Beneficial Effects of Propionyl L-Carnitine Therapy in Diabetic Cardiomyopathy

  • Khushman Kaur Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada;
  • Lorrie Kirshenbaum Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada;
  • Paramjit S Tappia Asper Clinical Research Institute, St. Boniface Hospital, Winnipeg, Canada
  • Naranjan S Dhalla Institute of Cardiovascular Sciences, St. Boniface Hospital Albrechtsen Research Centre, Department of Physiology and Pathophysiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada
Keywords: Diabetic cardiomyopathies, Propionyl L-carnitine, Palmitoyl L-carnitine, Oxidative stress, Sarcolemma, Sarcoplasmic reticulum, Mitochondria

Abstract


In this review, the beneficial effects of metabolic therapy with propionyl L-carnitine (PPLC) on cardiovascular complications during the development of diabetic cardiomyopathy was evaluated. Since metabolic abnormalities due to mitochondrial dysfunction are invariably associated with deficiency of carnitine, accumulation of toxic long-chain derivatives of fatty acids and development of oxidative stress in the heart, it appears that the effects of PPLC therapy are related to the attenuation of these derangements. Particularly, the beneficial effects of PPLC therapy in improving cardiac function in chronic diabetes were associated with attenuation of increase in sarcolemmal Ca2+-binding and Ca2+-ecto ATPase activities. Furthermore, depressed sarcolemmal Na+-K+ ATPase and Na+-dependent Ca2+-uptake as well as sarcoplasmic reticulum Ca2+-pump activities in diabetic hearts were attenuated by PPLC therapy. These actions of PPLC therapy were accompanied by improvement in mitochondrial oxidative phosphorylation and attenuation of changes in the high energy phosphate stores in the diabetic heart. Since incubation of sarcolemma with PPLC was found to reduce the inhibitory actions of palmitoyl L-carnitine on Na+-K+ ATPases and Na+-dependent Ca2+-uptake, it is suggested that PPLC therapy may attenuate cardiac abnormalities by antagonising the deleterious actions of accumulated long- chain lipids in diabetic cardiomyopathy.

References

Dhalla NS, Pierce GN, Innes IR, Beamish RE. Pathogenesis of cardiac dysfunction in diabetes mellitus. Can J Cardiol. 1985;1(4):263-281. PMID: 3850773.

Dhalla NS, Liu X, Panagia V, Takeda N. Subcellular remodeling and heart dysfunction in chronic diabetes. Cardiovasc Res. 1998;40(2):239-47. doi:10.1016/s0008-6363(98)00186-2.

Candido R, Srivastava P, Cooper ME, Burrell LM. Diabetes mellitus: a cardiovascular disease. Curr Opin Investig Drugs. 2003;4(9):1088-94. PMID: 14582453.

Asghar O, Al-Sunni A, Khavandi K, Khavandi A, Withers S, Greenstein A, Heagerty AM, Malik RA. Diabetic cardiomyopathy. Clin Sci (Lond). 2009;116(10):741-60. doi: 10.1042/CS20080500.

Watanabe K, Thandavarayan RA, Harima M, Sari FR, Gurusamy N, Veeraveedu PT, et al. Role of differential signaling pathways and oxidative stress in diabetic cardiomyopathy. Curr Cardiol Rev. 2010;6(4):280-90. doi: 10.2174/157340310793566145.

Sharma A, Tate M, Mathew G, Vince JE, Ritchie RH, de Haan JB. Oxidative stress and NLRP3-inflammasome activity as significant drivers of diabetic cardiovascular complications: therapeutic implications. Front Physiol. 2018;9:114. doi: 10.3389/fphys.2018.00114.

Ganguly PK, Pierce GN, Dhalla NS. Diabetic cardiomyopathy: membrane dysfunction and therapeutic strategies. J Appl Cardiol. 1987;2(4):323-38.

Karan A, Bhakkiyalakshmi E, Jayasuriya R, Sarada DVL, Ramkumar KM. The pivotal role of nuclear factor erythroid 2-related factor 2 in diabetes-induced endothelial dysfunction. Pharmacol Res. 2020;153:104601. PMID: 31838079.

De Blasio MJ, Huynh K, Qin C, Rosli S, Kiriazis H, Ayer A, et al. Therapeutic targeting of oxidative stress with coenzyme Q10 counteracts exaggerated diabetic cardiomyopathy in a mouse model of diabetes with diminished PI3K(p110α) signaling. Free Radic Biol Med. 2015;87:137-47. doi: 10.1016/j.freeradbiomed.2015.04.028.

Packer M. Differential pathophysiological mechanisms in heart failure with a reduced or preserved ejection fraction in diabetes. JACC Heart Fail. 2021;9(8):535-549. doi: 10.1016/j.jchf.2021.05.019.

Stanley WC, Lopaschuk GD, McCormack JG. Regulation of energy substrate metabolism in the diabetic heart. Cardiovasc Res. 1997;34(1):25-33. doi: 10.1016/s0008-6363(97)00047-3.

Lopaschuk GD, Ussher JR, Folmes CD, Jaswal JS, Stanley WC. Myocardial fatty acid metabolism in health and disease. Physiol Rev. 2010;90(1):207-58. doi: 10.1152/physrev.00015.2009.

Adameova A and Dhalla NS. Role of microangiopathy in diabetic cardiomyopathy. Heart Fail Rev. 2014; 19:25-33. doi: 10.1007/s10741-013-9378-7.

Dhalla NS, Takeda N, Rodriguez-Leyva D, Elimban V. Mechanisms of subcellular remodeling in heart failure due to diabetes. Heart Fail Rev. 2014;19(1):87-99. doi: 10.1007/s10741-013-9385-8.

Xu YJ, Tappia PS, Neki NS, Dhalla NS. Prevention of diabetes-induced cardiovascular complications upon treatment with antioxidants. Heart Fail Rev. 2014 ;19(1):113-21. doi: 10.1007/s10741-013-9379-6.

Shaffer SW. Cardiomyopathy associated with non-insulin-dependent diabetes. Mol Cell Biochem. 1991;107:1-20. doi: 10.1007/BF02424571.

Varga ZV, Giricz Z, Liaudet L, Haskó G, Ferdinandy P, Pacher P. Interplay of oxidative, nitrosative/nitrative stress, inflammation, cell death and autophagy in diabetic cardiomyopathy. Biochim Biophys Acta. 2015;1852(2):232-42. doi: 10.1016/j.bbadis.2014.06.030.

Verma SK, Garikipati VNS, Kishore R. Mitochondrial dysfunction and its impact on diabetic heart. Biochim Biophys Acta Mol Basis Dis. 2017;1863(5):1098-05. doi: 10.1016/j.bbadis.2016.08.021.

Roul D, Recchia FA. Metabolic alterations induce oxidative stress in diabetic and failing hearts: different pathways, same outcome. Antioxid Redox Signal. 2015 Jun ;22(17):1502-14. doi: 10.1089/ars.2015.6311.

Dhalla NS, Shah AK, Tappia PS. Role of oxidative stress in metabolic and subcellular abnormalities in diabetic cardiomyopathy. Int J Mol Sci. 2020;21(7):2413. doi: 10.3390/ijms21072413.

Tappia PS, Elimban V, Shah AK, Goyal RK, Dhalla NS. Improvement of cardiac function and subcellular defects due to chronic diabetes upon treatment with sarpogrelate. J Cardiovasc Dev Dis. 2024;11(7):215. doi: 10.3390/jcdd11070215.

Siliprandi N, Di Lisa F, Menabo R. Propionyl -L-Carnitine: biochemical significance and possible role in cardiac metabolism. 1991: 5(Suppl 1):11-5. doi: 10.1007/BF00128238.

Arsenian MA. Carnitine and its derivatives in cardiovascular disease. Prog Cardiovasc Dis. 1997;40(3):265-86. doi: 10.1016/s0033-0620(97)80037-0.

Retter AS. Carnitine and its role in cardiovascular disease. Heart Dis. 1999;1(2):108-13. PMID: 11720611.

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. doi: 10.1007/s003950050167.

Vargiu R, Licheri D, Carcassi AM, Naimi S, Collu M, Littarru GP, et al. Enhancement of muscular performance by a coformulation of propionyl-L-carnitine, coenzyme Q10, nicotinamide, riboflavin and pantothenic acid in the rat. Physiol Behav. 2002;76(2):257- 63. doi: 10.1016/s0031-9384(02)00717-5.

Mingorance C, Rodríguez-Rodríguez R, Justo ML, de Sotomayor AM, Herrera MD. Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders. Vasc Health Risk Manag. 2011;7:169-76. doi: 10.2147/VHRM.S14356.

Marcovina SM, Sirtori C, Peracino A, Gheorghiade M, Borum P, Remuzzi G, et al. Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine. Transl Res. 2013;161(2):73-84. doi: 10.1016/j.trsl.2012.10.006.

Arsenian MA. Carnitine and its derivatives in cardiovascular disease. Prog Cardiovasc Dis. 1997;40(3):265-86. doi: 10.1016/s0033-0620(97)80037-0.

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. doi: 10.1196/annals.1320.007.

Mingorance C, Rodriguez-Rodriguez R, Justo ML, Herrera MD, de Sotomayor AM. Pharmacological effects and clinical applications of propionyl-L-carnitine. Nutr Rev. 2011;69(5):279-90. doi: 10.1111/j.1753-4887.2011.00387.x.

Mingorance C, Rodríguez-Rodríguez R, Justo ML, de Sotomayor AM, Herrera MD. Critical update for the clinical use of L-carnitine analogs in cardiometabolic disorders. Vasc Health Risk Manag. 2011;7:169-76. doi: 10.2147/VHRM.S14356.

Marcovina SM, Sirtori C, Peracino A, Gheorghiade M, Borum P, Remuzzi G, et al. Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine. Transl Res. 2013;161(2):73-84. doi: 10.1016/j.trsl.2012.10.006.

Tripp ME, Katcher ML, Peters HA, Gilbert EF, Arya S, Hodach RJ, et al. Systemic carnitine deficiency presenting as familial endocardial fibroelastosis: a treatable cardiomyopathy. N Engl J Med. 1981;305(7):385-90. doi: 10.1056/NEJM198108133050707.

Kondrup J and Mortensen SA. Endomyocardial levels of free and total carnitine in patients with cardiomyopathy. Heart Failure. 1989;5:37-40.

Borum PR, Park JH, Law PK, Roelofs RI. Altered tissue carnitine levels in animals with hereditary muscular dystrophy. J Neurol Sci. 1978; 38:113-21. Doi: 10.1016/0022-510X(78)90251-4.

Reibel DK, Uboh CE, Kent RL. Altered coenzyme A and carnitine metabolism in pressure-overload hypertrophied hearts. Am J Physiol. 1983;244(6):H839-43. doi: 10.1152/ajpheart.1983.244.6.H839.

Fatani AG, Darweesh AQ, Rizwan L, Aleisa AM, Al-Shabanah OA, Sayed-Ahmed MM. Carnitine deficiency aggravates cyclophosphamide-induced cardiotoxicity in rats. Chemotherapy. 2010;56(1):71-81. doi: 10.1159/000298822.

Corr PB, Gross RW, Sobel BE. Amphipathic metabolites and membrane dysfunction in ischemic myocardium. Circ Res. 1984;55(2):135-54. doi: 10.1161/01.res.55.2.135.

Hara A, Hashizume H, Abiko Y. Dilazep and its derivative, K-7259, attenuate mechanical derangement induced by palmitoyl-L-carnitine in the isolated, perfused rat heart. J Pharmacol Exp Ther. 1996;279(1):32-8. PMID: 8858972.

Liedtke AJ. Lipid burden in ischemic myocardium. J Mol Cell Cardiol. 1988;20:65-74. doi: 10.1016/0022-2828(88)90333-1.

Dhalla NS, Kolár F, Shah KR, Ferrari R. Effects of some L-carnitine derivatives on heart membrane ATPases. Cardiovasc Drugs Ther. 1991;5:25-30. doi: 10.1007/BF00128240.

Ferrari R, Pasini E, Condorelli E, Boraso A, Lisciani R, Marzo A, et al. Effect of propinoyl-L-carnitine on mechanical function of isolated rabbit heart. 1991; 5:17-23. doi: 10.1007/BF00128239.

Ferrari R, Di Lisa F, de Jong JW, Ceconi C, Pasini E, Barbato R, et al. Prolonged propionyl -L-carnitine pre-treatment of rabbit: biochemical, hemodynamic and electrophysiological effects on myocardium. J Mol Cell Cardiol. 1992;24(3):219-32. doi: 10.1016/0022-2828(92)93160-1.

Russell RR 3rd, Mommessin JI, Taegtmeyer H. Propionyl-L-carnitine-mediated improvement in contractile function of rat hearts oxidizing acetoacetate. Am J Physiol. 1995;268(1 Pt 2):H441-7. doi: 10.1152/ajpheart.1995.268.1.H441.

Cevese A, Schena F, Cerutti G. Short-term hemodynamic effects of intravenous propionyl-L-carnitine in anesthetized dogs. Cardiovasc Drugs Ther. 1991; 5:45-56. doi: 10.1007/BF00128243.

Bevilacqua M, Vago T, Norbiato G. Effect of propionyl-L-carnitine on L-type calcium channels in human heart sarcolemma. Cardiovasc Drugs Ther. 1991, 5:31-5. doi: 10.1007/BF00128241.

Ferrari R, Ciampalini G, Agnoletti G, Cargnoni A, Ceconi C, Visioli O. Effect of L-carnitine derivatives on heart mitochondrial damage induced by lipid peroxidation. Pharmacol Res Commun. 1988 ;20(2):125-32. doi: 10.1016/s0031-6989(88)80005-5.

Wang DD, Wang TY, Yang Y, He SM, Wang YM. The effects of L-carnitine, acetyl-L-carnitine, and propionyl-L-carnitine on body mass in type 2 diabetes mellitus patients. Front Nutr. 2021;8:748075. doi: 10.3389/fnut.2021.748075.

Greco AV, Mingrone G, Bianchi M, Ghirlanda G. Effect of propionyl -L-carnitine in the treatment of diabetic angiopathy: controlled doubled blind trail versus placebo. Clin Trial Drugs Exp Clin Res. 1992;18(2):69-80. PMID: 1644013.

Riccioni C, Sarcinella R, Palermo G, Izzo A, Liguori M, Koverech A, 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):253-9. PMID: 18506129.

Hotta N, Koh N, Sakakibara F, Nakamura J, Hamada Y, Wakao T, et al. Effect of propionyl-L-carnitine on motor nerve conduction, autonomic cardiac function, and nerve blood flow in rats with streptozotocin-induced diabetes: comparison with an aldose reductase inhibitor. J Pharmacol Exp Ther. 1996;276(1):49-55. PMID: 8558455.

Hotta N, Koh N, Sakakibara F, Nakamura J, Hamada Y, Hara T, et al. Effect of propionyl-L-carnitine on oscillatory potentials in electroretinogram in streptozotocin-diabetic rats. Eur J Pharmacol. 1996;311(2-3):199-206. doi: 10.1016/0014-2999(96)00420-7.

Hotta N, Koh N, Sakakibara F, Nakamura J, Hamara Y, Hara T, et al. Effects of propionyl-L-carnitine and insulin on the electroretinogram, nerve conduction and nerve blood flow in rats with streptozotocin-induced diabetes. Pflugers Arch. 1996;431(4):564-70. doi: 10.1007/BF02191904.

Morano S, Mandosi E, Fallarino M, Gatti A, Tiberti C, Sensi M, et al. Antioxidant treatment associated with sildenafil reduces monocyte activation and markers of endothelial damage in patients with diabetic erectile dysfunction: a double-blind, placebo-controlled study. Eur Urol. 2007;52(6):1768-74. doi: 10.1016/j.eururo.2007.04.042.

Gentile V, Antonini G, Bertozzi AM, Dinelli N, Rizzo C, Virmani AM, et al. Effect of propionyl-L-carnitine, L-arginine and nicotinic acid on the efficacy of vardenafil in the treatment of erectile dysfunction in diabetes. Curr Med Res Opin. 2009;25(9):2223-8. doi: 10.1185/03007990903138416.

Gentile V, Vicini P, Prigiotti G, Koverech A, Di Silverio F. Preliminary observations on the use of propionyl-L-carnitine in combination with sildenafil in patients with erectile dysfunction and diabetes. Curr Med Res Opin. 2004;20(9):1377-84. doi: 10.1185/030079904X2394.

Terada R, Matsubara T, Koh N, Nakamura J, Hotta N. Effects of propionyl-L-carnitine on cardiac dysfunction in streptozotocin- diabetic rats. Eur J Pharmacol. 1998; 357(2-3):185-91. doi: 10.1016/s0014-2999(98)00539-1.

Pasini E, Comini L, Ferrari R, de Giuli F, Menotti A, Dhalla NS. Effect of propionyl-L-carnitine on experimental induced cardiomyopathy in rats. Am J Cardiovasc Pathol. 1992;4(3):216-22. PMID: 1298298.

Broderick TL. ATP production and TCA activity are stimulated by propionyl-L-carnitine in the diabetic rat heart. Drugs R D. 2008;9(2):83-91. doi: 10.2165/00126839-200809020-00003.

Arduini A, Dottori S, Sciarroni AF, Corsico N, Morabito E, Arrigoni-Martelli E, et al. Effect of propionyl-L-carnitine treatment on membrane phospholipid fatty acid turnover in diabetic rat erythrocytes. Mol Cell Biochem. 1995;152(1):31-7. doi: 10.1007/BF01076461.

Lango R, Smoleński RT, Rogowski J, Siebert J, Wujtewicz M, Słomińska EM, 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):267-75. doi: 10.1007/s10557-005-3349-8.

Broderick TL, Driedzic W, Paulson DJ. Propionyl-L-carnitine effects on postischemic recovery of heart function and substrate oxidation in the diabetic rat. Mol Cell Biochem. 2000;206(1-2):151-7. doi: 10.1023/a:1007022114594.

Felix C, Gillis M, Driedzic WR, Paulson DJ, Broderick TL. Effects of propionyl-L-carnitine on isolated mitochondrial function in the reperfused diabetic rat heart. Diabetes Res Clin Pract. 2001;53(1):17-24. doi: 10.1016/s0168-8227(01)00240-6.

Pierce GN, Kutryk MJ, Dhalla NS. Alterations in Ca2+ binding by and composition of the cardiac sarcolemmal membrane in chronic diabetes. Proc Natl Acad Sci USA. 1983;80(17):5412-6. doi: 10.1073/pnas.80.17.5412.

Ganguly PK, Pierce GN, Dhalla KS, Dhalla NS. Defective sarcoplasmic reticular calcium transport in diabetic cardiomyopathy. Am J Physiol. 1983;244(6):E528-35. doi: 10.1152/ajpendo.1983.244.6.E528.

Ferrari R, Shah KR, Hata T, Beamish RE, Dhalla, NS. Subcellular defects in diabetic myocardium: influence of propionyl L-carnitine on Ca2+-transport. In: Nagano M, Dhalla NS, eeds. The Diabetic Heart. New York: Raven Press Ltd, 1991; pp. 167-81.

Kaneko M, Singal PK, Dhalla NS. Alterations in heart sarcolemmal Ca2+-ATPase and Ca2+-binding activities due to oxygen free radicals. Basic Res Cardiol. 1990;85(1):45-54. doi: 10.1007/BF01907013.

Dhalla NS, Smith CI, Pierce GN, Elimban V, Makino N, Khatter JC. Heart sarcolemmal cation pumps and binding sites. In: Trupp H, ed. The Regulation of Heart Function. New York, 1986; pp. 121-36.

Makino N, Dhalla KS, Elimban V, Dhalla NS. Sarcolemmal Ca2+ transport in streptozotocin-induced diabetic cardiomyopathy in rats. Am J Physiol. 1987;253:E202-7. doi: 10.1152/ajpendo.1987.253.2.E202.

Pierce GN, Ramjiawan B, Dhalla NS, Ferrari R. Na+-H+ exchange in cardiac sarcolemmal vesicles isolated from diabetic rats. Am J Physiol. 1990;258(1 Pt 2):H255-61. doi: 10.1152/ajpheart.1990.258.1.H255.

Ou C, Majumder S, Dai J, Panagia V, Dhalla NS, Ferrari R. Cardiac phosphatidylethanolamine N-methylation in normal and diabetic rats treated with L- propionylcarnitine. In: Korecky B, Dhalla NS, Eds. Subcellular Basis of Contractile Failure. Developments in Cardiovascular Medicine. Boston, MA: Springer, 1990; pp. 219-34. doi: 10.1007/978-1-4613-1513-1_14.

Golfman L, Hata T, Netticadan T, Panagia V, Dhalla NS. Modification of cardiac sarcolemmal Na+-Ca2+ exchange activity by lysophosphatidylcholine and palmitoylcarnitine. Cardiovasc Pathobiol. 1998;2:181-5. PMID- 9434141.

Netticadan T, Yu L, Dhalla NS, Panagia V. Palmitoyl carnitine increases intracellular calcium in adult rat cardiomyocytes. J Mol Cell Cardiol. 1999;31(7):1357-67. doi: 10.1006/jmcc.1999.0968.

Published
2025/06/30
Section
Review article