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Possible effects of melatonin on reperfusion injury following coronary artery bypass graft surgery

Document Type : Original Article(s)

Authors

1 Professor, Department of Clinical Pharmacy, School of Pharmacy AND Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

2 Fellowship of Clinical Pharmacy, Department of Clinical Pharmacy, School of Pharmacy AND Cardiac Rehabilitation Research Center, Cardiovascular Research Institute,, Isfahan University of Medical Sciences, Isfahan, Iran

3 Professor, Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran

4 Professor, Department of Clinical Pharmacy, School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

5 Isfahan Cardiovascular Research Center, Cardiovascular Research Institute, Isfahan University of Medical Sciences, Isfahan, Iran

Abstract

BACKGROUND: Although coronary artery bypass graft (CABG) surgery has been reported to be one of the most effective internentions in terms of myocardial salvage, reperfusion itself can cause additional damage to the myocardium. Since there is strong evidence that free radicals are the principal offender in ischemia-reperfusion (I/R) injury, it has been suggested that treatment with antioxidant agents can be protective. Investigations have shown that melatonin secretion is partially disturbed in CABG patients. The aim of this study was to evaluate the protective effect of melatonin as an antioxidant agent on I/R injury.
METHODS: 164 elective CABG candidates participated in this randomized clinical trial during the preoperative period. The candidates were randomized to receive 3 mg of melatonin tablets (physiologic dose) from 3 days before surgery until the day of discharge. Cardiac biomarkers [troponin and creatine kinase myocardial band (CKMB)] were assessed once before surgery (24 hours before surgery), and 8 and 24 hours after surgery.
RESULTS: Finally, 130 patients, 65 (50%) patients in the melatonin group and 65 (50%) in the control arm finished our study. Mean age of melatonin and control groups was 59.90 ± 9.59 and 60.80 ± 8.00 years, respectively; moreover, 47 (72.30%) in melatonin and 45 (69.23%) in control group were men. No significant difference was seen in baseline cardiac biomarkers between two groups (P > 0.05). In both groups, cardiac biomarkers (CKMB and troponin) elevated after surgery in comparison to their preoperative values. There was no statistically significant difference between the control and melatonin groups regarding the 8-hour and 24-hour troponin and CKMB when adjusted for interacting factors (P > 0.05).
CONCLUSION: Although physiological concentration of melatonin is protective against I/R injury, substitution of endogenous melatonin with the oral supplement which creates physiologic concentration may not prevent I/R injury. In order to have antioxidant effect, pharmacologic doses of melatonin should be employed.

Keywords

Full Text
  1. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2012; 143(5): 1235.
  2. Moens AL, Claeys MJ, Timmermans JP, Vrints CJ. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol 2005; 100(2): 179-90.
  3. Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: Distant dream or near reality? Heart 2000; 83(4): 381-7.
  4. Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 1998; 38(2): 291-300.
  5. Chandrasena LG, Peiris H, Waikar HD. Biochemical changes associated with reperfusion after off-pump and on-pump coronary artery bypass graft surgery. Ann Clin Lab Sci 2009; 39(4): 372-7.
  6. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC, Reiter RJ, Jimenez-Sosa A. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial: study design and rationale. Contemp Clin Trials 2007; 28(4): 532-9.
  7. Yin YQ, Luo AL, Guo XY, Li LH, Huang YG. Postoperative neuropsychological change and its underlying mechanism in patients undergoing coronary artery bypass grafting. Chin Med J (Engl) 2007; 120(22): 1951-7.
  8. Altun A, Ugur-Altun B. Melatonin: Therapeutic and clinical utilization. Int J Clin Pract 2007; 61(5): 835-45.
  9. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez M, Reiter RJ. Prognostic value of nocturnal melatonin levels as a novel marker in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2006; 97(8): 1162-4.
  10. Dominguez-Rodriguez A, Abreu-Gonzalez P. Myocardial ischemia-reperfusion injury: Possible role of melatonin. World J Cardiol 2010; 2(8): 233-6.
  11. Petrosillo G, Di VN, Pistolese M, Casanova G, Tiravanti E, Colantuono G, et al. Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin. FASEB J 2006; 20(2): 269-76.
  12. Dianatkhah M, Najafi A, Sharifzadeh M, Ahmadi A, Sharifnia H, Mojtahedzadeh M, et al. Melatonin supplementation may improve the outcome of patients with hemorrhagic stroke in the intensive care unit. J Res Pharm Pract 2017; 6(3): 173-7.
  13. Sokullu O, Sanioglu S, Kurc E, Sargin M, Deniz H, Tartan Z, et al. Does the circadian rhythm of melatonin affect ischemia-reperfusion injury after coronary artery bypass grafting? Heart Surg Forum 2009; 12(2): E95-E99.
  14. Zhang Y, Wang Y, Xu J, Tian F, Hu S, Chen Y, et al. Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways. J Pineal Res 2019; 66(2): e12542.
  15. Dianatkhah M, Ghaeli P, Hajhossein TA, Karimi A, Salehiomran A, Bina P, et al. Evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder. J Tehran Heart Cent 2015; 10(3): 122-8.
  16. Guo XY, Luo AL, Ren HZ, Yie TH, Huang YG. Perioperative melatonin secretion rhyme in patients undergoing coronary artery bypass grafting surgery. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2003; 25(5): 594-8. [In Chinese].
  17. Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin concentration in postoperative critically ill patients: Its association with delirium. J Crit Care 2013; 28(3): 236-42.
  18. Yin YQ, Luo AL, Guo XY, Li LH, Ren HZ, Ye TH, et al. Perioperative melatonin circadian secretion in patients undergoing coronary artery bypass grafting surgery. Zhonghua Yi Xue Za Zhi 2004; 84(6): 456-9. [In Chinese].
  19. Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y. Protective role of melatonin in cardiac ischemia-
    reperfusion injury: From pathogenesis to targeted therapy. J Pineal Res 2018; 64(3).
  20. Bourne RS, Mills GH. Melatonin: Possible implications for the postoperative and critically ill patient. Intensive Care Med 2006; 32(3): 371-9.
  21. Mistraletti G, Sabbatini G, Taverna M, Figini MA, Umbrello M, Magni P, et al. Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res 2010; 48(2): 142-7.
  22. Gogenur I, Kucukakin B, Panduro JL, Reiter RJ, Rosenberg J. Melatonin reduces cardiac morbidity and markers of myocardial ischemia after elective abdominal aortic aneurism repair: A randomized, placebo-controlled, clinical trial. J Pineal Res 2014; 57(1): 10-5.
  23. Haghjooy JS, Ziaei A, Ziaei S, Ziaei E, Mirmohammad-Sadeghi M. The effect of preoperative melatonin on nuclear erythroid
    2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxid Med Cell Longev 2013; 2013: 676829.
  24. Reiter RJ, Tan DX. Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res 2003; 58(1): 10-9.
  25. Gitto E, Romeo C, Reiter RJ, Impellizzeri P, Pesce S, Basile M, et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39(2): 184-9.
  26. Vural EM, van Munster BC, de Rooij SE. Optimal dosages for melatonin supplementation therapy in older adults: A systematic review of current literature. Drugs Aging 2014; 31(6): 441-51.
References
  1. Hillis LD, Smith PK, Anderson JL, Bittl JA, Bridges CR, Byrne JG, et al. 2011 ACCF/AHA guideline for coronary artery bypass graft surgery: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Thorac Cardiovasc Surg 2012; 143(5): 1235.
  2. Moens AL, Claeys MJ, Timmermans JP, Vrints CJ. Myocardial ischemia/reperfusion-injury, a clinical view on a complex pathophysiological process. Int J Cardiol 2005; 100(2): 179-90.
  3. Yellon DM, Baxter GF. Protecting the ischaemic and reperfused myocardium in acute myocardial infarction: Distant dream or near reality? Heart 2000; 83(4): 381-7.
  4. Piper HM, Garcia-Dorado D, Ovize M. A fresh look at reperfusion injury. Cardiovasc Res 1998; 38(2): 291-300.
  5. Chandrasena LG, Peiris H, Waikar HD. Biochemical changes associated with reperfusion after off-pump and on-pump coronary artery bypass graft surgery. Ann Clin Lab Sci 2009; 39(4): 372-7.
  6. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez MJ, Kaski JC, Reiter RJ, Jimenez-Sosa A. A unicenter, randomized, double-blind, parallel-group, placebo-controlled study of Melatonin as an Adjunct in patients with acute myocaRdial Infarction undergoing primary Angioplasty the Melatonin Adjunct in the acute myocaRdial Infarction treated with Angioplasty (MARIA) trial: study design and rationale. Contemp Clin Trials 2007; 28(4): 532-9.
  7. Yin YQ, Luo AL, Guo XY, Li LH, Huang YG. Postoperative neuropsychological change and its underlying mechanism in patients undergoing coronary artery bypass grafting. Chin Med J (Engl) 2007; 120(22): 1951-7.
  8. Altun A, Ugur-Altun B. Melatonin: Therapeutic and clinical utilization. Int J Clin Pract 2007; 61(5): 835-45.
  9. Dominguez-Rodriguez A, Abreu-Gonzalez P, Garcia-Gonzalez M, Reiter RJ. Prognostic value of nocturnal melatonin levels as a novel marker in patients with ST-segment elevation myocardial infarction. Am J Cardiol 2006; 97(8): 1162-4.
  10. Dominguez-Rodriguez A, Abreu-Gonzalez P. Myocardial ischemia-reperfusion injury: Possible role of melatonin. World J Cardiol 2010; 2(8): 233-6.
  11. Petrosillo G, Di VN, Pistolese M, Casanova G, Tiravanti E, Colantuono G, et al. Protective effect of melatonin against mitochondrial dysfunction associated with cardiac ischemia- reperfusion: role of cardiolipin. FASEB J 2006; 20(2): 269-76.
  12. Dianatkhah M, Najafi A, Sharifzadeh M, Ahmadi A, Sharifnia H, Mojtahedzadeh M, et al. Melatonin supplementation may improve the outcome of patients with hemorrhagic stroke in the intensive care unit. J Res Pharm Pract 2017; 6(3): 173-7.
  13. Sokullu O, Sanioglu S, Kurc E, Sargin M, Deniz H, Tartan Z, et al. Does the circadian rhythm of melatonin affect ischemia-reperfusion injury after coronary artery bypass grafting? Heart Surg Forum 2009; 12(2): E95-E99.
  14. Zhang Y, Wang Y, Xu J, Tian F, Hu S, Chen Y, et al. Melatonin attenuates myocardial ischemia-reperfusion injury via improving mitochondrial fusion/mitophagy and activating the AMPK-OPA1 signaling pathways. J Pineal Res 2019; 66(2): e12542.
  15. Dianatkhah M, Ghaeli P, Hajhossein TA, Karimi A, Salehiomran A, Bina P, et al. Evaluating the potential effect of melatonin on the post-cardiac surgery sleep disorder. J Tehran Heart Cent 2015; 10(3): 122-8.
  16. Guo XY, Luo AL, Ren HZ, Yie TH, Huang YG. Perioperative melatonin secretion rhyme in patients undergoing coronary artery bypass grafting surgery. Zhongguo Yi Xue Ke Xue Yuan Xue Bao 2003; 25(5): 594-8. [In Chinese].
  17. Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin concentration in postoperative critically ill patients: Its association with delirium. J Crit Care 2013; 28(3): 236-42.
  18. Yin YQ, Luo AL, Guo XY, Li LH, Ren HZ, Ye TH, et al. Perioperative melatonin circadian secretion in patients undergoing coronary artery bypass grafting surgery. Zhonghua Yi Xue Za Zhi 2004; 84(6): 456-9. [In Chinese].
  19. Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y. Protective role of melatonin in cardiac ischemia-
    reperfusion injury: From pathogenesis to targeted therapy. J Pineal Res 2018; 64(3).
  20. Bourne RS, Mills GH. Melatonin: Possible implications for the postoperative and critically ill patient. Intensive Care Med 2006; 32(3): 371-9.
  21. Mistraletti G, Sabbatini G, Taverna M, Figini MA, Umbrello M, Magni P, et al. Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res 2010; 48(2): 142-7.
  22. Gogenur I, Kucukakin B, Panduro JL, Reiter RJ, Rosenberg J. Melatonin reduces cardiac morbidity and markers of myocardial ischemia after elective abdominal aortic aneurism repair: A randomized, placebo-controlled, clinical trial. J Pineal Res 2014; 57(1): 10-5.
  23. Haghjooy JS, Ziaei A, Ziaei S, Ziaei E, Mirmohammad-Sadeghi M. The effect of preoperative melatonin on nuclear erythroid 2-related factor 2 activation in patients undergoing coronary artery bypass grafting surgery. Oxid Med Cell Longev 2013; 2013: 676829.
  24. Reiter RJ, Tan DX. Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res 2003; 58(1): 10-9.
  25. Gitto E, Romeo C, Reiter RJ, Impellizzeri P, Pesce S, Basile M, et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39(2): 184-9.
  26. Vural EM, van Munster BC, de Rooij SE. Optimal dosages for melatonin supplementation therapy in older adults: A systematic review of current literature. Drugs Aging 2014; 31(6): 441-51.
ARYA Atherosclerosis Journal
Volume 18, Issue 2
February 2022
Pages 1-7
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