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Melatonin and the cardiovascular system in animals: systematic review and meta-analysis

Abstract

Melatonin, a hormone released by the pineal gland, demonstrates several effects on the cardiovascular system. Herein, we performed a systematic review and meta-analysis to verify the effects of melatonin in an experimental model of myocardial infarction. We performed a systematic review according to PRISMA recommendations and reviewed MEDLINE, Embase, and Cochrane databases. Only articles in English were considered. A systematic review of the literature published between November 2008 and June 2019 was performed. The meta-analysis was conducted using the RevMan 5.3 program provided by the Cochrane Collaboration. In total, 858 articles were identified, of which 13 were included in this review. The main results of this study revealed that melatonin benefits the cardiovascular system by reducing infarct size, improving cardiac function according to echocardiographic and hemodynamic analyses, affords antioxidant effects, improves the rate of apoptosis, decreases lactate dehydrogenase activity, enhances biometric analyses, and improves protein levels, as analyzed by western blotting and quantitative PCR. In the meta-analysis, we observed a statistically significant decrease in infarct size (mean difference [MD], -20.37 [-23.56, -17.18]), no statistical difference in systolic pressure (MD, -1.75 [-5.47, 1.97]), a statistically significant decrease in lactate dehydrogenase in animals in the melatonin group (MD, -4.61 [-6.83, -2.40]), and a statistically significant improvement in the cardiac ejection fraction (MD, -8.12 [-9.56, -6.69]). On analyzing potential bias, we observed that most studies presented a low risk of bias; two parameters were not included in the analysis, and one parameter had a high risk of bias. Melatonin exerts several effects on the cardiovascular system and could be a useful therapeutic target to combat various cardiovascular diseases.

Cardiology; Melatonin; Meta Analysis; Review; Systematic Review


BACKGROUND

Melatonin (N-acetyl-5-methoxytryptamine) is a hormone produced by the pineal gland exclusively at night and is released into the bloodstream and cerebrospinal fluid in a circadian manner to regulate several physiological and neuroendocrine functions (11. Tordjman S, Chokron S, Delorme R, Charrier A, Bellissant E, Jaafari N, et al. Melatonin: Pharmacology, Functions and Therapeutic Benefits. Curr Neuropharmacol. 2017;15(3):434-43. https://doi.org/10.2174/1570159X14666161228122115
https://doi.org/10.2174/1570159X14666161...
-2. Amaral FGD, Cipolla-Neto J. A brief review about melatonin, a pineal hormone. Arch Endocrinol Metab. 2018;62(4):472-9. https://doi.org/10.20945/2359-3997000000066
https://doi.org/10.20945/2359-3997000000...
33. Cipolla-Neto J, Amaral FGD. Melatonin as a Hormone: New Physiological and Clinical Insights. Endocr Rev. 2018;39(6):990-1028. https://doi.org/10.1210/er.2018-00084
https://doi.org/10.1210/er.2018-00084...
). The effects of melatonin are dependent on non-receptor- and receptor-mediated mechanisms of action. Membrane melatonin receptors (MT1, MTNR1A, MT1, and MTRN1B) are G-protein-coupled receptors, signaling through Gi-G0 or Gq-G11 transduction pathways, depending on the target organ. Melatonin secreted at night might interact with its effector and produce immediate effects when melatonin is present in the circulation (e.g., nighttime blood pressure dipping). Moreover, during the night and through several mechanisms of action, melatonin primes prospective effects (such as controlling autonomic nervous system activity) that can be observed only during the day when no pineal melatonin production occurs (33. Cipolla-Neto J, Amaral FGD. Melatonin as a Hormone: New Physiological and Clinical Insights. Endocr Rev. 2018;39(6):990-1028. https://doi.org/10.1210/er.2018-00084
https://doi.org/10.1210/er.2018-00084...
-4. Sharma S, Singh H, Ahmad N, Mishra P, Tiwari A. The role of melatonin in diabetes: therapeutic implications. Arch Endocrinol Metab. 2015;59(5):391-9. https://doi.org/10.1590/2359-3997000000098
https://doi.org/10.1590/2359-39970000000...
5. Favero G, Franceschetti L, Buffoli B, Moghadasian MH, Reiter RJ, Rodella LF, et al. Melatonin: Protection against age-related cardiac pathology. Ageing Res Rev. 2017;35:336-49. https://doi.org/10.1016/j.arr.2016.11.007
https://doi.org/10.1016/j.arr.2016.11.00...
66. Baltatu OC, Amaral FG, Campos LA, Cipolla-Neto J. Melatonin, mitochondria and hypertension. Cell Mol Life Sci. 2017;74(21):3955-64. https://doi.org/10.1007/s00018-017-2613-y
https://doi.org/10.1007/s00018-017-2613-...
).

Over the last 20 years, several studies have suggested that melatonin influences the cardiovascular system (77. Rodella LF, Favero G, Rossini C, Foglio E, Bonomini F, Reiter RJ, et al. Aging and vascular dysfunction: beneficial melatonin effects. Age (Dordr). 2013;35(1):103-15. https://doi.org/10.1007/s11357-011-9336-z
https://doi.org/10.1007/s11357-011-9336-...
,88. Dominguez-Rodriguez A, Abreu-Gonzalez P. Pharmacological cardioprotection in the acute myocardial infarction: potential of β-blockers and melatonin as forgotten cardioprotective agents. Int J Cardiol. 2014;172(2):e354-5. https://doi.org/10.1016/j.ijcard.2013.12.303
https://doi.org/10.1016/j.ijcard.2013.12...
). Melatonin may have significant anti-inflammatory and cardioprotective properties by directly eliminating free radicals, as well as indirectly via antioxidant activity. In addition, melatonin may be involved in blood pressure regulation and have significant anti-atherogenic effects (88. Dominguez-Rodriguez A, Abreu-Gonzalez P. Pharmacological cardioprotection in the acute myocardial infarction: potential of β-blockers and melatonin as forgotten cardioprotective agents. Int J Cardiol. 2014;172(2):e354-5. https://doi.org/10.1016/j.ijcard.2013.12.303
https://doi.org/10.1016/j.ijcard.2013.12...
-9. Dziegiel P, Murawska-Ciałowicz E, Jethon Z, Januszewska L, Podhorska- Okołów M, Surowiak P, et al. Melatonin stimulates the activity of protective antioxidative enzymes in myocardial cells of rats in the course of doxorubicin intoxication. J Pineal Res. 2003;35(3):183-7. https://doi.org/10.1034/j.1600-079X.2003.00079.x
https://doi.org/10.1034/j.1600-079X.2003...
10. 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(1):14-22. https://doi.org/10.1111/j.1600-079X.2010.00773.x
https://doi.org/10.1111/j.1600-079X.2010...
11. Dominguez-Rodriguez A, Abreu-Gonzalez P, Reiter RJ. Melatonin and cardiovascular disease: myth or reality? Rev Esp Cardiol (Engl Ed). 2012;65(3):215-8. https://doi.org/10.1016/j.recesp.2011.10.009
https://doi.org/10.1016/j.recesp.2011.10...
12. Paredes SD, Forman KA, García C, Vara E, Escames G, Tresguerres JA. Protective actions of melatonin and growth hormone on the aged cardiovascular system. Horm Mol Biol Clin Investig. 2014;18(2):79-88. https://doi.org/10.1515/hmbci-2014-0016
https://doi.org/10.1515/hmbci-2014-0016...
1313. Sun H, Gusdon AM, Qu S. Effects of melatonin on cardiovascular diseases: progress in the past year. Curr Opin Lipidol. 2016;27(4):408-13. https://doi.org/10.1097/MOL.0000000000000314
https://doi.org/10.1097/MOL.000000000000...
).

In this systematic review, cardiovascular diseases such as hypertension, myocardial infarction, ischemia, and reperfusion were selected to verify the action of melatonin, as we believe that these cardiopathies currently represent a large number of cardiovascular diseases (1313. Sun H, Gusdon AM, Qu S. Effects of melatonin on cardiovascular diseases: progress in the past year. Curr Opin Lipidol. 2016;27(4):408-13. https://doi.org/10.1097/MOL.0000000000000314
https://doi.org/10.1097/MOL.000000000000...
,1414. McSweeney JC, Rosenfeld AG, Abel WM, Braun LT, Burke LE, Daugherty SL, et al. Preventing and Experiencing Ischemic Heart Disease as a Woman: State of the Science: A Scientific Statement From the American Heart Association. Circulation. 2016;133(13):1302-31. https://doi.org/10.1161/CIR.0000000000000381
https://doi.org/10.1161/CIR.000000000000...
). Our study aimed to verify the effects of melatonin in an experimental model of myocardial infarction.

SEARCH STRATEGIES

In the present study, the search strategy was performed as described by Tawfik et al. (1515. Tawfik GM, Dila KAS, Mohamed MYF, Tam DNH, Kien ND, Ahmed AM, et al. A step by step guide for conducting a systematic review and meta-analysis with simulation data. Trop Med Health. 2019;47:46. https://doi.org/10.1186/s41182-019-0165-6
https://doi.org/10.1186/s41182-019-0165-...
). We used MEDLINE, Google Scholar, and Cochrane databases and reviewed literature published from November 2008 to June 2019; we restricted this systematic review to the last ten years, covering the latest and most relevant articles worldwide. First, we selected keywords from related articles, using Medical Subject Headings (MeSH) to identify more related keywords with similar meanings as follows: (“melatonin”) [MeSH Terms] AND (“cardiovascular system”) [MeSH Terms] [All Fields]. We then searched the three databases. Accordingly, we identified 2096 articles in PubMed using the “other animals” filter, 602 articles using Google Scholar filtering for keywords only in the title, and three articles using a Cochrane Library advanced search; the terms used were “melatonin and cardiovascular system” In addition, we reviewed retrieved articles to identify additional studies (Figure 1). This review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) (1616. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647. https://doi.org/10.1136/bmj.g7647
https://doi.org/10.1136/bmj.g7647...
,1717. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ.2016;353:i2229. https://doi.org/10.1136/bmj.i157
https://doi.org/10.1136/bmj.i157...
).

Figure 1
Flow chart of experimental design.

We excluded studies with cell culture experiments, as well as pre- and post-conditioning studies. The inclusion criteria were animal studies, cell culture studies, and in vivo experiments. The control group was the melatonin group in this study. The melatonin group varied in each article, as studies persistently experimented with a melatonin group related to a drug or an event.

The process of paper retrieval and titles and abstract evaluation was conducted by two independent blinded researchers capable of compiling systematic reviews (ECV and RS), following the inclusion and exclusion criteria according to the tenets of PICO (1616. Shamseer L, Moher D, Clarke M, Ghersi D, Liberati A, Petticrew M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015: elaboration and explanation. BMJ. 2015;350:g7647. https://doi.org/10.1136/bmj.g7647
https://doi.org/10.1136/bmj.g7647...
-17. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ.2016;353:i2229. https://doi.org/10.1136/bmj.i157
https://doi.org/10.1136/bmj.i157...
18. Henderson VC, Kimmelman J, Fergusson D, Grimshaw JM, Hackam DG. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Med. 2013;10(7):e1001489. https://doi.org/10.1371/journal.pmed.1001489
https://doi.org/10.1371/journal.pmed.100...
1919. Adriaenssens P, Eggermont E, Smeyers L. Een regionaal vangnet voor kindermishandeling: Het netwerk kind en gezin in nood. Tijdschrift voor Kindergeneeskunde. 1996.). The PICO was defined as patients in case the systematic review was performed in animals, interventions considering the administration of melatonin in animals using an experimental model of myocardial infarction, comparison, to compare the melatonin group with the control group receiving no melatonin, and outcome, which were results of administering melatonin. The selected articles were critically evaluated to determine their potential inclusion in the review. In the event of a disagreement between investigators regarding studies selected, a third reviewer was consulted (LCA).

In the present systematic review, data obtained from selected studies were tabulated, and the following characteristics were listed when present in the articles: authors’ names, year of publication, animal type, sex (M/F), animal species, age (months), weight, induction model, and site injury (Table 1). Table 2 presents the following information: authors, sample size, number of groups, number of animals per group, melatonin administration, melatonin doses, and dependent variables. Table 3 lists the most frequent recommendations in preclinical research guidelines for in vivo animal experiments (1818. Henderson VC, Kimmelman J, Fergusson D, Grimshaw JM, Hackam DG. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Med. 2013;10(7):e1001489. https://doi.org/10.1371/journal.pmed.1001489
https://doi.org/10.1371/journal.pmed.100...
). Table 4 evaluates the study characteristics of selected controlled animal studies, with prior exercise and myocardial infarction as variables that showed a significant difference between the melatonin control group and the study group. These were classified as S for “significant difference,” and variables that did not present a significant difference were classified as NS (not significant).

Table 1
Study characteristics of selected control experimental studies assessing melatonin and the cardiovascular system.

Table 2
Characteristics (samples size, number of groups, number of animals/groups, dependent variables) of selected experimental studies assessing the effects of melatonin and the cardiovascular system.

Table 3
Most frequent recommendations appearing in preclinical research guidelines for in vivo animal experiments [Hendersen et al. (1818. Henderson VC, Kimmelman J, Fergusson D, Grimshaw JM, Hackam DG. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Med. 2013;10(7):e1001489. https://doi.org/10.1371/journal.pmed.1001489
https://doi.org/10.1371/journal.pmed.100...
)].

Table 4
Most frequent recommendations in preclinical research guidelines for in vivo animal experiments [Henderson et al. (1818. Henderson VC, Kimmelman J, Fergusson D, Grimshaw JM, Hackam DG. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Med. 2013;10(7):e1001489. https://doi.org/10.1371/journal.pmed.1001489
https://doi.org/10.1371/journal.pmed.100...
)].

RevMan (version 5.3; Cochrane Collaboration, Oxford, UK) was used to perform the meta-analysis. The random-effects model was used to account for the heterogeneity.

Statistical analysis

Mean values and standard deviation between studies, presented as the mean difference (MD) of post-intervention values after calculating the inverse variance, were employed to verify the magnitude of the protection afforded by melatonin (1919. Adriaenssens P, Eggermont E, Smeyers L. Een regionaal vangnet voor kindermishandeling: Het netwerk kind en gezin in nood. Tijdschrift voor Kindergeneeskunde. 1996.). In addition, heterogeneity was assessed using Cochran’s Q and I2 tests, followed by visual inspection of the graph. The analyses were performed using the RevMan software (version 3.3.1) (2020. Rhodes KM, Turner RM, Savović J, Jones HE, Mawdsley D, Higgins JPT. Between-trial heterogeneity in meta-analyses may be partially explained by reported design characteristics. J Clin Epidemiol. 2018;95:45-54. https://doi.org/10.1016/j.jclinepi.2017.11.025
https://doi.org/10.1016/j.jclinepi.2017....
).

RESULTS

Figure 1 presents the search process, identification, and selection of articles. Based on our search strategies, 73 articles were retrieved from 2099 identified articles in PubMed using the “other animals” filter; among these, 18 were selected after reading the title and abstract. In addition, we selected three articles from BIREME and 0 articles from the Cochrane database. The inclusion and exclusion criteria are described in Figure 1 (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
25. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
). Articles were primarily excluded when assessments were performed in human subjects, apart from being unrelated to components of PICO; we mainly focused on experimental animal studies.

In Table 4, we employed the criteria of Henderson et al. (1818. Henderson VC, Kimmelman J, Fergusson D, Grimshaw JM, Hackam DG. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments. PLoS Med. 2013;10(7):e1001489. https://doi.org/10.1371/journal.pmed.1001489
https://doi.org/10.1371/journal.pmed.100...
). We found that 61.11% (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
,2222. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
-26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
2727. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
,3030. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
,3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
,3333. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6.,3535. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41,3636. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35.,3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) of selected studies had an appropriate sample size and 61.11% (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
,2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
,2626. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
,2727. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
,3030. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
,3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
,3333. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6.-34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 3636. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35.) had randomized animals, according to their materials and methods. All articles were blinded to the outcome assessment (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
25. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
). We could not determine the criterion underlying the flow of animals through experiments, as no explicit statement regarding the same was available in the materials and methods. We observed that 77.77% of articles selected appropriate control groups (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
,2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
-26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
,3434. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44.,3636. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35.) and 61.11% (2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
,2626. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
,2828. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18,3030. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
-31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
3232. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
,3434. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44.,3636. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35.,3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) had well-defined dose-response relationships. Moreover, all studies analyzed (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
25. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) had standard characterizations of animal properties at baseline. Overall, 89% of studies had employed an appropriate animal model that simulated the human manifestation of the disease (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
-26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
2727. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
,2929. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
-30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
). All studies that examined treatment responses according to a known mechanism (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
25. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) had characteristics within the requested standards. Only 67% (2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
-24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
,3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
,3333. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6.,3535. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41,3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
,3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) of selected manuscripts were within the range of the standard model of patient age in clinical settings. All studies did not follow other standard application models. In replicating different models of the same disease, 78% of studies (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
-26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 2929. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
3030. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
,3232. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
,3434. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44.-35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) were independently replicated, whereas 88.88% (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
,2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
-26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 2929. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
,3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
-32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) were replicated in different species. For studies where the objective was inter-study standardization of an experimental design, 39% (2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
-26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
2828. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18,3232. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
,3535. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41,3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
) reached this standard (Table 4).

In Table 5, we analyzed the study characteristics of selected controlled animal studies. Accordingly, we obtained the following results according to each experiment performed in articles examined in this systematic review. Table 5 presents experiments in which melatonin significantly improved the investigated variable (marked as S), as well as those where melatonin showed no significant improvements (NS). Chen et al. (2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
), Liu et al. (3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
), and Petrosillo et al. (3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) reported that melatonin significantly decreased infarct size. Zhang et al. (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
) and Liu et al. (2424. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
) reported that melatonin improved echocardiographic measurements. Furthermore, studies by Benova et al. (2222. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
), Liu et al. (2424. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
), Simko et al. (2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
), Simko et al. (2626. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
), Liu et al. (3333. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6.), Repova et al. (3535. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41), and Chen et al. (3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
) showed that melatonin had a positive effect on hemodynamic variables. In addition, we observed that the effects of melatonin were not significantly different from those reported in the study by Chaudagar et al. (2828. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18). These findings indicated the substantial benefit of using melatonin to stabilize hemodynamic parameters. Moreover, Zhu et al. (3232. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
) and Chen et al. (3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
) revealed that melatonin improved left ventricular cardiac function (Figure 2, Table 5).

Table 5
Study characteristics of selected controlled animal studies assessing melatonin and the cardiovascular system.
Figure 2
Representation of the SYRCLE’s risk of bias tool for animal studies. Hooijmans et al. (4343. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW. SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol. 2014;14:43. https://doi.org/10.1186/1471-2288-14-43
https://doi.org/10.1186/1471-2288-14-43...
).

Zhang et al. (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
), Liu et al. (2424. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
), Simko et al. (2626. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
), Salmanoglu et al. (2929. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
), Zhu et al. (3232. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
), and Chen et al. (3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
) revealed that melatonin had positive effects on the rate of apoptosis (Table 5). Melatonin showed positive effects in studies examining western blotting of various proteins and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), including those by Zhang et al. (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
), Benova et al. (2222. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
), Chen et al. (3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
), Liu et al. (3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
), and Liu et al. (2424. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
) (Table 5). Drobnik et al. (3434. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44.) and Repova et al. reported that melatonin reportedly reduced collagen deposition (3535. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41) (Table 5). Immunohistochemical analyses were performed by Zhang et al. (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
), Stacchiiotti et al. (2727. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
), Cheng et al. (3030. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
), Liu et al. (3333. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6.), Drobnik et al. (3434. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44.), and Cheng et al. (3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
), revealing that melatonin consistently yielded a positive result (Table 5). Melatonin showed benefits in biometric analyses, as determined by Benova et al. (2222. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
), Simko et al. (2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
), and Chaudagar et al. (2828. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18) (Table 5).

Furthermore, melatonin showed beneficial effects on autophagosome evaluation, lactose dehydrogenase measurements, angiotensin, and aldosterone, nitric oxide levels, and mitochondrial analysis, as determined by Zhang et al. (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
), Chen et al. (2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
), Simko et al. (2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
), Liu et al. (3131. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
), Liu et al. (3333. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6.), Chen et al. (3737. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
), and Petrosillo et al. (3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
) (Table 5).

The meta-analysis revealed a statistically significant decrease in infarct size (MD -20.37 [-23.56, -17.18]). However, there was no statistical difference in systolic pressure between articles analyzed (MD -1.75 [-5.47, 1.97]). In articles analyzing lactate dehydrogenase, a statistically significant decrease in the levels of this enzyme was noted in animals in melatonin groups (MD -4.61 [-6.83, -2.40]). With regard to the ejection fraction, two articles showed improvement in melatonin-treated groups. Another study analyzed the influence of melatonin in infarcted animals with the same ejection fraction; however, this parameter was not statistically significant in the meta-analysis (MD -8.12 [-9.56, -6.69]) (Figure 3 ).

Figure 3a
Metanalysis of infarct size measurement by echocardiography (% left ventricular).
Figure 3b
Metanalysis of systolic blood pressure (mmHg).
Figure 3c
Metanalysis of lactate dehydrogenase (U/L).
Figure 3d
Metanalysis of ejection fraction measured by echocardiography (% left ventricular).

In terms of selection bias, the results were well-balanced between low risk, no clear risk, and high risk of bias. All studies presented a low risk of bias in the baseline variable characteristics. On analyzing allocation concealment, most selected articles had a high risk, and a little less than half presented a low risk of bias. The randomization parameter was also fairly balanced between low risk, no clear risk, and high risk of bias. On analyzing random outcome assessment, most studies (more than 50%) had a low risk of bias, and some presented an unclear risk of bias. On analyzing blinding bias, most articles were unclear as to whether investigators were blinded. The articles presented a low risk of bias in the results of incomplete outcome data (Figure 4 and 5).

Figure 4
Risk of bias graph: review of authors’ judgment regarding each risk of bias item presented as percentages across all included studies.
Figure 5
Risk of bias summary: review of authors’ judgment regarding each risk of bias item for each included study.

DISCUSSION

This systematic review revealed that melatonin has various beneficial effects on the cardiovascular system; these effects include decreased infarct size, improved cardiac function and cellular oxidation functions, reduced apoptosis, and healthier cellular histomorphology.

In the present review, studies that analyzed echocardiographic measures exhibited melatonin benefits such as decreased infarct size, improved ejection fractions, improved systolic and diastolic diameters, and ameliorated recovery rates of cardiac function (2424. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
), while also favoring the treatment of cardiac hypertrophy and hearts that experienced myocardial infarction, ischemia, or reperfusion (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
25. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
). On analyzing hemodynamic and biometric variables, melatonin appeared to confer significant benefits, such as improvements in systolic pressure, positive pressure derivative, lower left ventricular end-diastolic pressure, reduced left ventricular weight in relation to the total heart weight, and improved lung water content (2222. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
-23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
,2828. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18,3535. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41,3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
). Experimental models of obesity, hypertension, and other cardiovascular diseases reinforce the scientific practice of adopting animal models and assessing results prior to human application. These preclinical results indicate the effect of melatonin on the examined cardiovascular diseases.

Reportedly, melatonin is an important anti-apoptotic agent in various tissues, reducing calcium uptake, mitigating reactive oxygen species generation, and decreasing the levels of pro-apoptotic proteins, such as Bax (3939. Ferreira Cda S, Maganhin CC, Simões Rdos S, Girão MJ, Baracat EC, Soares JM Jr. [Melatonin: cell death modulator]. Rev Assoc Med Bras (1992). 2010;56(6):715-8. https://doi.org/10.1590/S0104-42302010000600024
https://doi.org/10.1590/S0104-4230201000...
). In addition, melatonin destabilizes hypoxia-induced hypoxia-inducible factor (HIF)-1α protein expression. Moreover, melatonin suppresses HIF-1α transcriptional activity under hypoxic conditions, resulting in vascular endothelial growth factor expression (4040. Park SY, Jang WJ, Yi EY, Jang JY, Jung Y, Jeong JW, et al. Melatonin supresses tumor angiogenesis by inhibiting HIF-1alpha stabilization under hypoxia. J Pineal Res. 2010;48(2):178-84. https://doi.org/10.1111/j.1600-079X.2009.00742.x
https://doi.org/10.1111/j.1600-079X.2009...
). Melatonin also confers anti-inflammatory effects on the cardiovascular system (4141. Paredes SD, Forman KA, Garcia C, Vara E, Escames G, Tresguerres JA. Protective actions of melatonin and growth hormone on the aged cardiovascular system. Horm Mol Biol Clin Investig. 2014;18(2):79-88. https://doi.org/10.1515/hmbci-2014-0016
https://doi.org/10.1515/hmbci-2014-0016...
). Furthermore, a systematic review and recent meta-analysis have identified that melatonin supplementation facilitates blood pressure regulation (4242. Hadi A, Ghaedi E, Moradi S, Pourmasoumi M, Ghavami A, Kafeshani M. Effects of Melatonin Supplementation On Blood Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Horm Metab Res. 2019;51(3):157-64. https://doi.org/10.1055/a-0841-6638
https://doi.org/10.1055/a-0841-6638...
).

Melatonin has substantial benefits in the heart, involving various proteins (including superoxide dismutase [SOD], catalase [CAT], and glutathione peroxidase [Gpx]), while also improving the apoptosis rate. These findings were determined using several techniques, including western blotting analysis of BCL and Bx expression and the TUNEL assay, which measured the decrease in the level of apoptosis in myocardial cells when melatonin was added (2323. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
-24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
2525. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
,2929. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
,3232. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
). Other important variables analyzed following melatonin administration in the cardiovascular system were lactate dehydrogenase levels, mitochondrial analysis, lipid peroxidation, glycosaminoglycan, collagen level reduction, culture measurements, the antioxidant action of cells, opening gradient of mitochondrial channels, improvement in vasoconstriction, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and cholesterol level measurements, nitric oxide synthase level measurements, histomorphometric evaluations, determination of hydroxyproline levels, and assessment of autophagosomes (2121. Zhang WX, He BM, Wu Y, Qiao JF, Peng ZY. Melatonin protects against sepsis-induced cardiac dysfunction by regulating apoptosis and autophagy via activation of SIRT1 in mice. Life Sci. 2019;217:8-15. https://doi.org/10.1016/j.lfs.2018.11.055
https://doi.org/10.1016/j.lfs.2018.11.05...
-22. Egan Benova T, Viczenczova C, Szeiffova Bacova B, Knezl V, Dosenko V, Rauchova H, et al. Obesity-associated alterations in cardiac connexin-43 and PKC signaling are attenuated by melatonina and omega-3 fatty acids in female rats. Mol Cell Biochem. 2019;454(1-2):191-202. https://doi.org/10.1007/s11010-018-3463-0
https://doi.org/10.1007/s11010-018-3463-...
23. Chen WR, Liu HB, Chen YD, Sha Y, Ma Q, Zhu PJ, et al. Melatonin Attenuates Myocardial Ischemia/Reperfusion Injury by Inhibiting Autophagy Via an AMPK/mTOR Signaling Pathway. Cell Physiol Biochem. 2018;47(5):2067-76. https://doi.org/10.1159/000491474
https://doi.org/10.1159/000491474...
24. Liu Y, Li LN, Guo S, Zhao XY, Liu YZ, Liang C, et al. Melatonin improves cardiac function in a mouse model of heart failure with preserved ejection fraction. Redox Biol. 2018;18:211-21. https://doi.org/10.1016/j.redox.2018.07.007
https://doi.org/10.1016/j.redox.2018.07....
25. Simko F, Baka T, Krajcirovicova K, Repova K, Aziriova S, Zorad S, et al. Effect of Melatonin on the Renin-Angiotensin-Aldosterone System in l-NAME-Induced Hypertension. Molecules. 2018;23(2):265. https://doi.org/10.3390/molecules23020265
https://doi.org/10.3390/molecules2302026...
26. Simko F, Pechanova O, Repova K, Aziriova S, Krajcirovicova K, Celec P, et al. Lactacystin-Induced Model of Hypertension in Rats: Effects of Melatonin and Captopril. Int J Mol Sci. 2017;18(8):1612. https://doi.org/10.3390/ijms18081612
https://doi.org/10.3390/ijms18081612...
27. Stacchiotti A, Favero G, Giugno L, Golic I, Korac A, Rezzani R. Melatonin Efficacy in Obese Lepti-Deficient Mice Heart. Nutrients. 2017;9(12):1323. https://doi.org/10.3390/nu9121323
https://doi.org/10.3390/nu9121323...
28. Chaudagar KK, Viczenczova C, Szeiffova Bacova B, Egan Benova T, Barancik M, Tribulova N. Modulation of systemic and aortic nitric oxide by melatonin and n-3 polyunsaturated fatty acids in isoproterenol affected spontaneously hypertensive and normotensive Wistar rats. Physiol Res. 2016;65 Suppl 1:S109-18 29. Salmanoglu DS, Gurpinar T, Vural K, Ekerbicer N, Dariverenli E, Var A. Melatonin and L-carnitin improves endothelial disfunction and oxidative stress in Type 2 diabetic rats. Redox Biol. 2016;8:199-204. https://doi.org/10.1016/j.redox.2015.11.007
https://doi.org/10.1016/j.redox.2015.11....
30. Cheng X, Wan Y, Xu Y, Zhou Q, Wang Y, Zhu H. Melatonin alleviates myosin light chain kinase expression and activity via the mitogen-activated protein kinase pathway during atherosclerosis in rabbits. Mol Med Rep. 2015;11(1):99-104. https://doi.org/10.3892/mmr.2014.2753
https://doi.org/10.3892/mmr.2014.2753...
31. Liu LF, Qian ZH, Qin Q, Shi M, Zhang H, Tao XM, et al. Effect of melatonin on oncosis of myocardial cells in the myocardial ischemia/reperfusion injury rat and the role of the mitochondrial permeability transition pore. Genet Mol Res. 2015;14(3):7481-9. https://doi.org/10.4238/2015.July.3.24
https://doi.org/10.4238/2015.July.3.24...
32. Zhu P, Liu J, Shi J, Zhou Q, Liu J, Zhang X, et al. Melatonin protects ADSCs from ROS and enhances their therapeutic potency in a rat model of myocardial infarction. J Cell Mol Med. 2015;19(9):2232-43. https://doi.org/10.1111/jcmm.12610
https://doi.org/10.1111/jcmm.12610...
33. Liu LF, Qin Q, Qian ZH, Shi M, Deng QC, Zhu WP, et al. Protective effects of melatonin on ischemia-reperfusion induced myocardial damage and hemodynamic recovery in rats. Eur Rev Med Pharmacol Sci. 2014;18(23):3681-6. 34. Drobnik J, Tosik D, Piera L, Szczepanowska A, Olczak S, Zielinska A, et al. Melatonin-induced glycosaminoglycans augmentation in myocardium remote to infarction. J Physiol Pharmacol. 2013;64(6):737-44. 35. Repová-Bednárová K, Aziriová S, Hrenák J, Krajcirovicova K, Adamcová M, Paulis L, et al. Effect of captopril and melatonin on fibrotic rebuilding of the aorta in 24 hour light-induced hypertension. Physiol Res. 2013;62(Suppl 1):S135-41 36. Drobnik J, Slotwinska D, Olczak S, Tosik D, Pieniazek A, Matczak K, et al. Pharmacological doses of melatonin reduce the glycosaminoglycan level within the infarcted heart scar. J Physiol Pharmacol. 2011;62(1):29-35. 37. Chen Z, Chua CC, Gao, J, Chua KW, Ho YS, Hamdy RC, et al. Prevention of ischemia/reperfusion-induced cardiac apoptosis and injury by melatonin is independent of glutathione peroxidase 1. J Pineal Res. 2009;46(2):235-41. https://doi.org/10.1111/j.1600-079X.2008.00654.x
https://doi.org/10.1111/j.1600-079X.2008...
3838. Petrosillo G, Colantuono G, Moro N, Ruggiero FM, Tiravanti E, Di Venosa N, et al. Melatonin protects against heart ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening. Am J Physiol Heart Circ Physiol. 2009;297(4):H1487-93. https://doi.org/10.1152/ajpheart.00163.2009
https://doi.org/10.1152/ajpheart.00163.2...
).

The main novelty of this study is that it highlights the benefits assimilated by melatonin in experimental models of myocardial infarction, such as improved ejection fraction. Apart from limitations such as differences between animal organisms and humans, experimental research in Brazil is often restricted due to limited funding for animal studies when compared with human trials. In addition, results from animal studies fail to precisely correlate with the experience of testing melatonin or other substances in an environment that differs from the human body. Another limitation that must be considered is the nature of systematic reviews, which examine non-published data and data previously published by other authors, thus hindering novel scientific findings.

CONCLUSION

Notably, this systematic review is based on animal experiments. Melatonin may impact the cardiovascular system, including experimental myocardial infarction, and further studies are necessary to determine its use in clinical settings for treating cardiovascular diseases.

ACKNOWLEDGMENTS

The author Cipolla-Neto is financed by FAPESP (2014/50457-0), and the authors Veiga and Cavalli, as well as all other authors, are financed by CNPq and CAPES (Brasíla-Br; financing number CNPq 301293 / 2018-0).

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Publication Dates

  • Publication in this collection
    11 Oct 2021
  • Date of issue
    2021

History

  • Received
    26 Feb 2021
  • Accepted
    16 Aug 2021
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