Document Type : Original Article


1 Department of Anatomy, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

2 Department of Clinical Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran

3 Neurophysiology Research Center, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran


Myocardial infarction is commonly considered as a leading cause of cardiovascular disease taking the lives of seven million people annually. Liver dysfunction is associated with cardiac diseases. The profile of abnormal liver functions in heart failure is not clearly defined. This study was designed to investigate the protective effects of betaine on liver injury after myocardial infarction induced by isoprenaline in rats. Forty-eight male rats were divided into four groups: the control group received normal diet and the experimental groups received 50, 150, and 250 mg kg-1 body weight of betaine daily through gastric gavages for 60 days. All of experimental and control groups experienced myocardial infarction, induced by subcutaneous injection of 100 mg kg-1 isoprenaline in two consecutive doses )8:00 AM to 8:00 PM). Liver enzymes including aspartate transaminase (AST) and alanine transaminase (ALT) were significantly reduced in the groups treated with betaine, compared with the control group. The total antioxidant capacity in the experimental groups, treated with betaine, showed a significant increase, compared with the control group. In the control group, severe lesions were created in the liver tissue, while degenerative changes of liver tissue significantly reduced in groups treated with different doses of betaine, showing the repair of liver tissue. Betaine decreased apoptosis in the experimental groups in comparison with the control group. Betaine showed a protective effect against biochemical and histological changes in liver tissue caused by the induction of myocardial infarction via isoprenaline injection.


Main Subjects


    1. Nichols M, Townsend N, Scarborough P, et al. Cardiovascular disease in Europe: Epidemiological update. Eur heart J 2014;35(42):2950-2959.
    2. Møller S, Bernardi M. Interactions of the heart and the liver. Eur Heart J 2013;34:2804-2811.
    3. Soultati A, SP Dourakis A. Liver dysfunction in the intensive care unit. Ann Gastroenterol 2007; 18(1):35-45.
    4. Biegus J, Zymlinski R, Sokolski M, et al. Liver function tests in patients with acute heart failure. Pol Arch Med Wewn 2012;122(10):471-479.
    5. Ambrosy AP, Vaduganathan M, Huffman MD, et al. Clinical course and predictive value of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial. Eur J Heart Fail 2012;14(3):302-311.
    6. Giallourakis CC, Rosenberg PM, Friedman LS. The liver in heart failure. Clin Liver Dis2002;6(4):947-967.
    7. Malhi H, Gores GJ, Lemasters JJ. Apoptosis and necrosis in the liver: Atale of two deaths? Hepatology 2006;43(2 Suppl. 1):S31-44.
    8. Rahmathulla SM, Sailaja K, Devi KL. Tribulus terrestris (I) protects heart and liver from beta adrenergic-stimulated cardiotoxicity: Biochemical and histological study in Wistar rats. Int J Drug Dev Res 2013; 5(1): 264-270.
    9. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000;342(17):1266-1271.
    10. Apel K, Hirt H. Reactive oxygen species: Metabolism, oxidative stress, and signal transduction. Annu Rev Plant Biol 2004;55:373-399.
    11. McCord JM. The evolution of free radicals and oxidative stress. Am J Med 2000;108(8):652-659.
    12. Di Filippo C, Cuzzocrea S, Rossi F, et al. Oxidative stress as the leading cause of acute myocardial infarction in diabetics. Cardiovasc Drug Rev 2006;24(2):77-87.
    13. Sanchez-Valle V, Chavez-Tapia NC, Uribe M, et al. Role of oxidative stress and molecular changes in liver fibrosis: A review. Curr Med Chem 2012; 19(28):4850-4860.
    14. Feng Y, Wang N, Ye X, et al. Hepatoprotective effect and its possible mechanism of Coptidis rhizoma aqueous extract on carbon tetrachloride-induced chronic liver hepatotoxicity in rats. J Ethnopharmacol 2011; 138(3):683-690.
    15. Singal AK, Jampana SC, Weinman SA. Antioxidants as therapeutic agents for liver disease. Liver Int 2011;31(10):1432-1448.
    16. Sakamoto A, Nishimura Y, Ono H, et al. Betaine and homocysteine concentrations in foods. Pediatr Int 2002;44(4):409-413.
    17. Barve A, Khan R, Marsano L, et al. Treatment of alcoholic liver disease. Ann Hepatol 2008;7(1):5-15.
    18. Lever M, George PM, Elmslie JL, et al. Betaine and secondary events in an acute coronary syndrome cohort. PLoS ONE 2012;7(5):e37883.
    19. Graf D, Kurz AK, Reinehr R, et al. Prevention of bile acid-induced apoptosis by betaine in rat liver. Hepatology 2002;36(4 Pt 1):829-839.
    20. Rahmathulla SM, Maruthi E, Bheemewsaraiah K, et al. Effect of Tribulus terrestris (L.) on liver in isoproterenol-induced myocardial infarction. Int J Res Biochem Biophys2012;2(4):10-12.
    21. Ghodratizadeh S, Rasmi Y, Khadem Ansari MH. Effect of betaine supplement on isoprenaline induced myocardial infarction and serum cathepsin G level in rat model. Urmia Med J 2017;28(8):48-54.
    22. Cuce G, Cetinkaya S, Koc T, et al. Chemoprotective effect of vitamin E in cyclophosphamide-induced hepato-toxicity in rats. Chem Biol Interact 2015;232:7-11.
    23. Lee J, Jung Y, Park JY, et al. LC/MS-based polar metabolite profiling reveals gender differences in serum from patients with myocardial infarction. J Pharm Biomed Anal 2015;115:475-486.
    24. Mohanty I, Arya D, Gupta S. Dietary Curcuma longa protects myocardium against isoproterenol induced hemodynamic, biochemical and histopathological alternations in rats. Int J Appl 2008;1(4):19-28.
    25. Huang H, Geng Q, Yao H, et al. Protective effect of scutellarin on myocardial infarction induced by isoprenaline in rats. Iran J Basic Med Sci 2018;21:267-276.
    26. Noronha-Dutra AA, Steen EM, Woolf N. The early changes induced by isoproterenol in the endocardium and adjacent myocardium. Am J Pathol 1984; 114(2):231-239.
    27. Cagli K, Basar FN, Tok D, et al. How to interpret liver function tests in heart failure patients? Turk J Gastroenterol 2015;26(3):197-203.
    28. Fouad YM, Yehia R. Hepato-cardiac disorders. World J Hepatol 2014;6(1):41-54.
    29. Kubo SH, Walter BA, John DH, et al. Liver function abnormalities in chronic heart failure. Influence of systemic hemodynamics. Arch Intern Med 1987;147(7):1227-1230.
    30. Craig SA. Betaine in human nutrition. Am J Clin Nutr 2004;80(3):539-549.
    31. Ji C, Kaplowitz N. Betaine decreases hyperhomo-cysteinemia, endoplasmic reticulum stress, and liver injury in alcohol-fed mice. Gastroenterology 2003;124(5):1488-1499.
    32. Ji C, Deng Q, Kaplowitz N. Role of TNF-alpha in ethanol-induced hyperhomocysteinemia and murine alcoholic liver injury. Hepatology 2004;40(2):442-451.
    33. Barak AJ, Beckenhauer HC, Mailliard ME, et al. Betaine lowers elevated s-adenosylhomocysteine levels in hepatocytes from ethanol-fed rats. J Nutr 2003;133(9):2845-2848.
    34. Junnila M, Barak AJ, Beckenhauer HC, et al. Betaine reduces hepatic lipidosis induced by carbon tetrachloride in Sprague-Dawley rats. Vet Hum Toxicol 1998;40(5):263-266.
    35. Hagar H, Al Malki W. Betaine supplementation protects against renal injury induced by cadmium intoxication in rats: role of oxidative stress and caspase-3. Environ Toxicol Pharmacol 2014;37(2):803-811.
    36. Kharbanda KK, Mailliard ME, Baldwin CR, et al. Betaine attenuates alcoholic steatosis by restoring phosphatidylcholine generation via the phosphatidyl-ethanolamine methyltransferase pathway. J Hepatol 2007;46(2):314-321.
    37. Ganesan B, Rajesh R, Anandan R. Biochemical studies on the protective effect of betaine on mitochondrial function in experimentally induced myocardial infarction in rats. J Health Sci 2007;53(6):671-681.
    38. Alvarez AM, Mukherjee D. Liver abnormalities in cardiac diseases and heart failure. Int J Angiol 2011;20(3):135-142.
    39. Kunutsor SK, Apekey TA, Khan H. Liver enzymes and risk of cardiovascular disease in the general population: A meta-analysis of prospective cohort studies. Atherosclerosis 2014;236(1):7-17.
    40. van Deursen VM, Damman K, Hillege HL, et al. Abnormal liver function in relation to hemodynamic profile in heart failure patients. J Card Fail 2010;16(1):84-90.
    41. Shinohara M, Ji C, Kaplowitz N. Differences in betaine-homocysteine methyltransferase expression, endo-plasmic reticulum stress response, and liver injury between alcohol-fed mice and rats. Hepatology 2010;51(3):796-805.
    42. Kanbak G, Akyuz F, Inal M. Preventive effect of betaine on ethanol-induced membrane lipid composition and membrane ATPases. Arch Toxicol 2001;75(1):59-61.
    43. Bartosz G. Total antioxidant capacity. Adv Clin Chem 2003;37:219-292.
    44. Yao D, Vlessidis AG, Evmiridis NP, et al. Possible mechanism for nitric oxide and oxidative stress induced pathophysiological variance in acute myocardial infarction development: A study by a flow injection-chemiluminescence method. Anal Chim Acta 2004;505(1):115-123.
    45. Kasap S, Gonenc A, Sener DE, et al. Serum cardiac markers in patients with acute myocardial infarction: oxidative stress, C-reactive protein and N-terminal probrain natriuretic Peptide. J Clin Biochem Nutr 2007;41(1):50-57.
    46. Herzer K, Kneiseler G, Bechmann LP, et al. Onset of heart failure determines the hepatic cell death pattern. Ann Hepatol 2011;10(2):174-179.
    47. Horio M, Ito A, Matsuoka Y, et al. Apoptosis induced by hypertonicity in Madin Darley canine kidney cells: Protective effect of betaine. Nephrol Dial Transplant 2001;16(3):483-490.
    48. Hagar H, Medany AE, Salam R, et al. Betaine supplementation mitigates cisplatin-induced nephrotoxicity by abrogation of oxidative/nitrosative stress and suppression of inflammation and apoptosis in rats. Exp Toxicol Pathol 2015;67(2):133-141.
    49. Schoemaker MH, Gommans WM, Conde de la Rosa L, et al. Resistance of rat hepatocytes against bile acid-induced apoptosis in cholestatic liver injury is due to nuclear factor-kappa B activation. J Hepatol 2003;39(2):153-161.
    50. Oberhammer F, Bursch W, Tiefenbacher R, et al. Apoptosis is induced by transforming growth factor-beta 1 within 5 hours in regressing liver without significant fragmentation of the DNA. Hepatology 1993;18(5):1238-1246.