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Medium-chain Fatty Acids as Metabolic Therapy in Cardiac Disease

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Abstract

Introduction

Medium-chain fatty acids (MCFAs) have physical and metabolic properties that are distinct from those of long-chain fatty acids, which make them a readily available cellular energy source. These properties have been used advantageously in the clinics for more than 50 years for treating lipid absorption disorders, undernourished patients, and more recently subjects with long-chain fatty acid oxidation defects. In these latter subjects, nutritional interventions with MCFA-containing triglycerides have been shown to improve clinical symptoms, particularly cardiomyopathies.

Potential benefits of MCFA metabolism in cardiac diseases

There is, however, only a limited number of studies that have considered the potential use of MCFAs as metabolic therapy for cardiac diseases in general. Nevertheless, current experimental evidence does support the notion that the diseased heart is energy deficient and that alterations in myocardial energy substrate metabolism contribute to contractile dysfunction and cardiac disease development and progression. Hence, this article will review current literature on MCFAs with a specific emphasis on their metabolism and potential benefits for the heart. It will include practical considerations about the potential clinical application of MCFA therapy for the management of patients with cardiac diseases.

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References

  1. Ruiz-Sanz JI, Aldamiz-Echevarria L, Arrizabalaga J, et al. Polyunsaturated fatty acid deficiency during dietary treatment of very long-chain acyl-CoA dehydrogenase deficiency. Rescue with soybean oil. J Inherit Metab Dis. 2001;24:493–503.

    Article  PubMed  CAS  Google Scholar 

  2. Bach AC, Babayan VK. Medium-chain triglycerides: an update. Am J Clin Nutr. 1982;36:950–62.

    PubMed  CAS  Google Scholar 

  3. Ulrich H, Pastores SM, Katz DP, Kvetan V. Parenteral use of medium-chain triglycerides: a reappraisal. Nutrition. 1996;12:231–8.

    Article  PubMed  CAS  Google Scholar 

  4. Kaunitz H. Medium chain triglycerides (MCT) in aging and arteriosclerosis. J Environ Pathol Toxicol Oncol. 1986;6:115–21.

    PubMed  CAS  Google Scholar 

  5. Decuypere JA, Dierick NA. The combined use of triacylglycerols containing medium-chain fatty acids and exogenous lipolytic enzymes as an alternative to in-feed antibiotics in piglets: concept, possibilities and limitations. An overview. Nutr Res Rev. 2003;16:193–209.

    Article  CAS  PubMed  Google Scholar 

  6. Hu FB, Stampfer MJ, Manson JE, et al. Dietary saturated fats and their food sources in relation to the risk of coronary heart disease in women. Am J Clin Nutr. 1999;70:1001–8.

    PubMed  CAS  Google Scholar 

  7. Graham GG, Baertl JM, Cordano A, Morales E. Lactose-free, medium-chain triglyceride formulas in severe malnutrition. Am J Dis Child. 1973;126:330–5.

    PubMed  CAS  Google Scholar 

  8. Tantibhedhyangkul P, Hashim SA. Medium-chain triglyceride feeding in premature infants: effects on fat and nitrogen absorption. Pediatrics. 1975;55:359–70.

    PubMed  CAS  Google Scholar 

  9. St-Onge MP, Jones PJ. Physiological effects of medium-chain triglycerides: potential agents in the prevention of obesity. J Nutr. 2002;132:329–32.

    PubMed  CAS  Google Scholar 

  10. Geliebter A, Torbay N, Bracco EF, Hashim SA, Van Itallie TB. Overfeeding with medium-chain triglyceride diet results in diminished deposition of fat. Am J Clin Nutr. 1983;37:1–4.

    PubMed  CAS  Google Scholar 

  11. Baba N, Bracco EF, Hashim SA. Enhanced thermogenesis and diminished deposition of fat in response to overfeeding with diet containing medium chain triglyceride. Am J Clin Nutr. 1982;35:678–82.

    PubMed  CAS  Google Scholar 

  12. Papamandjaris AA, MacDougall DE, Jones PJ. Medium chain fatty acid metabolism and energy expenditure: obesity treatment implications. Life Sci. 1998;62:1203–15.

    Article  PubMed  CAS  Google Scholar 

  13. Saudubray JM, Martin D, de Lonlay P, et al. Recognition and management of fatty acid oxidation defects: a series of 107 patients. J Inherit Metab Dis. 1999;22:488–502.

    Article  PubMed  CAS  Google Scholar 

  14. Duran M, Wanders RJ, de Jager JP, et al. 3-Hydroxydicarboxylic aciduria due to long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency associated with sudden neonatal death: protective effect of medium-chain triglyceride treatment. Eur J Pediatr. 1991;150:190–5.

    Article  PubMed  CAS  Google Scholar 

  15. Touma EH, Rashed MS, Vianey-Saban C, et al. A severe genotype with favourable outcome in very long chain acyl-CoA dehydrogenase deficiency. Arch Dis Child. 2001;84:58–60.

    Article  PubMed  CAS  Google Scholar 

  16. Brown-Harrison MC, Nada MA, Sprecher H, et al. Very long chain acyl-CoA dehydrogenase deficiency: successful treatment of acute cardiomyopathy. Biochem Mol Med. 1996;58:59–65.

    Article  PubMed  CAS  Google Scholar 

  17. Cox GF, Souri M, Aoyama T, et al. Reversal of severe hypertrophic cardiomyopathy and excellent neuropsychologic outcome in very-long-chain acyl-coenzyme A dehydrogenase deficiency. J Pediatr. 1998;133:247–53.

    Article  PubMed  CAS  Google Scholar 

  18. Roe CR, Sweetman L, Roe DS, David F, Brunengraber H. Treatment of cardiomyopathy and rhabdomyolysis in long-chain fat oxidation disorders using an anaplerotic odd-chain triglyceride. J Clin Invest. 2002;110:259–69.

    PubMed  CAS  Google Scholar 

  19. Brunengraber H, Roe CR. Anaplerotic molecules: current and future. J Inherit Metab Dis. 2006;29:327–31.

    Article  PubMed  Google Scholar 

  20. Stanley WC, Recchia FA, Lopaschuk GD. Myocardial substrate metabolism in the normal and failing heart. Physiol Rev. 2005;85:1093–129.

    Article  PubMed  CAS  Google Scholar 

  21. Sambandam N, Lopaschuk GD, Brownsey RW, Allard MF. Energy metabolism in the hypertrophied heart. Heart Fail Rev. 2002;7:161–73.

    Article  PubMed  CAS  Google Scholar 

  22. Taegtmeyer H, Ballal K. No low-fat diet for the failing heart? Circulation. 2006;114:2092–3.

    Article  PubMed  CAS  Google Scholar 

  23. 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;264:135–44.

    PubMed  CAS  Google Scholar 

  24. Neubauer S. The failing heart—an engine out of fuel. N Engl J Med. 2007;356:1140–51.

    Article  PubMed  Google Scholar 

  25. Rennison JH, McElfresh TA, Okere IC, et al. High-fat diet postinfarction enhances mitochondrial function and does not exacerbate left ventricular dysfunction. Am J Physiol Heart Circ Physiol. 2007;292:H1498–1506.

    Article  PubMed  CAS  Google Scholar 

  26. Okere IC, McElfresh TA, Brunengraber DZ, et al. Differential effects of heptanoate and hexanoate on myocardial citric acid cycle intermediates following ischemia-reperfusion. J Appl Physiol. 2006;100:76–82.

    Article  PubMed  CAS  Google Scholar 

  27. Tuunanen H, Engblom E, Naum A, et al. Free fatty acid depletion acutely decreases cardiac work and efficiency in cardiomyopathic heart failure. Circulation. 2006;114:2130–7.

    Article  PubMed  CAS  Google Scholar 

  28. Rinaldo P, Matern D, Bennett MJ. Fatty acid oxidation disorders. Annu Rev Physiol. 2002;64:477–502.

    Article  PubMed  CAS  Google Scholar 

  29. Coort SL, Bonen A, van der Vusse GJ, Glatz JF, Luiken JJ. Cardiac substrate uptake and metabolism in obesity and type-2 diabetes: role of sarcolemmal substrate transporters. Mol Cell Biochem. 2007;299:5–18.

    Article  PubMed  CAS  Google Scholar 

  30. Saggerson ED, Carpenter CA. Carnitine palmitoyltransferase and carnitine octanoyltransferase activities in liver, kidney cortex, adipocyte, lactating mammary gland, skeletal muscle and heart. FEBS Lett. 1981;129:229–32.

    Article  PubMed  CAS  Google Scholar 

  31. Schulz H. Regulation of fatty acid oxidation in heart. J Nutr. 1994;124:165–71.

    PubMed  CAS  Google Scholar 

  32. Bian F, Kasumov T, Thomas KR, et al. Peroxisomal and mitochondrial oxidation of fatty acids in the heart, assessed from the 13C labeling of malonyl-CoA and the acetyl moiety of citrate. J Biol Chem. 2005;280:9265–71.

    Article  PubMed  CAS  Google Scholar 

  33. Johnson RC, Young SK, Cotter R, Lin L, Rowe WB. Medium-chain-triglyceride lipid emulsion: metabolism and tissue distribution. Am J Clin Nutr. 1990;52:502–8.

    PubMed  CAS  Google Scholar 

  34. Kinman RP, Kasumov T, Jobbins KA, et al. Parenteral and enteral metabolism of anaplerotic triheptanoin in normal rats. Am J Physiol Endocrinol Metab. 2006;291:E860–866.

    Article  PubMed  CAS  Google Scholar 

  35. Metges CC, Wolfram G. Medium- and long-chain triglycerides labeled with 13C: a comparison of oxidation after oral or parenteral administration in humans. J Nutr. 1991;121:31–6.

    PubMed  CAS  Google Scholar 

  36. Ala-Rami A, Ylihautala M, Ingman P, Hassinen IE. Influence of calcium-induced workload transitions and fatty acid supply on myocardial substrate selection. Metabolism. 2005;54:410–20.

    Article  PubMed  CAS  Google Scholar 

  37. Longnus SL, Wambolt RB, Barr RL, Lopaschuk GD, Allard MF. Regulation of myocardial fatty acid oxidation by substrate supply. Am J Physiol Heart Circ Physiol. 2001;281:H1561–1567.

    PubMed  CAS  Google Scholar 

  38. Montessuit C, Papageorgiou I, Tardy-Cantalupi I, Rosenblatt-Velin N, Lerch R. Postischemic recovery of heart metabolism and function: role of mitochondrial fatty acid transfer. J Appl Physiol. 2000;89:111–9.

    PubMed  CAS  Google Scholar 

  39. Chatham JC, Forder JR. Relationship between cardiac function and substrate oxidation in hearts of diabetic rats. Am J Physiol. 1997;273:H52–58.

    PubMed  CAS  Google Scholar 

  40. Vincent G, Comte B, Poirier M, Des Rosiers C. Citrate release by perfused rat hearts: a window on mitochondrial cataplerosis. Am J Physiol Endocrinol Metab. 2000;278:E846–856.

    PubMed  CAS  Google Scholar 

  41. Poirier M, Vincent G, Reszko AE, et al. Probing the link between citrate and malonyl-CoA in perfused rat hearts. Am J Physiol Heart Circ Physiol. 2002;283:H1379–1386.

    PubMed  CAS  Google Scholar 

  42. Allard MF, Parsons HL, Saeedi R, Wambolt RB, Brownsey R. AMPK and metabolic adaptation by the heart to pressure overload. Am J Physiol Heart Circ Physiol. 2007;292:H140–148.

    Article  PubMed  CAS  Google Scholar 

  43. Vincent G, Bouchard B, Khairallah M, Des Rosiers C. Differential modulation of citrate synthesis and release by fatty acids in perfused working rat hearts. Am J Physiol Heart Circ Physiol. 2004;286:H257–266.

    Article  PubMed  CAS  Google Scholar 

  44. Labarthe F, Khairallah M, Bouchard B, Stanley WC, Des Rosiers C. Fatty acid oxidation and its impact on response of spontaneously hypertensive rat hearts to an adrenergic stress: benefits of a medium-chain fatty acid. Am J Physiol Heart Circ Physiol. 2005;288:H1425–1436.

    Article  PubMed  CAS  Google Scholar 

  45. Pravenec M, Kren V. Genetic analysis of complex cardiovascular traits in the spontaneously hypertensive rat. Exp Physiol. 2005;90:273–6.

    Article  PubMed  CAS  Google Scholar 

  46. Vincent G, Khairallah M, Bouchard B, Des Rosiers C. Metabolic phenotyping of the diseased rat heart using 13C-substrates and ex vivo perfusion in the working mode. Mol Cell Biochem. 2003;242:89–99.

    Article  PubMed  CAS  Google Scholar 

  47. Hajri T, Ibrahimi A, Coburn CT, et al. Defective fatty acid uptake in the spontaneously hypertensive rat is a primary determinant of altered glucose metabolism, hyperinsulinemia, and myocardial hypertrophy. J Biol Chem. 2001;276:23661–6.

    Article  PubMed  CAS  Google Scholar 

  48. Panchal AR, Comte B, Huang H, et al. Partitioning of pyruvate between oxidation and anaplerosis in swine hearts. Am J Physiol Heart Circ Physiol. 2000;279:H2390–2398.

    PubMed  CAS  Google Scholar 

  49. Comte B, Vincent G, Bouchard B, Benderdour M, Des Rosiers C. Reverse flux through cardiac NADP(+)-isocitrate dehydrogenase under normoxia and ischemia. Am J Physiol Heart Circ Physiol. 2002;283:H1505–1514.

    PubMed  CAS  Google Scholar 

  50. Sundqvist KE, Vuorinen KH, Peuhkurinen KJ, Hassinen IE. Metabolic effects of propionate, hexanoate and propionylcarnitine in normoxia, ischaemia and reperfusion. Does an anaplerotic substrate protect the ischaemic myocardium? Eur Heart J. 1994;15:561–70.

    PubMed  CAS  Google Scholar 

  51. Bonnet D, Martin D, de Lonlay P, et al. Arrhythmias and conduction defects as presenting symptoms of fatty acid oxidation disorders in children. Circulation. 1999;100:2248–53.

    PubMed  CAS  Google Scholar 

  52. Gillingham MB, Scott B, Elliott D, Harding CO. Metabolic control during exercise with and without medium-chain triglycerides (MCT) in children with long-chain 3-hydroxy acyl-CoA dehydrogenase (LCHAD) or trifunctional protein (TFP) deficiency. Mol Genet Metab. 2006;89:58–63.

    Article  PubMed  CAS  Google Scholar 

  53. Olpin SE. Implications of impaired ketogenesis in fatty acid oxidation disorders. Prostaglandins Leukot Essent Fatty Acids. 2004;70:293–308.

    Article  PubMed  CAS  Google Scholar 

  54. Schuler AM, Gower BA, Matern D, Rinaldo P, Wood PA. Influence of dietary fatty acid chain-length on metabolic tolerance in mouse models of inherited defects in mitochondrial fatty acid beta-oxidation. Mol Genet Metab. 2004;83:322–9.

    Article  PubMed  CAS  Google Scholar 

  55. Shen JJ, Matern D, Millington DS, et al. Acylcarnitines in fibroblasts of patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency and other fatty acid oxidation disorders. J Inherit Metab Dis. 2000;23:27–44.

    Article  PubMed  CAS  Google Scholar 

  56. Vianey-Saban C, Divry P, Brivet M, et al. Mitochondrial very-long-chain acyl-coenzyme A dehydrogenase deficiency: clinical characteristics and diagnostic considerations in 30 patients. Clin Chim Acta. 1998;269:43–62.

    Article  PubMed  CAS  Google Scholar 

  57. Jones PM, Butt Y, Bennett MJ. Accumulation of 3-hydroxy-fatty acids in the culture medium of long-chain L-3-hydroxyacyl CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein-deficient skin fibroblasts: implications for medium chain triglyceride dietary treatment of LCHAD deficiency. Pediatr Res. 2003;53:783–7.

    Article  PubMed  CAS  Google Scholar 

  58. Parini R, Invernizzi F, Menni F, et al. Medium-chain triglyceride loading test in carnitine-acylcarnitine translocase deficiency: insights on treatment. J Inherit Metab Dis. 1999;22:733–9.

    Article  PubMed  CAS  Google Scholar 

  59. Shimojo N, Miyauchi T, Iemitsu M, et al. Effects of medium-chain triglyceride (MCT) application to SHR on cardiac function, hypertrophy and expression of endothelin-1 mRNA and other genes. J Cardiovasc Pharmacol. 2004;44:S181–185.

    Article  Google Scholar 

  60. Rupp H, Schulze W, Vetter R. Dietary medium-chain triglycerides can prevent changes in myosin and SR due to CPT-1 inhibition by etomoxir. Am J Physiol. 1995;269:R630–640.

    PubMed  CAS  Google Scholar 

  61. Madden MC, Wolkowicz PE, Pohost GM, McMillin JB, Pike MM. Acylcarnitine accumulation does not correlate with reperfusion recovery in palmitate-perfused rat hearts. Am J Physiol. 1995;268:H2505–2512.

    PubMed  CAS  Google Scholar 

  62. Finck BN, Han X, Courtois M, et al. A critical role for PPAR alpha-mediated lipotoxicity in the pathogenesis of diabetic cardiomyopathy: modulation by dietary fat content. Proc Natl Acad Sci U S A. 2003;100:1226–31.

    Article  PubMed  CAS  Google Scholar 

  63. Borradaile NM, Schaffer JE. Lipotoxicity in the heart. Curr Hypertens Rep. 2005;7:412–7.

    Article  PubMed  CAS  Google Scholar 

  64. Okere IC, Chandler MP, McElfresh TA, et al. Carnitine palmitoyl transferase-I inhibition is not associated with cardiac hypertrophy in rats fed a high-fat diet. Clin Exp Pharmacol Physiol. 2007;34:113–9.

    Article  PubMed  CAS  Google Scholar 

  65. Fox JE, Magga J, Giles WR, Light PE. Acyl coenzyme A esters differentially activate cardiac and beta-cell adenosine triphosphate-sensitive potassium channels in a side-chain length-specific manner. Metabolism. 2003;52:1313–9.

    Article  PubMed  CAS  Google Scholar 

  66. Yamada KA, Kanter EM, Newatia A. Long-chain acylcarnitine induces Ca2+ efflux from the sarcoplasmic reticulum. J Cardiovasc Pharmacol. 2000;36:14–21.

    Article  PubMed  CAS  Google Scholar 

  67. Paradies G, Ruggiero FM. Enhanced activity of the tricarboxylate carrier and modification of lipids in hepatic mitochondria from hyperthyroid rats. Arch Biochem Biophys. 1990;278:425–30.

    Article  PubMed  CAS  Google Scholar 

  68. Lai JC, Liang BB, Jarvi EJ, Cooper AJ, Lu DR. Differential effects of fatty acyl coenzyme A derivatives on citrate synthase and glutamate dehydrogenase. Res Commun Chem Pathol Pharmacol. 1993;82:331–8.

    PubMed  CAS  Google Scholar 

  69. Han J, Hamilton JA, Kirkland JL, Corkey BE, Guo W. Medium-chain oil reduces fat mass and down-regulates expression of adipogenic genes in rats. Obes Res. 2003;11:734–44.

    Article  PubMed  CAS  Google Scholar 

  70. Wanten GJ, Calder PC. Immune modulation by parenteral lipid emulsions. Am J Clin Nutr. 2007;85:1171–84.

    PubMed  CAS  Google Scholar 

  71. Miller GJ. Effects of diet composition on coagulation pathways. Am J Clin Nutr. 1998;67:542–5.

    Google Scholar 

  72. Covington DK, Briscoe CA, Brown AJ, Jayawickreme CK. The G-protein-coupled receptor 40 family (GPR40-GPR43) and its role in nutrient sensing. Biochem Soc Trans. 2006;34:770–3.

    Article  PubMed  CAS  Google Scholar 

  73. Kostenis E. A glance at G-protein-coupled receptors for lipid mediators: a growing receptor family with remarkably diverse ligands. Pharmacol Ther. 2004;102:243–57.

    Article  PubMed  CAS  Google Scholar 

  74. Hill JO, Peters JC, Swift LL, et al. Changes in blood lipids during six days of overfeeding with medium or long chain triglycerides. J Lipid Res. 1990;31:407–16.

    PubMed  CAS  Google Scholar 

  75. Wollin SD, Wang Y, Kubow S, Jones PJ. Effects of a medium chain triglyceride oil mixture and alpha-lipoic acid diet on body composition, antioxidant status, and plasma lipid levels in the Golden Syrian hamster. J Nutr Biochem. 2004;15:402–10.

    Article  PubMed  CAS  Google Scholar 

  76. Buxton DB, Barron LL, Taylor MK, Olson MS. Regulatory effects of fatty acids on decarboxylation of leucine and 4-methyl-2-oxopentanoate in the perfused rat heart. Biochem J. 1984;221:593–9.

    PubMed  CAS  Google Scholar 

  77. Paxton R, Harris RA. Regulation of branched-chain alpha-keto acid dehydrogenase kinase. Arch Biochem Biophys. 1984;231:48–57.

    Article  PubMed  CAS  Google Scholar 

  78. Kimball SR, Jefferson LS. New functions for amino acids: effects on gene transcription and translation. Am J Clin Nutr. 2006;83:500S–7S.

    PubMed  CAS  Google Scholar 

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Acknowledgements

This work was supported by the Canadian Institutes of Health Research (CIHR Grant # 9575 to C.D.R.) and by the Montreal Heart Institute Foundation. The authors are grateful to Dr Henri Brunengraber, for providing 13C-labelled heptanoate, Dr Robert A. Harris for stimulating discussions, and Bertrand Bouchard for technical assistance.

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Correspondence to Christine Des Rosiers.

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Grants: This study was supported by the Canadian Institutes of Health Research (CIHR Grant # 9575 to C.D.R.) and by the Montreal Heart Institute Foundation.

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Labarthe, F., Gélinas, R. & Des Rosiers, C. Medium-chain Fatty Acids as Metabolic Therapy in Cardiac Disease. Cardiovasc Drugs Ther 22, 97–106 (2008). https://doi.org/10.1007/s10557-008-6084-0

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