Effects of melatonin in the prevention of cardiovascular diseases: a systematic review

Introduction: Obesity represents a multifactorial disease that causes major public health problems. There are about 2.0 billion overweight and obese people in the world, represented by 39.6% of adults. Melatonin may provide cardioprotection at low pharmacological doses. Melatonin's ability to improve cardiovascular function and its hypotensive effect because of

systematic review. According to the GRADE instrument, most studies showed homogeneity in their results, with X 2 =90.4%>50%. The Funnel Plot showed a symmetrical behavior, not suggesting a significant risk of bias in studies with smaller sample sizes. It was concluded that melatonin can reduce body weight and fat mass and regulate energy expenditure, glucose/lipid metabolism, and insulin secretion; therefore, it can play an effective role in weight management. There is a growing consensus that the antioxidant and antiinflammatory properties of melatonin are of great importance in preserving the body's function and homeostasis. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The consumption of melatonin supplements can be effective in controlling blood pressure and anthropometric indices (as predictors of obesity) in patients with T2DM. Furthermore, melatonin has significant effects on ischemia-reperfusion injury, myocardial injury, pulmonary hypertension, hypertension, vascular diseases, valvular heart diseases, and lipid metabolism. As an inexpensive and well-tolerated drug, melatonin could be a new therapeutic option for cardiovascular diseases.

Introduction
Obesity represents a multifactorial disease that causes major public health problems [1]. There are about 2.0 billion overweight and obese people in the world, represented by 39.6% of adults [1]. Brazil ranks fifth, with around 18 million and the prospect of reaching 70 million individuals with obesity [2]. Studies indicate that a 5% to 10% reduction in weight also favors the reduction of type 2 diabetes mellitus (T2DM), as well as cardiovascular diseases [3]. About 415 million people live with diabetes in the world, corresponding to 1 in every 11 individuals of the adult population, with a perspective of 642 million in 20 years [3].
In this context, research has advanced on the physiological role of melatonin (Nacetyl-5methoxytryptamide) and its pharmacological analogs as therapeutic agents for the treatment of various diseases, mainly obesity, metabolic diseases, and diabetes. Thus, there is solid experimental and clinical evidence accumulated over the last 20 years about the important role of melatonin in the regulation of energy metabolism [3-6].
The sleep/wake cycle is critical for the secretion and physiological variations of several hormones, including melatonin [5-9]. Melatonin is a hormone produced mainly by the pineal gland, but also in the gastrointestinal tract, retina, lacrimal glands, skin, erythrocytes, platelets, lymphocytes, and bone marrow mononuclear cells, derived from noradrenergic stimulation of tryptophan and serotonin by α1 and β1 adrenergic receptors in postsynaptic pinealocytes [10][11][12].
In this sense, individuals with altered melatonin production may develop insulin resistance, glucose intolerance, insulin secretion disorders, dyslipidemia, energy balance disorders, and obesity [13]. Furthermore, the usual metabolism of the daily distribution of sleep/wake and fasting/eating cycles completely disappears [14 -16]. It should be noted that the daily metabolic cycle is characterized by a phase that temporally associates increased insulin sensitivity and glucose-stimulated insulin secretion with the fed state. Additionally, there is another phase that associates insulin resistance, mainly hepatic, with subsequent gluconeogenesis during sleep or rest. In this context, both phases disappear completely, characterizing a picture of circadian rhythm disturbance, called photodisruption [17][18][19][20][21][22][23][24].
Also, melatonin secretion decreases with aging and the presence of various diseases [25]. The sleep pattern changes throughout life and this has a great impact with advancing age and the development of certain diseases such as obesity and diabetes. Melatonin has been recommended for use in cases of sleep disorders such as insomnia and jet lag. However, pleiotropic actions of melatonin such as metabolic functions, and regulation of obesity and diabetes can be extremely useful in numerous diseases [26].
In this context, Mukherjee et al. proposed that melatonin can provide cardioprotection at low pharmacological doses [27]. Melatonin's ability to improve cardiovascular function and its hypotensive effect because of its direct and receptordependent antioxidant actions suggest that melatonin may have some beneficial effects in controlling diabetic vascular complications [28,29]. Furthermore, animal studies have shown that melatonin can reduce body weight and fat mass and regulate energy expenditure, glucose/lipid metabolism, and insulin secretion; therefore, it can play an effective role in weight management [30][31][32].
Studies suggest a possible role for melatonin in metabolic diseases such as obesity, T2DM, and metabolic syndrome [27][28][29][30][31]. However, there is no consensus on melatonin as an adjuvant in the treatment of metabolic diseases. Thus, studies are needed to define the possible risks and benefits of melatonin as a therapeutic agent. In the timeline, melatonin has developed exclusive or non-receptor-mediated forms of action. The immediate mode of action is similar to the classic and well-known hormone-effector interaction. The difference is that, in addition to the immediate measurable effects, melatonin initiates overnight effects that will only be observed the next day, after the signal ends. Furthermore, due to its special mechanisms of synthesis and synchronization with the environmental light/dark cycle, melatonin acts as an internal synchronizer of circadian rhythms [33].
Therefore, the present study aimed to carry out a systematic review of the main effects of melatonin in the treatment of obesity and diabetes mellitus, as well as in the prevention of cardiovascular diseases.

Study Design
The systematic review rules of the PRISMA Platform were followed. Available at: www.prisma-statement.org/. Accessed: 04/14/2023.

Research Strategy and Research Sources
The literary search process was carried out from April to May 2023 and was developed based on Scopus,

Vol 16 Iss 2 Year 2023 International Journal of Nutrology
PubMed, Science Direct, Scielo, and Google Scholar, using scientific articles until 2023, using the descriptors (MeSH Terms): Melatonin. Obesity. Diabetes. Cardiovascular diseases, and using the Boolean "and" between MeSH terms and "or" between historical findings.

Quality of Studies and Risk of Bias
Quality was rated as high, moderate, low, or very low for risk of bias, clarity of comparisons, accuracy, and consistency of analyses. High ranking was for systematic review articles or meta-analysis of RCTs, followed by RCTs. The low quality of evidence was attributed to case reports, editorials, and brief communications, according to the GRADE instrument. The risk of bias was analyzed according to the Cochrane instrument through Funnel Plot analysis.

Summary of Findings
A total of 168 articles were found. Initially, duplication of articles was excluded. After this process, the abstracts were evaluated and a new exclusion was performed, removing the articles that did not include the theme of this article, resulting in 98 articles. A total of 68 articles were evaluated in full and 46 articles were included and developed in this systematic review study (Figure 1). Considering the Cochrane tool for risk of bias, the overall assessment resulted in 4 studies with a high risk of bias and 26 studies that did not meet GRADE. According to the GRADE instrument, most studies showed homogeneity in their results, with X 2 =90.4%>50%.

Highlight Outcomes -Melatonin and Metabolic and Cardiovascular Diseases
Melatonin or N-acetyl-5-methoxytryptamine is a hormone produced by the pineal gland. It is synthesized from serotonin by the initial conversion of tryptophan into serotonin which produces N-acetylserotonin, which molecule will then be converted into melatonin. This hormone works as a circadian rhythm regulator, and is also a potent antioxidant and anti-inflammatory. Melatonin secretion decreases with age and influences seasonal and circadian rhythms, the sleep-wake cycle and reproduction. It has a day/night secretion pattern, sensitive to light, with an increase in the beginning of the night and a decrease at the end of this period. In addition, it participates in several other biological functions, including the control of energy balance with a modulating effect on insulin secretion and action, as well as on lipid metabolism [3-6].
Melatonin is considered an important chronobiotic that influences the circadian distribution of metabolic processes, synchronizing them with the feeding, resting and fasting cycle. In this context, there is a reference to its association with insulin resistance, glucose Vol 16 Iss 2 Year 2023 International Journal of Nutrology intolerance, sleep disorders and circadian metabolic disorganization, characterizing a state of chronological interruption and metabolic diseases with harm to general health. Thus, melatonin replacement may be an important factor in the control of these diseases, as well as in the inflammatory process [8,9].
Melatonin can modulate inflammatory processes by eliminating nitrogen oxide, a molecule involved in tissue injury as a secondary inflammatory mediator. There are reports that melatonin can reduce the synthesis or inhibit other pro-inflammatory mediators, including tumor necrosis factor alpha (TNF-a), interleukin 6 (IL-6) and interleukin . In this sense, metabolic and liver diseases become targets of studies with melatonin, aiming to clarify its association with molecular mechanisms, and possible use in clinical practice [3, 9,10].
In this context, it is emphasized that obesity is a chronic disease resulting from an imbalance between caloric intake and energy expenditure, triggering excessive accumulation of body fat. It is noted that the global incidence of obesity has increased since 1980, as almost a third of the world's population has this type of dysfunction [34].
Obesity is associated with an increased risk of chronic diseases including type II diabetes mellitus, dyslipidemia, systemic arterial hypertension, cardiovascular disease and some types of cancer. The association of obesity with low-grade chronic inflammation is highlighted, which collaborates with the development of the aforementioned systemic metabolic disorders. Obesity causes several intrinsic and extrinsic signals capable of triggering an inflammatory response in adipose tissue. These mechanisms are commonly considered to be the link between chronic caloric excess and adipose tissue inflammation. Some of these mechanisms include dysregulation of fatty acid homeostasis, local hypoxia, mitochondrial dysfunction, increased size and death of adipose cells, in addition to mechanical stress [35].
It is known that inflammation is related to a state of oxidative stress with a large production of reactive oxygen species, compared to the levels of antioxidants, allowing their action and compromising the natural defense systems. In this context, melatonin has been highlighted for its antioxidant and anti-inflammatory properties. Considering that melatonin modulates several processes involved in obesity, there is reference to the possibility of acquiring benefits from its use in various treatments [36].
There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body's function and homeostasis. Melatonin supplementation during pregnancy may reduce ischemia-induced oxidative damage in the fetal brain, increase offspring survival in inflammatory states, and reduce blood pressure in adult offspring. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The most studied cardiovascular effects of melatonin are linked to hypertension and myocardial ischemia/reperfusion injury, while the most promising ones are linked to the recovery of control of the components of the metabolic syndrome [37,38].
In this sense, dyslipidemia and hypertension are two complications that can develop in diabetic patients if hyperglycemia, insulin resistance, and weight gain are not controlled. A double-blind, randomized, placebocontrolled study investigated the effects of melatonin supplementation on some risk factors for cardiovascular disease and anthropometric indices in patients with T2DM. A total of 50 T2DM patients were randomly allocated into intervention and control groups who received either two melatonin tablets or a placebo (250 mg) once daily for 8 weeks. Systolic blood pressure (SBP), mean arterial pressure (MAP), pulse pressure (PP), plasma atherogenic index (AIP), weight, body mass index (BMI), waist and waist circumference (WC), shape index (ABSI), abdominal volume index (AVI), body adiposity index (BAI), lipid accumulation product (LAP), conicity index and waist-to-height ratio (WHtR) were evaluated in all patients pre and post-intervention. Melatonin supplementation for 8 weeks significantly decreased mean levels of SBP, MAP, PP, weight, BMI, WC, HC, BAI, AVI, conicity index, and WHtR postintervention (p<0.05). Furthermore, median changes in SBP, MAP, PP, weight, BMI, WC, HC BAI, AVI, and conicity index were significantly lower in the intervention group compared to the control group (p<0.05). A significant increase (p<0.001) was observed in mean ABSI levels in the intervention group. Median ABSI changes were significantly greater in the intervention group compared to the control group (p < 0.001). Therefore, melatonin supplement consumption can be effective in controlling blood pressure, including SBP, MAP, and PP, and anthropometric indices (as predictors of obesity) in patients with T2DM [39].
Previous studies have proposed that melatonin can regulate BP through multiple mechanisms. Melatonin can act directly as a free radical scavenger and provide appropriate concentrations of nitrogen oxide (NO), which may indirectly improve endothelial function and reduce the activity of the adrenergic system. Furthermore, it is suggested that melatonin may provide . Therefore, AVI, ABSI, BAI, and WHR together with BMI can be used as an investigation tool in the field to detect cardiovascular problems.

Conclusion
It was concluded that melatonin can reduce body weight and fat mass and regulate energy expenditure, glucose/lipid metabolism, and insulin secretion; therefore, it can play an effective role in weight management. There is a growing consensus that the antioxidant and anti-inflammatory properties of melatonin are of great importance in preserving the body's function and homeostasis. In adulthood, disturbances in melatonin production negatively impact the progression of cardiovascular risk factors and promote cardiovascular and neurodegenerative diseases. The consumption of melatonin supplements can be effective in controlling blood pressure and anthropometric indices (as predictors of obesity) in patients with T2DM. Furthermore, melatonin has significant effects on ischemia-reperfusion injury, myocardial injury, pulmonary hypertension, hypertension, vascular diseases, valvular heart diseases, and lipid metabolism. As an inexpensive and welltolerated drug, melatonin could be a new therapeutic option for cardiovascular diseases.