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Table of Contents
ORIGINAL ARTICLE
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 41-49

The cardioprotective role of melatonin against myocardial injury in patients undergoing coronary artery bypass grafting surgery


1 Department of Pharmacology and Therapeutics, Ministry of Health and Environment, Karbala Health Directorate, Iraq
2 Department of Cardiothoracic Surgical, University of Kufa, Iraq
3 Department of Pharmacology and Therapeutics, College of Pharmacy, University of Al-Qadisiyah, Iraq
4 Department of Medicine, Faculty of Medicine, University of Al muthanna, Iraq
5 Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Kufa, Iraq

Date of Web Publication26-Sep-2018

Correspondence Address:
Najah R Hadi
Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Kufa, Najaf
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/VIT.VIT_12_18

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  Abstract 

BACKGROUND: Myocardial ischemia/reperfusion injury associated with coronary artery bypass graft (CABG) surgery characterizes as a clinically critical problem. The incidence of oxidative stress, inflammation, and apoptosis are induced throughout the reperfusion of the cardiac muscles following ischemia. The present study aims to examine the protective role of melatonin in ameliorating the degree of myocardial injury in patients undergoing bypass surgery, and whether this effect is dose related.
PATIENTS AND METHODS: A total of 45 patients who were undergoing CABG in (Al-Najaf Cardiac Center, Al-Najaf, Iraq) were enrolled in this study between January 2015 and November 2015. Patients were randomly allocated into three study groups: placebo-controlled group (C), low-dose melatonin treatment group, 10 mg capsule once daily (M1) and high-dose melatonin treatment group 20 mg capsule once daily (M2).
RESULTS: Compared to the control group, there was a significant increase in the plasma level of melatonin associated with a significant reduction in plasma levels of high sensitive C-reactive protein, creatine kinase isoenzyme muscle/brain, and cardiac troponin-I, in the melatonin groups (Group M1 and M2) compared to the control group, (P < 0.05) in melatonin-treated groups. Comparing the two melatonin study groups, the changes in the parameters mentioned above were more significant in the M2 group compared to the M1 group (P < 0.05).
CONCLUSION: These findings suggested that melatonin administration can ameliorate the degree of myocardial injury, dose-dependent effects.

Keywords: Coronary artery bypass grafting, melatonin, myocardial ischemia-reperfusion injury, oxidative stress


How to cite this article:
Dwaich KH, Al-Amran FG, Al-Sheibani BI, Yousif NG, Hadi NR. The cardioprotective role of melatonin against myocardial injury in patients undergoing coronary artery bypass grafting surgery. Vasc Invest Ther 2018;1:41-9

How to cite this URL:
Dwaich KH, Al-Amran FG, Al-Sheibani BI, Yousif NG, Hadi NR. The cardioprotective role of melatonin against myocardial injury in patients undergoing coronary artery bypass grafting surgery. Vasc Invest Ther [serial online] 2018 [cited 2018 Dec 18];1:41-9. Available from: http://www.vitonline.org/text.asp?2018/1/2/41/242261


  Introduction Top


Myocardial ischemia is a situation where inadequate blood supply and oxygen to the heart muscle by the partial or complete closure of an artery transfers blood to the myocardium predisposing an affected cardiac muscle to death, while the restoration of blood supply to an ischemic myocardium submit to myocardial reperfusion.[1]

On the other hand, reperfusion injury is the tissue injury raised as soon as blood flow incomes to the tissue following an episode of ischemia or a need for oxygen.[2] Ischemia/reperfusion (I/R) injuries are a main cause of cardiac failure, morbidity, and mortality after cardiac surgery.[3]

Cardiac troponin I (cTnI) degradation throughout I/R consist of both cleavage of cTnI and cross-bridging between the troponin complex elements. cTnI released into the systemic circulation induces an autoimmune response of both the humoral and cellular immune system, further contributing to myocardial injury.[4] Cardiac TnI stated to be an extremely sensitive serum marker of physical or metabolic myocardial injury and cardiomyocytes death with a cardiac specificity of 100% that done due to extensive investigations in people.[5] In addition to that, the liberation of creatine kinase isoenzyme muscle/brain (CK-MB) arises on cardiomyocytes death only and it does not release in the situation of ischemia. For that explanations, CK-MB was measured to be the most helpful biomarker for evaluating myocardial injury.[6] By means of the detection of the central association among arterial injury, inflammatory responses, and coronary artery atherosclerosis, high sensitive C-reactive protein (hsCRP) evaluation has believed to have a vital role in cardiac risk evaluation.[7] It is an indoleamine (n-acetyl methoxytryptamine) widely distributed in nature and occurs in plants, algae, bacteria, and humans. In humans, it functions as a neurohormone released from the pineal gland in association with the light-dark cycle that regulates sleep.[8],[9] The side effect profile of melatonin therapy is quite reassuring and is largely superior to other sleep-inducing agents. For example, melatonin therapy does not cause withdrawal or dependence symptoms unlike benzodiazepines and z-drugs such as zolpidem.[10] In recent times, and somewhat unpredictably, melatonin was recognized as a potent direct-free radical scavenger [11] and indirect antioxidant.[12],[13] Furthermore, melatonin shown a considerable dose-dependent protecting effect against the injure caused by the peroxyl radical in a study done by.[14] The present study aims to examine the protective role of melatonin in ameliorating the degree of myocardial injury in patients undergoing bypass surgery, and whether this effect is dose.


  Patients and Methods Top


Chemicals and instruments

Placebo capsules filled by cornstarch powder (Beijing, China) were prescribed to placebo control (C) group once daily for 5 days.

Melatonin capsules (Vital nutrients, USA) were prescribed in two doses: M1 group received (10 mg) once daily for 5 days, while M2 group received (20 mg) once daily for 5 days.

Human Melatonin and Cardiac markers: Human hsCRP, CK-MB, and CTnI enzyme were measured using enzyme-linked immunosorbent assay kits, Elabscience Biotechnology, Beijing, China.

Patients enrollment

Patients were undergoing elective coronary artery bypass grafting (CABG), and they were invited to participate in this study. A total of 45 patients (36 males vs. 9 females, age range between 45 and 65 years) were admitted to Al-Najaf Center for Cardiothoracic Surgery with ischemic heart diseases.

This study was approved by the Ethics Committee of College of Medicine/University of Kufa. All participants were given information sheets explaining the study, and they were asked to fill and sign the consent form before enrolling in the study.

Study design

This is a double-blinded placebo-control study, which was conducted at the Department of Pharmacology and Therapeutics, College of Medicine, University of Kufa and Cardiology Center, Al-Sadir Medical City, Najaf, Iraq for 10 months (January 2015 to November 2015).

The patients were randomly allocated into three study groups: Group 1 (n = 15) patients treated by placebo capsules (C) from the day 5 before surgery. Group 2 (n = 15) patients treated by administration of 10 mg/day melatonin capsule (M1) from the day 5 before surgery. Group 3 (n = 15) patients treated with administration of 20 mg/day of melatonin (M2) from the day 5 before surgery. [Table 1] summarizes the patient's demographic data in each group of this study.
Table 1: Demographic data for participants in the three groups of the study

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Surgical procedure

All of the operations assigned in the present study accomplished by the surgical team of cardiothoracic surgery in open heart center at Al-Sadr Medical City who's mainly using off-pump CABG surgical technique or which mean beating heart technique that performed without the need for heart/lung device.

Collection of blood samples

Serial different blood samples were collected from each patient as the following:

  • At the start of the study sample (S1), the first sample collected at day 5 preoperatively before administration of medication and that used for measurement of plasma level of melatonin (premedication)
  • Preoperative samples (S2) collected after 5 days of medication intake (at the day of operation) which were also used for measurement of plasma level of melatonin (postmedication). Moreover, take in consideration that both S1 and S2 drown at morning (at 09:00 am)
  • Intraoperative samples collected just before the aortic cross-clamp placed (S3) and then another sample collected after 5 min of cross-clamp release (S4) which were used for measurement of plasma level of biochemical markers (hsCRP, CK-MB, and CTnI)
  • Postoperative samples collected after 2 h of operation (S5) and the last sample collected after 1 day of operation (S6) which were also used for measurement of plasma level of biochemical markers (hsCRP, CK-MB, CTnI).


By getting into consideration of that S1 and S2 blood samples drowned from the radial vein (venous blood samples); while S3, S4, S5, and S6 blood samples drowned from the internal mammary artery (arterial blood samples).

For each collection, a 2.5 ml of blood was collected as mentioned above and was situated in a test tube contained anticoagulant (disodium ethylenediaminetetraacetic acid [22 mg/ml]), mixed thoroughly, centrifuged at 3000 rpm for 15 min. Plasma obtained and stored in a deep freeze (at-−80°C) for measurement of plasma levels of melatonin and cardiac markers (hsCRP, CK-MB, and CTnI).

Statistical analysis

Data were interpreted into a computerized database structure. The database was examined for errors using range and logical data cleaning methods, and inconsistencies were remedied. Statistical analyses were done using IBM Statistical Package for Social Sciences version 21 computer software (SPSS Inc. and acquired by IBM in 2009, Chicago, USA). The statistical significance of difference in mean of a continuous response variable which is known or assumed to be normally distributed between >2 groups was assessed by ANOVA, and when ANOVA model shows statistically significant differences, further exploration of the statistical significance of the difference in mean between each two groups was assessed by Bonferroni t-test.


  Results Top


Patients in the three groups of the study were not statistically significantly different with respect to sex, age, associated diseases (hypertension and diabetes mellitus). None of the patients had acute myocardial infarction.

Changes in plasma level of melatonin

As shown in [Table 2] and [Figure 1], after 5 days of medication use, there was a statistically significant increase in melatonin plasma level by a mean ranging between 21 and 35.5 pg/ml for both low- and high-dose treatment groups. The effects were evaluated as strong effects (Cohen's d > 0.8); on the other hand, there are neglected effect in placebo treatment (Cohen's < 0.8).
Table 2: Changes in plasma level of melatonin after 5 days of medication compared to premedication value stratified by melatonin treatment status (n=15)

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Figure 1: Changes in plasma level of melatonin after 5 days of medication compared to premedication value stratified by melatonin treatment status

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The difference in changes after medication among the three groups was statistically significant (P< 0.001). The changes associated with medication were significantly higher in both high- and low-dose treatment as compared to placebo-controlled group.

The effect of high dose was significantly different (higher) from that of low dose (P< 0.001 and Cohen's d > 0.8).

Changes in biochemical parameters of the study

Changes in the plasma level of high sensitive C-reactive protein

As shown in [Table 3] and [Figure 2], postclamping (5 min and 2 h) there was a statistically significant increase in plasma level of hsCRP by mean ranging between 18.7 and 1056.1 ng/ml for the three treatment groups. On the other hand, for 1st day postoperatively, there was a statistically significant decrease in plasma level of hsCRP by mean ranging between −28.3 and −789.4 ng/ml for the three treatment groups. The effect evaluated as strong effect (Cohen's d > 0.8).
Table 3: Changes in plasma level of high sensitive C-reactive protein after 5 min, 2 h postclamping and 1 day after operation compared to baseline (preclamping) level (n=15)

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Figure 2: Changes in plasma level of high sensitive C-reactive protein after 5 min, 2 h postclamping and 1 day after operation compared to baseline (preclamping) level

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The difference in changes after clamping among the three treatment groups was statistically significant. The changes associated with the operation were significantly higher in both low and high dose as compared to placebo-controlled group. On the other hand, the effect of high dose was significantly higher than that of low-dose treatment group (P< 0.001).

Changes in the plasma level of creatine kinase isoenzyme muscle/brain

As shown in [Table 4] and [Figure 3], postclamping (5 min and 2 h) and 1-day postoperative, there was a statistically significant increase in plasma level of CK-MB by mean ranging between 0.06 and 6.18 ng/ml for the three treatment groups. The effect evaluated as strong effect (Cohen's d > 0.8).
Table 4: Changes in plasma level of creatine kinase isoenzyme MB after 5 min, 2 h postclamping and 1 day after operation compared to baseline (preclamping) level

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Figure 3: Changes in plasma level of creatine kinase isoenzyme muscle/brain after 5 min, 2 h postclamping and 1 day after operation compared to baseline (preclamping) level

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The difference in changes after clamping among the three treatment groups was statistically significant. The changes associated with operation were significantly higher in both low and high dose as compared to placebo-controlled group. On the other hand, the effect of high dose was significantly higher than that of low-dose treatment group (P< 0.001).

Changes in the plasma level of cardiac troponin-I

As shown in [Table 5] and [Figure 4], postclamping (5 min and 2 h) there was a statistically significant increase in plasma level of CTnI by mean ranging between −0.02 and 4.45 ng/ml for the three treatment groups. On the other hand, for 1 day postoperative, there was a statistically significant decrease in plasma level of CTnI by mean ranging between 3.1 and 0.31 ng/ml for the three treatment groups. The effect evaluated as strong effect (Cohen's d > 0.8).
Table 5: Changes in plasma level of cardiac troponin-I after 5 min, 2 h postclamping and 1 day after operation compared to baseline (preclamping) level

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Figure 4: Changes in troponin I plasma level after 5 min, 2 h postclamping and 1 day after operation compared to baseline (preclamping) level

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The difference in changes after clamping among the three treatment groups was statistically significant. The changes associated with operation were significantly higher in both low and high dose as compared to placebo-controlled group. On the other hand, the effect of high dose was significantly higher than that of low-dose treatment group (P< 0.001).


  Discussion Top


Plasma level of melatonin among the study groups

In our study, there was no important difference in melatonin levels among three sets of participants at the start of our study, while following to 5 days of melatonin administration the preoperative level of melatonin in plasma (S2) was significantly elevated in melatonin-treated groups than in placebo-controlled group. On the other hand, the plasma melatonin level in high-dose group (M2) was higher than in low-dose group (M1); that proves the effect of melatonin on I/R injury which is more defensive with higher level of melatonin as we show below; with taking in consideration that sampling drown at morning (09:00 am).

The severity of the coronary artery disease related to plasma level of melatonin that attributed to patients with coronary artery disease have lesser rates of melatonin production and so the plasma level of melatonin lower, i.e., superior decline in synthesis of melatonin are found in patients with an elevated risk of cardiac infarction and/or sudden death. It is doubtful whether low melatonin levels in these patients are the result of melatonin “consumption” cause by scavenging of the high free radical production, or correspond to lower melatonin production, and therefore less defense against oxidative stress.[15],[16],[17]

Sokullu et al., 2009 suggested that the elevated plasma concentrations of melatonin can be directly correlated to low concentrations of I/R biomarkers; furthermore, they supposed that protecting effect of melatonin to prevent I/R injury in CABG surgery.[18]

Effects of melatonin on the biochemical parameters of the study

Effect of melatonin on myocardial injury markers (high sensitive C-reactive protein, creatine kinase isoenzyme muscle/brain, cardiac troponin-I)

The present study shows significant decrease in plasma level of (hsCRP, CKMB, CTnI) for melatonin-treated groups in comparison with placebo-controlled group. On the other hand, that was a significant reduction in plasma level of (hsCRP, CKMB, and CTnI) for high dose melatonin-treated groups as compared to low-dose melatonin-treated group.

cTnI has previously been shown to be an extremely specific marker of acute myocardial infarction,[19] and of reperfusion after thrombolytic therapy.[20] The serum level of cTnI increased markedly after I/R injury that noted by Oksuz et al., 2009[21] and Yun et al., 2010.[22]

Our results in agreement with numerous previous studies; Lee et al., 2002 were reported an important effect of melatonin administration in reducing the infarcted size; they determined that the effect of melatonin in cardioprotection may be attributed to its anti-oxidative role and owing to its ability for inhibition of neutrophil in cardiac tissue.[23]

Acikel et al., 2003 reported a protecting role of melatonin in preventing isoproterenol-induced myocardial injury in mice and its possible clinical appliance in the management of myocardial injury; by measuring cardiac troponins T and cTnI were considerably decreased in the isoproterenol + melatonin group in comparison with the isoproterenol only group.[24]

Bilginoğlu et al., 2014 presented by an animal study that the administration of melatonin preserved the antioxidant enzyme concentrations and enhanced the work of heart after adriamycin administration. The cardiotoxicity grade induced by adriamycin was evaluated chemically by measuring the plasma levels of CK-MB and troponin I; In contrast to the adriamycin-treated set, only the melatonin-treated set exhibited a decline in the levels of myocardial injury biomarkers.[25]

Ghaeli et al., 2015 revealed that melatonin may be capable to decrease the incidence of adverse cardiac events after percutaneous coronary intervention; whose measured troponin and CK-MB as biomarkers of myocardial injury after intake of melatonin or not and found a significant difference in the biomarkers.[26]

The explanation for these results is due to cardioprotective of melatonin attributed to its scavenger role to reactive oxygen species and also to its ability to inhibit neutrophils in cardiac tissue.[23]


  Conclusion Top


The administration of melatonin supplements can ameliorate myocardial injury by interfering with the oxidative stress damage, inflammation processes, and elevation of melatonin level. These effects are dose dependent.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

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Dobsak P, Siegelova J, Eicher JC, Jancik J, Svacinova H, Vasku J, et al. Melatonin protects against ischemia-reperfusion injury and inhibits apoptosis in isolated working rat heart. Pathophysiology 2003;9:179-87.  Back to cited text no. 14
    
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Dominguez-Rodriguez A, Abreu-Gonzalez P, Sanchez-Sanchez JJ, Kaski JC, Reiter RJ. Melatonin and circadian biology in human cardiovascular disease. J Pineal Res 2010;49:14-22.  Back to cited text no. 15
    
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Sokullu O, Sanioğlu S, Kurç 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:E95-9.  Back to cited text no. 18
    
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Adams JE 3rd, Bodor GS, Dávila-Román VG, Delmez JA, Apple FS, Ladenson JH, et al. Cardiac troponin I. A marker with high specificity for cardiac injury. Circulation 1993; 88:101-6.  Back to cited text no. 19
    
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Larue C, Calzolari C, Bertinchant JP, Leclercq F, Grolleau R, Pau B, et al. Cardiac-specific immunoenzymometric assay of troponin I in the early phase of acute myocardial infarction. Clin Chem 1993;39:972-9.  Back to cited text no. 20
    
21.
Oksuz H, Senoglu N, Yasim A, Turut H, Tolun F, Ciralik H, et al. Propofol with N-acetylcysteine reduces global myocardial ischemic reperfusion injury more than ketamine in a rat model. J Invest Surg 2009;22:348-52.  Back to cited text no. 21
    
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23.
Lee YM, Chen HR, Hsiao G, Sheu JR, Wang JJ, Yen MH, et al. Protective effects of melatonin on myocardial ischemia/reperfusion injury in vivo. J Pineal Res 2002;33:72-80.  Back to cited text no. 23
    
24.
Acikel M, Buyukokuroglu ME, Aksoy H, Erdogan F, Erol MK. Protective effects of melatonin against myocardial injury induced by isoproterenol in rats. J Pineal Res 2003;35:75-9.  Back to cited text no. 24
    
25.
Bilginoğlu A, Aydın D, Ozsoy S, Aygün H. Protective effect of melatonin on adriamycin-induced cardiotoxicity in rats. Turk Kardiyol Dern Ars 2014;42:265-73.  Back to cited text no. 25
    
26.
Ghaeli P, Vejdani S, Ariamanesh A, Hajhossein Talasaz A. Effect of melatonin on cardiac injury after primary percutaneous coronary intervention: A Randomized controlled trial. Iran J Pharm Res 2015;14:851-5.  Back to cited text no. 26
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5]



 

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