Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders

Vascular Health and Risk Management

Volumn 7, Issue 1, 2011, Pages 169-176

  Mingorance, Carmen ^a   Rodríguez Rodríguez, Rosalía ^a   Justo, María Luisa ^a   de Sotomayor, María Álvarez ^a   Herrera, María Dolores ^a  

^a UNIVERSITY OF SEVILLE   (Spain)

Author keywords

Acetyl L carnitine; Cardiovascular diseases; Insulin resistance; L carnitine; Propionyl L carnitine

Indexed keywords

ACETYLCARNITINE; ANTIDIABETIC AGENT; CARDIOVASCULAR AGENT; CARNITINE; DRUG DERIVATIVE; PROPIONYLCARNITINE;

ANIMAL; CARDIOVASCULAR DISEASE; EVIDENCE BASED MEDICINE; HUMAN; INSULIN RESISTANCE; METABOLISM; NON INSULIN DEPENDENT DIABETES MELLITUS; PATHOPHYSIOLOGY; REVIEW; TREATMENT OUTCOME;

ACETYLCARNITINE; ANIMALS; CARDIOVASCULAR AGENTS; CARDIOVASCULAR DISEASES; CARNITINE; DIABETES MELLITUS, TYPE 2; EVIDENCE-BASED MEDICINE; HUMANS; HYPOGLYCEMIC AGENTS; INSULIN RESISTANCE; TREATMENT OUTCOME;

EID: 79961174463     PISSN: 11766344     EISSN: 11782048     Source Type: Journal    
DOI: 10.2147/VHRM.S14356     Document Type: Review

References (82)

1. Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6(15):3379-3386.
2. Demarquoy J, Georges B, Rigault C, Royer MC. Radioisotopic determination of L-carnitine content in foods commonly eaten in Western countries. Food Chem. 2004;86:137-142.
3. Zammit VA. Carnitine acyltransferases: functional significance of subcellular distribution and membrane topology. Prog Lipid Res. 1999; 38(3):199-224.
4. Ferri L, Valente M, Ursini F, et al. Acetyl-carnitine formation and pyruvate oxidation in mitochondria from different rat tissues. Bull Mol Biol Med. 1981;6(1-2):16-23.
5. Lysiak W, Lilly K, DiLisa F, Toth PP, Bieber LL. Quantitation of the effect of L-carnitine on the levels of acid-soluble short-chain acyl-CoA and CoASH in rat heart and liver mitochondria. J Biol Chem. 1988; 263(3):1151-1156.
6. 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(6):3758-3763.
7. Broderick TL, Panagakis G, DiDomenico D, et al. L-carnitine improvement of cardiac function is associated with stimulation in glucose but not fatty acid metabolism in carnitine-deficient hearts. Cardiovasc Res. 1995;30(5):815-820.
8. Abozguia K, Shivu GN, Ahmed I, Phan TT, Frenneaux MP. The heart metabolism: pathophysiological aspects in ischaemia and heart failure. Curr Pharm Des. 2009;15(8):827-835.
9. Ferrari R, Merli E, Cicchitelli G, Mele D, Fucili A, Ceconi C. Therapeutic effects of L-carnitine and propionyl-L-carnitine on cardiovascular diseases: a review. Ann N Y Acad Sci. 2004;1033:79-91.
10. Revenco D, Morgan JP. Metabolic modulation and cellular therapy of cardiac dysfunction and failure. J Cell Mol Med. 2009;13(5):811-825.
11. Anon. Acetyl-L-carnitine. Monograph. Altern Med Rev. 2010;15(1): 76-83.
12. Chapela SP, Kriguer N, Fernández EH, Stella CA. Involvement of L-carnitine in cellular metabolism: beyond Acyl-CoA transport. Mini Rev Med Chem. 2009;9(13):1518-1526.
13. Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim Biophys Acta. 2010; 1801(1):1-22.
14. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet. 2010;375(9733):2267-2277.
15. Chess DJ, Stanley WC. Role of diet and fuel overabundance in the development and progression of heart failure. Cardiovasc Res. 2008; 79(2):269-278.
16. Van der Vusse GJ, Prinzen FW, van Bilsen M, Engels W, Reneman RS. Accumulation of lipids and lipid-intermediates in the heart during ischaemia. Basic Res Cardiol. 1987;82(Suppl 1):157-167.
17. Paulson DJ, Traxler J, Schmidt M, et al. Protection of the ischemic myocardium by L-propionylcarnitine: effects on the recovery of cardiac output after ischaemia and reperfusion, carnitine transport and fatty acid oxidation. Cardiovasc Res. 1986;20:536-541.
18. Paulson DJ, Schmidt MJ, Romens J, Shug AL. Metabolic and physiologic differences between zeroflow and low-flow myocardial ischemia: effects of L-acetylcarnitine. Basic Res Cardo. 1984;79(5):551-561.
19. Arsenian MA. Carnitine and its derivatives in cardiovascular disease. Prog Cardiovasc Dis. 1997;40(3):265-286.
20. Ferrari R, De Giuli F. The propionyl-L-carnitine hypothesis: an alternative approach to treating heart failure. J Card Fail. 1997;3(3):217-224.
21. Retter AS. Carnitine and its role in cardiovascular disease. Heart Dis. 1999;1(2):108-113.
22. Calvani M, Arrigoni-Martelli E. Attenuation by acetyl-L-carnitine of neurological damage and biochemical derangement following brain ischemia and reperfusion. Int J Tissue React. 1999;21(1):1-6.
23. Calvani M, Reda E, Arrigoni-Martelli E. Regulation by carnitine of myocardial fatty acid and carbohydrate metabolism under normal and pathological conditions. Basic Res Cardiol. 2000;95(2):75-83.
24. Lango R, Smolenski RT, Narkiewicz M, Suchorzewska J, Lysiak-Szydlowska W. Influence of L-carnitine and its derivatives on myocardial metabolism and function in ischemic heart disease and during cardiopulmonary bypass. Cardiovasc Res. 2001;51(1):21-29.
25. Hagen TM, Moreau R, Suh JH, Visioli F. Mitochondrial decay in the aging rat heart: evidence for improvement by dietary supplementation with acetyl-L-carnitine and/or lipoic acid. Ann N Y Acad Sci. 2002; 959:491-507.
26. Hiatt WR. Carnitine and peripheral arterial disease. Ann N Y Acad Sci. 2004;1033:92-98.
27. Andreozzi GM. Propionyl l-carnitine: intermittent claudication and peripheral arterial disease. Expert Opin Pharmacother. 2009;10(16): 2697-2707.
28. Rosca MG, Lemieux H, Hoppel CL. Mitochondria in the elderly: is acetylcarnitine a rejuvenator? Adv Drug Deliv Rev. 2009;61(14): 1332-1342.
29. Wiseman LR, Brogden RN. Propionyl-L-carnitine. Drugs Aging. 1998; 12(3):243-248.
30. Brevetti G, Perna S, Sabba C, et al. Superiority of L-propionylcarnitine vs L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J. 1992;13(2):251-255.
31. Norgren L, Hiatt WR, Dormandy JA, et al. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). Eur J Vasc Endovasc Surg. 2007;33(Suppl 1):S1-S75.
32. Coto V, D'Alessandro L, Grattarola G, et al. Evaluation of the therapeutic efficacy and tolerability of levocarnitine propionyl in the treatment of chronic obstructive arteriopathies of the lower extremities: a multicentre controlled study vs placebo. Drugs Exp Clin Res. 1992; 18(1):29-36.
33. Brevetti G, Perna S, Sabbá C, Martone VD, Condorelli M. Propionyl-L-carnitine in intermittent claudication: double-blind, placebo-controlled, dose titration, multicenter study. J Am Coll Cardiol. 1995; 26(6):1411-1416.
34. Brevetti G, Perna S, Sabba C, Martone VD, Di Iorio A, Barletta G. Effect of propionyl-L-carnitine on quality of life in intermittent claudication. Am J Cardiol. 1997;79(6):777-780.
35. Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol. 1999;34(5):1618-1624.
36. Dal Lago A, De Martini D, Flore R, et al. Effects of propionyl-L-carnitine on peripheral arterial obliterative disease of the lower limbs: a double-blind clinical trial. Drugs Exp Clin Res. 1999;25(1):29-36.
37. Hiatt WR. New treatment options in intermittent claudication: the US experience. Int J Clin Pract Suppl. 2001;(119):20-27.
38. Barker GA, Green S, Askew CD, Green AA, Walker PJ. Effect of propionyl-L-carnitine on exercise performance in peripheral arterial disease. Med Sci Sports Exerc. 2001;33(9):1415-1422.
39. Ragozzino G, Mattera E, Madrid E, et al. Effects of propionyl-carnitine in patients with type 2 diabetes and peripheral vascular disease: results of a pilot trial. Drugs R D. 2004;5(4):185-190.
40. Andreozzi GM, Leone A, Laudani R, Martin R, Deinit G, Cataldi V. Levo-propionyl-carnitine improves the effectiveness of supervised physical training on the absolute claudication distance in patients with intermittent claudication. Angiology. 2008;59(1):84-89.
41. Allegra C, Antignani PL, Schachter I, Koverech A, Messano M, Virmani A. Propionyl-L-carnitine in Leriche-Fontaine stage II peripheral arterial obstructive disease. Ann Vasc Surg. 2008;22(4): 552-558.
42. Cipolla MJ, Nicoloff A, Rebello T, Amato A, Porter JM. Propionyl-Lcarnitine dilates human subcutaneous arteries through an endotheliumdependent mechanism. J Vasc Surg. 1999;29(6):1097-1103.
43. Loffredo L, Marcoccia A, Pignatelli P, et al. Oxidative-stress-mediated arterial dysfunction in patients with peripheral arterial disease. Eur Heart J. 2007;28(5):608-612.
44. Silvestro A, Schiano V, Bucur R, et al. Effect of propionylcarnitine on changes in endothelial function and plasma levels of adhesion molecules induced by acute exercise in patients with intermittent claudication. Angiology. 2006;57(2):145-154.
45. Pola P, Flore R, Serricchio M, et al. New carnitine derivatives for the therapy of cutaneous ulcers in vasculopathies. Drugs Exp Clin Res. 1991;17(5):277-282.
46. Persico G, Amato B, Aprea G, et al. The early effects of intravenous L-propionyl carnitine on ulcerative trophic lesions of the lower limbs in arteriopathic patients: a controlled randomized study. Drugs Exp Clin Res. 1995;21(5):187-198.
47. Riccioni C, Sarcinella R, Palermo G, et al. Evaluation of the efficacy of propionyl-L-carnitine versus pulsed muscular compressions in diabetic and non-diabetic patients affected by obliterating arteriopathy Leriche stage II. Int Angiol. 2008;27(3):253-259.
48. Milio G, Novo G, Genova C, Luigi Almasio P, Novo S, Pinto A. Pharmacological treatment of patients with chronic critical limb ischemia: L-propionyl-carnitine enhances the short-term effects of PGE-1. Cardiovasc Drugs Ther. 2009;23(4):301-306.
49. Hiatt WR, Creager MA, Amato A, Brass EP. Effect of Propionyl-L-carnitine on a Background of Monitored Exercise in Patients with Claudication secondary to Peripheral Artery Disease. J Cardiopulm Rehabil Prev. 2010. DOI: 10.1097/HCR.0b013e3181f1fd65.
50. Spagnoli LG, Corsi M, Villaschi S, Palmieri G, Maccari F. Myocardial carnitine deficiency in acute myocardial infarction. Lancet. 1982;1(8286): 1419-1420.
51. Dhalla NS, Kolár F, Shah KR, Ferrari R. Effects of some L-carnitine derivatives on heart membrane ATPases. Cardiovasc Drugs Ther. 1991; 5(Suppl 1):25-30.
52. Löster H, Keller T, Grommisch J, Gründer W. Effects of L-carnitine and its acetyl and propionyl esters on ATP and PCr levels of isolated rat hearts perfused without fatty acids and investigated by means of 31PNMR spectroscopy. Mol Cell Biochem. 1999;200(1-2):93-102.
53. Lesnefsky EJ, He D, Moghaddas S, Hoppel CL. Reversal of mitochondrial defects before ischemia protects the aged heart. FASEB J. 2006; 20(9):1543-1545.
54. Cui J, Das DK, Bertelli A, Tosaki A. Effects of L-carnitine and its derivatives on postischemic cardiac function, ventricular fibrillation and necrotic and apoptotic cardiomyocyte death in isolated rat hearts. Mol Cell Biochem. 2003;254(1-2):227-234.
55. Bartels GL, Remme WJ, Pillay M, Schönfeld DH, Kruijssen DA. Effects of L-propionylcarnitine on ischemia-induced myocardial dysfunction in men with angina pectoris. Am J Cardiol. 1994;74(2):125-130.
56. Cherchi A, Lai C, Onnis E, et al. Propionyl carnitine in stable effort angina. Cardiovasc Drugs Ther. 1990;4(2):481-486.
57. Chiddo A, Gaglione A, Musci S, et al. Hemodynamic study of intravenous propionyl-L-carnitine in patients with ischemic heart disease and normal left ventricular function. Cardiovasc Drugs Ther. 1991; 5(Suppl 1):107-111.
58. Lagioia R, Scrutinio D, Mangini SG, et al. Propionyl-L-carnitine: a new compound in the metabolic approach to the treatment of effort angina. Int J Cardiol. 1992;34(2):167-172.
59. Bartels GL, Remme WJ, Holwerda KJ, Kruijssen DA. Anti-ischaemic efficacy of L-propionylcarnitine-a promising novel metabolic approach to ischaemia? Eur Heart J. 1996;17(3):414-420.
60. Lango R, Smoleński RT, Rogowski J, et al. Propionyl-L-carnitine improves hemodynamics and metabolic markers of cardiac perfusion during coronary surgery in diabetic patients. Cardiovasc Drugs Ther. 2005;19(4)267-275.
61. Al-Majed AA, Sayed-Ahmed MM, Al-Omar FA, Al-Yahya AA, Aleisa AM, Al-Shabanah OA. Carnitine esters prevent oxidative stress damage and energy depletion following transient forebrain ischaemia in the rat hippocampus. Clin Exp Pharmacol Physiol. 2006;33(8):725-733.
62. Martin E, Rosenthal RE, Fiskum G. Pyruvate dehydrogenase complex: metabolic link to ischemic brain injury and target of oxidative stress. J Neurosci Res. 2005;79(1-2):240-247.
63. Zanelli SA, Solenski NJ, Rosenthal RE, Fiskum G. Mechanisms of ischemic neuroprotection by acetyl-L-carnitine. Ann N Y Acad Sci. 2005; 1053:153-161.
64. Rosenthal RE, WiUiams R, Bogaert YE, et al. Prevention of postischemic canine neurological injury through potentiation of brain energy metabolism by acetyl-Lcarnitine. Stroke 1992;23:1312-1317.
65. Aureli T, Miccheh A, Di Coceo ME, et al. Effect of acetyl-L-carnitine on recovery of brain phosphorus metabolites and lactic acid level during reperfusion after cerebral ischemia in the rat-study by 13P-and lHNMR spectroscopy. Brain Res 1994;643:92-99.
66. Jalal FY, Böhlke M, Maher TJ. Acetyl-L-carnitine reduces the infarct size and striatal glutamate outflow following focal cerebral ischemia in rats. Ann N Y Acad Sci. 2010;1199:95-104.
67. Rosadini G, Marenco S, Nobili F, et al. Acute effects of acetyl-L-carnitine on regional cerebral blood flow in patients with brain ischaemia. Int J Clin Pharmacol Res. 1990;10:123-128.
68. McMackin CJ, Widlansky ME, Hamburg NM, et al. Effect of combined treatment with alpha-Lipoic acid and acetyl-L-carnitine on vascular function and blood pressure in patients with coronary artery disease. J Clin Hypertens (Greenwich). 2007;9(4):249-255.
69. Gasparetto A, Corbucci GG, De Blasi RA, et al. Influence of acetyl-Lcarnitine infusion on haemodynamic parameters and survival of circulatory-shock patients. Int J Clin Pharmacol Res. 1991;11(2):83-92.
70. Ferrari R, De Giuli F. The propionyl-L-carnitine hypothesis: an alternative approach to treating heart failure. J Card Fail. 1997;3(3):217-224.
71. Ferrari R, Bachetti T, Confortini R, et al. Tumor necrosis factor soluble receptors in patients with various degrees of congestive heart failure. Circulation. 1995;92(6):1479-1486.
72. Ferrari R. Tumor necrosis factor in CHF: a double facet cytokine. Cardiovasc Res.1998;37(3):554-559.
73. The investigators of the study on propionyl-L-carnitine in chronic heart failure. Study on propionyl-L-carnitine in chronic heart failure. Eur Heart J. 1999;20(1):70-76.
74. Anon. Diabetes mellitus: a major risk factor for cardiovascular disease. A joint editorial statement by the American Diabetes Association; The National Heart, Lung, and Blood Institute; The Juvenile Diabetes Foundation International; The National Institute of Diabetes and Digestive and Kidney Diseases; and The American Heart Association. Circulation. 1999;100(10):1132-1133.
75. Zhang L, Keung W, Samokhvalov V, Wang W, Lopaschuk GD. Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. Biochim Biophys Acta. 2010; 1801(1):1-22.
76. Adams SH, Hoppel CL, Lok KH, et al. Plasma acylcarnitine profiles suggest incomplete long-chain fatty acid beta-oxidation and altered tricarboxylic acid cycle activity in type 2 diabetic African-American women. J Nutr. 2009;139(6):1073-1081.
77. Ramsay RR, Zammit VA. Carnitine acyltransferases and their influence on CoA pools in health and disease. Mol Aspects Med. 2004;25(5-6): 475-493.
78. Mingrone G. Carnitine in type 2 diabetes. Ann N Y Acad Sci. 2004; 1033:99-107.
79. Giancaterini A, De Gaetano A, Mingrone G, et al. Acetyl-L-carnitine infusion increases glucose disposal in type 2 diabetic patients. Metabolism. 2000;49(6):704-708.
80. Bloomer RJ, Fisher-Wellman KH, Tucker PS. Effect of oral acetyl L-carnitine arginate on resting and postprandial blood biomarkers in pre-diabetics. Nutr Metab (Lond). 2009;6:25.
81. Ruggenenti P, Cattaneo D, Loriga G, et al. Ameliorating hypertension and insulin resistance in subjects at increased cardiovascular risk: effects of acetyl-L-carnitine therapy. Hypertension. 2009;54(3):567-574.
82. Mingorance C, Gonzalez del Pozo M, Dolores Herrera M, Alvarez de Sotomayor M. Oral supplementation of propionyl-l-carnitine reduces body weight and hyperinsulinaemia in obese Zucker rats. Br J Nutr. 2009;102(8):1145-1153.