Res 1979; 44:166–175.Google Scholar
  34. 34.
    Rovetto MJ, Lamberton WF, Neely JR. Mechanism of glycolytic inhibition in ischemic rat hearts. Circ Res 1975;37:742–751.Google Scholar
  35. 35.
    Gertz EW, Wisneski JA, Stanley WC, Neese RA. Myocardial substrate utilization during exercise in humans: dual carbon-labeled carbohydrate isotope experiments. J Clin Invest 1988;82:2017–2025.Google Scholar
  36. 36.
    Stanley WC. Myocardial lactate metabolism duringf exercise. Med Sci Sport Exerc 1991;23:920–924.Google Scholar
  37. 37.
    Garcia C, Goldstein JL, Pathak RK, Anderson RGW, Brown MS. Molecular characterization of a membrane transporter for lactate, pyruvate, and other monocarboxylates: implication for the Cori cycle. Cell 1994;76:865–873.Google Scholar
  38. 38.
    Wang X, Levi AJ, Halestrap AP. Kinetics of the sarcolemmal lactate carrier in single heart cells using BCECF to measure pHi. Am J Physiol 1994;267:H1759–H1769.Google Scholar
  39. 39.
    Gertz EW, Wisneski JA, Neese RA, Bristow JD, Searle GL, Hanlon JT. Myocardial lactate metabolism: evidence of lactate release during net chemical extraction in man. Circulation 1981;63:1273–1279.Google Scholar
  40. 40.
    Randle PJ. Fuel selection in animals. Biochem Soc Trans 1986;14:799–806.Google Scholar
  41. 41.
    Kerbey AL, Randle PJ, Cooper RH, Whitehouse S, Pask HT, Denton RM. Regulation of pyruvate dehydrogenase. Biochem J 1976;154:327–348.Google Scholar
  42. 42.
    McCormack JG, Halestrap AP, Denton RM. Role of calcium ions in regulation of mammalian intramitochondrial metabolism. Physiol Rev 1990;70: 391–425.Google Scholar
  43. 43.
    Randle PJ, Newsholme EA, Garland PB. Regulation of glucose uptake by muscle. Effects of fatty acids, ketone bodies and pyruvate, and of alloxan diabetes and starvation, on the uptake and metabolic fate of glucose in rat heart and diaphragm muscles. Biochem J 1964;93:652–665.Google Scholar
  44. 44.
    Wieland O, Siess E, Schulze-Wethmar FH, Funcke HG, Winton B. Active and inactive forms of pyruvate dehydrogenase in rat heart and kidney: effect of diabetes, fasting and refeeding on pyruvate dehydrogenase interconversion. Arch Biochem Biophys 1971; 143:593–601.Google Scholar
  45. 45.
    Bowker-Kinley MM, Davis WI, Wu P, Harris RA, Popov KM. Evidence for existence of tissue-specific regulation of the mammalian pyruvate dehydrogenase complex. Biochem J 1998;329:191–196.Google Scholar
  46. 46.
    Wu P, Sato J, Zhao Y, Jaskiewicz J, Popov KM, Harris RA. Starvation and diabetes increase the amount of pyruvate dehydrogenase kinase isoenzyme 4 in rat heart. Biochem J 1998;329:197–201.Google Scholar
  47. 47.
    Hansford RG, Cohen L. Relative importance of pyruvate dehydrogenase interconversion and feed-back inhibition in the effect of fatty acids on pyruvate oxidation by rat heart mitochondria. Arch Biochem Biophys 1978;191:65–81.Google Scholar
  48. 48.
    Higgins AJ, Morville M, Burges RA, Blackburn KJ. Mechanism of action of oxfenicine on muscle metabolism. Biochem Biophys Res Com 1981;100:291–296.Google Scholar
  49. 49.
    Higgins AJ, Morville M, Burges RA, Gardiner DG, Page MG, Blackburn KJ. Oxfenicine diverts rat muscle metabolism from fatty acid to carbohydrate oxidation and protects the ischemia rat heart. Life Sci 1980;27:963–970.Google Scholar
  50. 50.
    Kerner J, Zaluzec E, Cage D, Bieber LL. Characterization of the malonyl-CoA-sensitive carnitine palmitoyltransferase (CPTO) of a rat heart mitochondrial particle. J Biol Chem 1994;269:8209–8219.Google Scholar
  51. 51.
    Thampy KG. Formation of malonyl coenzyme A in rat heart. J Biol Chem 1989;264:17631–17634.Google Scholar
  52. 52.
    Kim YS, Kolattukudy PE. Purification and properties of malonyl-CoA decarboxylase from rat liver mitochondria and its immunological comparison with the enzymes from rat brain, heart, and mammary gland. Arch Biochem Biophys 1978;190:234–246.Google Scholar
  53. 53.
    Kudo N, Barr AJ, Barr RL, Desai S, Lopaschuk GD. 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.Google Scholar
  54. 54.
    Whitehouse S, Cooper RH, Randle PJ. Mechanism of activation of pyruvate dehydrogenase by dichloroacetate and other halogenated carboxylic acids. Biochem J 1974;141:761–774.Google Scholar
  55. 55.
    Saddik M, Gamble J, Witters LA, Lopaschuk GD. Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart. J Biol Chem 1993;286: 25836–25845.Google Scholar
  56. 56.
    Stanley WC, Hernandez LA, Spires DA, Bringas J, Wallace S, McCormack JG. Pyruvate dehydrogenase activity and malonyl-CoA levels in normal and ischemic swine myocardium: effects of dichloroacetate. J Mol Cell Cardiol 1996;29:905–914.Google Scholar
  57. 57.
    Lysiak W, Toth PP, Suelter CH, Bieber L. Quantification of the efflux of acylcarnitines on the levels of acid-soluble short-chain acyl-CoA and CoASH on rat heart and liver mitochondria. J Biol Chem 1986;261:10698–10703.Google Scholar
  58. 58.
    Guth BD, Wisneski JA, Neese RA, White FC, Heusch G, Mazer CD. Myocardial lactate release during ischemia in swine. Relation to regional blood flow. Circulation 1990;81:1948–1958.Google Scholar
  59. 59.
    McNulty PH, Sinusas AJ, Shi CQ, Dione D, Young LH, Cline GC, Shulman GI. Glucose metabolism distal to a critical coronary stenosis in a canine model of low-flow myocardial ischemia. J Clin Invest 1996;98:62–69.Google Scholar
  60. 60.
    Liedtke AJ, Nellis SH, Neely JR. Effects of excess free fatty acids on mechanical and metabolic function in normal and ischemia myocardium in swine. Circ Res 1978;43:652–661.Google Scholar
  61. 61.
    Liedtke AJ, NeIlis SH, Mjos OD. Effects of reducing fatty acid metabolism on mechanical function in regionally ischemia hearts. Am J Physiol 1984; 247:H387–H394.Google Scholar
  62. 62.
    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.Google Scholar
  63. 63.
    Renstrom B, Nellis SH, Liedtke AJ. Metabolic oxidation of glucose during early myocardial reperfusion. Circ Res 1989;65:1094–1101.Google Scholar
  64. 64.
    Schwaiger M, Neese RA, Araujo L, Wyns W, Wisneski JA, Socher H, Swank S, Kulber D, Selin C, Phelps M. Sustained nonoxidative glucose utilization and depletion of glycogen in reperfused canine myocardium. J Am Coll Cardiol 1989;13:745–754.Google Scholar
  65. 65.
    Jeffrey FMH, Diczku V, Sherry AD, Malloy CR. Substrate selection in the isolated working rat heart: effects of reperfusion, afterload and concentration. Basic Res Cardiol 1995;90:388–396.Google Scholar
  66. 66.
    Lewandowski ED, White LT. Pyruvate dehydrogenase influences postischemic heart function. Circulation 1995;91:2071–2079.Google Scholar
  67. 67.
    Paolisso G, Gambardella A, Galzerano D, D'Amore A, Rubino P, Verza M, Teasuro P, Varricchio M, D'Onofrio F. Total body and myocardial substrate oxidation in congestive heart failure. Metabolism 1994;43:174–179.Google Scholar
  68. 68.
    Recchia FA, McConnell PI, Bernstein RD, Vogel TR, Xu X, Hintze TH. Reduced nitric oxide production and altered myocardial metabolism during the decompensation of pacing-induced heart failure in the conscious dog. Circ Res 1998;83: 969–979.Google Scholar
  69. 69.
    Sack MN, Rader TA, Park S, Bastin J, McCune SA, Kelly DP. Fatty acid oxidation enzyme gene expression is downregulated in the failing heart. Circulation 1996;94:2837–2842.Google Scholar
  70. 70.
    Bashore TM, Magorien DJ, Letterio J, Shaffer P, Unverferth DV. Histologic and biochemical correlates of left ventricular chamber dynamics in man. J Am Coll Cardiol 1987;9:734–742.Google Scholar
  71. 71.
    Sanbe A, Tanonake K, Kobayasi R, Takeo S. Effect of long-term therapy with ACE inhibitors on myocardial energy metabolism in rats with heart failure following myocardial infarction. J Mol Cell Cardiol 1995;27:2209–2222.Google Scholar
  72. 72.
    Sabbah HN, Sharov VG, Riddle JM, Kono T, Lesch M, Goldstein S. Mitochondrial abnormalities in myocardium of dogs with chronic heart failure. J Mol Cell Cardiol 1992;24:1333–1347.Google Scholar
  73. 73.
    Sharov VG, Sabbah HN, Cook JM, Silverman N, Lesch M, Goldstein S. Abnormal mitochondrial respiration in failed human and dog myocardium. J Mol Cell Cardiol 1998;30:1757–1762.Google Scholar
  74. 74.
    Jarreta D, Orius J, Barrientos A, Miro O, Roig E, Heras M, Moraes CT, Cardellach F, Casademont J. Mitochondrial function in heart muscle from patients with idiopathic dilated cardiomyopathy. Cardiovasc Res 2000;45:805–806.Google Scholar
  75. 75.
    Kelly DP, Strauss AW. Inherited Cardiomyopathies. N Engl J Med 1994;330:913–919.Google Scholar
  76. 76.
    Moourmans J, Wendel U, Bentlage HACM, Trijbels JMF, Smeitink JAM, de Coo IFM, Gabreels FJM, Senders RCA, Ruitenbeek W. Clinical heterogeneity in respiratory chain complex III deficiency in childhood. J Neurol Sci 1997;149:111–117.Google Scholar
  77. 77.
    Palmer JW, Tandler B, Hoppel CL. Biochemical properties of subsarcolemmar and interfibrillar mitochondria isolated from rat cardiac muscle. J Biol Chem 1977;252:8731–8739.Google Scholar
  78. 78.
    Lesnefsky EJ, Tandler B, Ye J, Slabe TJ, Turkaly J, Hoppel CL. Myocardial ischemia decreases oxidative phosphorylation through cytochrome oxidase in subsarcolemmal mitochondria. Am J Physiol 1997; 273:H1544–H1554.Google Scholar
  79. 79.
    Fannin SW, Lesnefsky EJ, Slabe TJ, Hassan MO, Hoppel CL. Aging selectively decreases oxidative capacity in rat heart interfibrillar mitochondria. Arch Biochem Biophys 2000;372:399–407.Google Scholar
  80. 80.
    Hoppel CL, Tandler B, Parland W, Turkaly JS, Albers LD. Hamster cardiomyopathy: a defect in oxidative phosphorylation in the cardiac interfibrillar mitochondria. J Biol Chem 1982;257:1540–1548.Google Scholar
  81. 81.
    Di Lisa F, Chong-Zu F, Gambassi G, Hogue GA, Kudryashova I, Hansford RG. Altered pyruvate dehydrogenase control and mitochondrial and free Ca2+ in hearts of cardiomyopathic hamsters. Am J Physiol 1993;264:H2188–H2197.Google Scholar
  82. 82.
    Panchal AR, Stanley WC, Kerner J, Sabbah HN. Beta-receptor blockade decreases carnitine palmitoyl transferase I activity in dogs with heart failure. J Cardiac Failure 1998;4:121–126.Google Scholar
  83. 83.
    Hall JL, Stanley WC, Lopaschuk GD, Wisneski JA, Pizzurro RD, Hamilton CD, McCormack JG. Impaired pyruvate oxidation but not glucose uptake in diabetic pig heart during dobutamine stress. Am J Physiol 1996;271:H2320–H2329.Google Scholar
  84. 84.
    Hall JL, Lopaschuk GD, Pizzurro RD, Bringas J, Stanley WC. Increased cardiac fatty acid uptake with dobutamine infusion in swine is accompanied by a decrease in malonyl-CoA levels. Cardiovasc Res 1996;32:879–885.Google Scholar
  85. 85.
    Depre C, Shipley GL, Chen W, Han Q, Doenst T, Moore ML, Stepkowski S, Davies PJA, Taegtmeyer H. Unloaded heart in vivo replicates fetal gene expression of cardiac hypertrophy. Nature Med 1998;4:1269–1275.Google Scholar
  86. 86.
    Weis BC, Esser V, Foster DW, McGarry JD. Rat heart expresses two forms of mitochondrial carnitine palmitoyltransferase I. J Biol Chem 1994;269: 18712–18715.Google Scholar
  87. 87.
    Xia, Y, Buja M, McMillin JB. Change in expression of heart carnitine palmitoyltransferase I isoforms with electrical stimulation of cultured rat neonatal cardiac myocytes. J Biol Chem 1996;271:12082–12087.Google Scholar
  88. 88.
    Katz AM. Mechanisms and abnormalities of contractility and relaxation in the failing heart. Cardiologia 1993;38:39–43.Google Scholar
  89. 89.
    Katz AM. Metabolism of the failing heart. Cardioscience 1993;4:199–203.Google Scholar
  90. 90.
    Clarke B, Spedding M, Patmore L, McCormack JG. Protective effects of ranolazine in guinea-pig hearts during low-flow ischemia and their association with increases in active pyruvate dehydrogenase. Br J Pharmacol 1993;109:748–750.Google Scholar
  91. 91.
    Clarke B, Wyatt KM, McCormack JG. Ranolazine increases active pyruvate dehydrogenase in perfused normoxic rat hears: evidence for an indirect mechanism. J Mol Cell Cardiol 1996;28:341–350.Google Scholar
  92. 92.
    Fantini E, Demaison L, Sentex E, Grynberg A, Athias P. Some biochemical aspects of the protective effect of trimetazidine on rat cardiomyocytes during hypoxia and reoxygenation. J Mol Cell Cardiol 1994;26:949–958.Google Scholar
  93. 93.
    Passeron J. Effectiveness of trimetazidine instable effort angina due to chronic coronary insufficiency: a double-blind placebo study. Presse Med 1986;15:1775–1778.Google Scholar
  94. 94.
    Wolff A. 49th Annual Scientific Session of the American College of Cardiology. MARISA: monotherapy assessment of Ranolazine in stable angina. J Am Coll Cardiol 2000; 35(Suppl A):408A.Google Scholar
  95. 95.
    Bersin RM, Wolfe C, Kwasman M, Lau D, Klinski C, Tanaka K, Khorrami P, Henderson GN, de-Marco T, Chatterjee K. Improved hemodynamic function and mechanical efficiency in congestive heart failure with sodium dichloroacetate. J Am Coll Cardiol 1994;23: 1617–1624.Google Scholar
  96. 96.
    Sabbah HN, Mishima T, Biesiadecki BJ, Suzuki G, Chaudhry P, Blackburn B, Huang HL, Stanley WC. Ranolazine improves left ventricular performance in dogs with chronic heart failure. J Am Col Cardiol 2000;35(Suppl. A):218A.Google Scholar
  97. 97.
    Hermann HP, Peike B, Schwarzuller E, Jeul J, Just H, Hasenfuss G. Haemodynamic effects of intracoronary pyruvate in patients with congestive heart failure: an open study. Lancet 1999;353:1321–1323.Google Scholar
  98. 98.
    Mallet RT. Pyruvate: metabolic protector of cardiac performance. Proc Soc Exp Biol Med 2000;223:136–148.Google Scholar
  99. 99.
    D'hahan N, Taouil K, Dassouli A, Morel JE. Longterm therapy with trimetazidine in cardiomyopathic Syrian hamster BIO 14:6. Euro J Pharmacol 1997;328:163–174.Google Scholar
  100. 100.
    Byrson JM, Cooney GJ, Wensley VR, Phuyal JL, Caterson JD. The effects of the inhibition of fatty acid oxidation on pyruvate dehydrogenase complex activity in tissues of lean and obese mice. Internat J Obesity 1996;20:733–738.Google Scholar
  101. 101.
    Schmitz FJ, Rosen P, Reinauer H. Improvement of myocardial function and metabolism in diabetic rats by the carnitine palmitoyl transferase inhibitor etomoxir. Hormone Metab Res 1995;27:515–522.Google Scholar
  102. 102.
    Rupp H, Schulze W, Vetter R. Dietary medium-chain triglycerides can prevent changes in myosin and SR due to CPT-I inhibition by etomoxir. Am J Physiol 1995;269:R630–R640.Google Scholar
  103. 103.
    Rupp H, Brilla CG, Maisch B, Turcani M. Effects of CPT-I inhibition on myocyte gene expression in overloaded hearts. J Cell Mol Cardiol 1997;L42 (abstract).Google Scholar
  104. 104.
    Turcani M, H Rupp. Etomoxir improves left ventricular performance of pressure-overloaded rat heart. Circulation 1997;96:3681–3686.Google Scholar
  105. 105.
    Vetter R, Rupp H. CPT-I inhibition by etomoxir has a chamber-related action on cardiac sarcoplasmic reticulum and isomyosins. Am J Physiol 1994;267: H2091–H2099.Google Scholar
  106. 106.
    Schmidt-Schweda S, Holubarsch C. First clinical trial with etomoxir in patients with chronic heart failure NYHA II-III. J Mol Cell Cardiol 1997;29:A55.Google Scholar
  107. 107.
    Broderick TL, Quinney HA, Lopaschuk GD. Carnitine stimulation of glucose oxidation in the fatty acid perfused isolated working rat heart. J Biol Chem 1992;267:3758–3763.Google Scholar
  108. 108.
    Iliceto S, Scrutinio D, Bruzzi P, D'Ambrosio G, Boni L, Di Biase M, Biasco G, Hugenholtz PG, Rizzon P, on behalf of the CEDIM investigators. Effects of L-carnitine administration on left ventricular re modeling after acute anterior myocardial infarction: the L-carnitine ecocardiografia digitalizzsta infarto miocardico (CEDIM) tria. J Am Coll Cardiol 1995;26: 380–387.Google Scholar
  109. 109.
    Rizos I. Three-year survival of patients with heart failure caused by dilated cardiomyopathy and Lcarnitine administration. Am Heart J 2000;139: S120–S123.Google Scholar
  110. 110.
    Andersson B, Hamm C, Persson S, Wikstrom G, Sinagra G, Hjalmarson A, Waagstein F. Improved exercise hemodynamic status in dilated cardiomyopathy after beta-adrenergic blockade treatment. J Am Coll Cardiol 1994;23:1397–1404.Google Scholar
  111. 111.
    Andersson B, Lomsky M, Waagstein F. The link between acute haemodynamic adrenergic beta-blockade and long-term effects in patients with heart failure. A study on diastolic function, heart rate and myocardial metabolism following intravenous metoprolol. Eur Heart J 1993;14:1375–1385.Google Scholar
  112. 112.
    Bristow MR, Gilbert EM, Abraham WT, Adams KF, Fowler MB, Hershberger R, et al. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation 1996;94:2807–2816.Google Scholar
  113. 113.
    Colucci WS, Packer M, Bristow MR, Gilbert M, Cohn JN, Fowler MB, et al. Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. Circulation 1996;94:2800–2806.Google Scholar
  114. 114.
    Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, et al. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet 1993;342:1441–1446.Google Scholar
  115. 115.
    Andersson B, Blomstrom-Lundqvist C, Hedner T, Waagstein F. Exercise haemodynamics and myocardial metabolism during long-term beta-adrenergic blockade in severe heart failure. J Am Coll Cardiol 1991;18:1059–1066.Google Scholar
  116. 116.
    Eichhorn EJ, Heesch CM, Barnett JH, Alvarez LG, Fass SM, Grayburn PA, et al. Effect of metoprolol on myocardial function and energetics in patients with non-ischemic dilated cardiomyopathy: a randomized, double-blind, placebo controlled study. J Am Coll Cardiol 1994;24:1310–1320.Google Scholar
  117. 117.
    Eichhorn EJ, Bedotto JB, Malloy CR, Hatfield BA, Deitchman D, Brown M, et al. Effect of beta-adrenergic blockade on myocardial function and energetics in congestive heart failure. Circulation 1990;82:473–483.Google Scholar
  118. 118.
    Wallhaus TR, Taylor M, DeGrado TR, Russell DC, Stanko P, Nickles RJ, Stone CK. Myocardial fatty acid and glucose use after cardveditol treatment in patients with congestive heart failure. Circulation 2001;103:2441–2446.Google Scholar

Copyright information

© Kluwer Academic Publishers 2002

Authors and Affiliations

  • William C. Stanley
    • 1
  • Margaret P. Chandler
    • 1
  1. 1.Department of Physiology and BiophysicsCase Western Reserve UniversityCleveland

Personalised recommendations