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Keywords:

  • cardiovascular disease;
  • cardiovascular system;
  • circadian rhythm;
  • heart;
  • melatonin

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References

Abstract:  Diurnal rhythms influence cardiovascular physiology, i.e. heart rate and blood pressure, and they appear to also modulate the incidence of serious adverse cardiac events. Diurnal variations occur also at the molecular level including changes in gene expression in the heart and blood vessels. Moreover, the risk/benefit ratio of some therapeutic strategies and the concentration of circulating cardiovascular system biomarkers may also vary across the 24-hr light/dark cycle. Synchrony between external and internal diurnal rhythms and harmony among molecular rhythms within the cell are essential for normal organ biology. Diurnal variations in the responsiveness of the cardiovascular system to environmental stimuli are mediated by a complex interplay between extracellular (i.e. neurohumoral factors) and intracellular (i.e. specific genes that are differentially light/dark regulated) mechanisms. Neurohormones, which are particularly relevant to the cardiovascular system, such as melatonin, exhibit a diurnal variation and may play a role in the synchronization of molecular circadian clocks in the peripheral tissue and the suprachiasmatic nucleus. Moreover, mounting evidence reveals that the blood melatonin rhythm has a crucial role in several cardiovascular functions, including daily variations in blood pressure. Melatonin has antioxidant, anti-inflammatory, chronobiotic and, possibly, epigenetic regulatory functions. This article reviews current knowledge related to the biological role of melatonin and its circadian rhythm in cardiovascular disease.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References

Heart rate, blood pressure, endothelial function and fibrinolytic activity, among other cardiovascular variables, exhibit diurnal variations consistent with a circadian rhythm [1]. Moreover, serious cardiovascular events also appear to exhibit circadian patterns. Indeed, the incidence of acute myocardial infarction, myocardial ischemia, cardiac arrest, ventricular tachycardia and sudden death in patients with heart failure all vary according to the time of day [2]. It has been suggested that social and commercial pressures, such as shift work, which opposes the ‘physiological’ temporal circadian order, may be factors underlying chronic illnesses, such as cardiovascular disease [3, 4].

In many disease states (e.g. diabetes mellitus, hypertension), neurohumoral circadian rhythms are ‘chronically’ impaired and result in dyssynchrony of cellular cross talk in different tissues [5]. The cardiovascular system actually exhibits significant daily variation regarding physiological, pathophysiological and molecular processes. Diurnal variations also affect gene and protein expression. An increasing number of experimental and clinical studies have shown that the coordination of these rhythmic processes plays a fundamental role in organ function [6].

The existence of a circadian clock mechanism has recently been documented in cardiomyocytes. This information helps to explain the circadian rhythms in cardiac physiology (e.g. heart rate, cardiac output) and pathophysiology (e.g. arrhythmias) [6, 7].

The internal ‘oscillator’, or control station regulating the body’s circadian clock, is the suprachiasmatic nucleus, a small group of cells (comprising approximately 70,000 neurons) located in the hypothalamus above the optic chiasm [8]. The suprachiasmatic nucleus processes external signals, such as ambient light information as well as inputs from the brain to regulate a variety of cyclic functions including body temperature, sleep/wake cycles and the secretion of hormones such as melatonin [9]. This review describes the current understanding of the role of melatonin in modulation of circadian rhythms with particular focus on cardiovascular disease.

Circadian rhythm and cardiovascular function

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References

The existence of a daily rhythm affecting heart rate, blood pressure, platelet and endothelial function, among other components of the cardiovascular system, has been known for several decades. Epidemiological studies reported a morning peak regarding the incidents of cardiovascular events, such as ischemic strokes, myocardial infarction, sudden cardiac death and ventricular arrhythmias [10–12].

Circadian clocks exist in cardiomyocytes, vascular smooth muscle cells and endothelial cells. Circadian clocks within individual cells of the cardiovascular system have the potential to influence cardiovascular function by allowing anticipation of the onset of neurohumoral stimuli (e.g. increased sympathetic nervous stimulation before awakening), thereby ensuring an appropriately rapid response. [6]. In the in vivo setting, a complex interplay occurs between environmental influences and intrinsic mechanisms (i.e. central and peripheral circadian clocks), which contributes to changes in cardiovascular function over the course of a given 24-hr period (Fig. 1). For example, day-to-night differences in physical and mental activity appear to be the major determinates of blood pressure circadian rhythms [10, 13]. Diabetes mellitus, a major risk factor for the development of heart disease in humans, is associated with a phase shift in the cardiac circadian clock [14, 15]. Shift workers have an increased incidence of cardiovascular disease [16–18], which might be related to alterations in cardiovascular intracellular circadian clock function.

image

Figure 1.  The suprachiasmatic nucleus synchronizes peripheral oscillators including those within the cardiomyocytes, vascular smooth muscle cells and endothelial cells through a combination of autonomic, behavioral, endocrine and genetics cues. Thus, the network of peripheral circadian oscillators in vascular tissues likely influences clock-dependent cardiovascular phenomenon, including blood pressure (BP), heart rate (HR) and myocardial infarction (MI).

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There is a temporal incidence in adverse cardiovascular events, including transient myocardial ischemia [19], myocardial infarction [20], sudden cardiac death [21] and stroke [22, 23]. These events typically occur more often in the early morning hours, just after awakening. There are also second more subtle peaks of these events in the late afternoon.

There are published reports supporting the view that the timing of onset of adverse cardiovascular events is linked directly to the intrinsic clock mechanism, as opposed to the ‘stress’ caused by awakening. Using creatine kinase MB (CK-MB) as a marker of myocardial damage, the peak incidence of acute myocardial infarction around 06:00 hr and its coincidence with a reported chest pain is documented [24]. In another retrospective study of sudden cardiac death on the Hawaiian island of Kauai [25], the prevalence of sudden cardiac death peaked between 06:00 and 12:00 hr for native Kauaians and between 12:00 and 16:00 hr for recent Japanese visitors to the island, corresponding to the early morning in Japan. Krantz et al. [26] studied 63 patients with stable coronary artery disease using a well-validated structured events diary and electrocardiographic monitoring; the results of this study further supported the idea that an intrinsic diurnal mechanism influenced the timing of onset of adverse cardiovascular events, possibly more than increased physical or mental activity. Hu et al. [27] used a mathematical analysis of heart beat dynamics to support the hypothesis that intrinsic diurnal influences on cardiac control, as opposed to extrinsic behavior, may be involved in the diurnal pattern of adverse cardiac events in vulnerable individuals. In addition to the morning peaks in CK-MB and reported pain, Muller et al. [24] also observed a secondary peak in the evening. Manfredini et al. [28], in a review on ischemic stroke, noted a secondary peak in the evening in the occurrence of myocardial infarction in patients with sleep apnea [29].

Others factors involved in the development of cardiovascular disease are likewise temporally modulated. Endothelial function, vascular tone, lipid metabolism, platelet and leukocyte reactivity, and fibrinolysis all vary with the time of day [30]. Scheer et al. [31] demonstrated a circadian rhythm in the platelet function, while Brezinski et al. [32] found that platelet aggregability is higher during the morning hours.

Core molecular oscillators have been identified in both the heart [33] and vascular tissue [34] encompassing both the vascular smooth muscle and endothelial compartments. Recent evidence has documented a role of molecular oscillators in regulating cardiovascular physiology [35, 36]. The endothelium secretes low levels of tissue plasminogen activator (tPA) along with platelet inhibitors, prostacyclin and nitric oxide [37, 38], which are also responsible for regulating vascular tone [39] and blood pressure [40]. An early morning surge in blood pressure is accompanied by a decline in endothelial function, as assessed by flow-mediated vasodilation [41–43]; both phenomena coincide with the clinically observed morning peak incidence in thrombotic events [44]. The tendency of platelets to aggregate, which can promote thrombogenesis, has suggested a diurnal pattern of this process in humans. However, aggregometry studies are conflicting and potentially affected by artifact [30]. Other mediators of the hemostatic system display diurnal variations, including coagulation factors (II, VII, X and tissue factor pathology inhibitor) [45–47]. The morning onset of myocardial infarction may partly result from circadian variation of fibrinolytic activity. Fibrinogen, the circulating precursor of fibrin (a clot-stabilizing protein), displays a circadian variation in humans [48].

Taken together, these data suggest that suprachiasmatic nucleus-driven diurnal variations in autonomic stimulation, coupled to the cardiomyocyte circadian clock-driven daily fluctuations in responsiveness of the heart to autonomic stimulation, act as major determinants of cyclic cardiovascular functions [6]. Whether environmental modulation of the synchronization of peripheral and central clocks contributes to the development of cardiovascular disease has not been established but is suspected. Loss of synchronization occurs when there are changes in feeding or sleep patterns, and during exposure to light at abnormal times, i.e. at night [49, 50]. Such dyssynchronization is seen in patients with hypertension, diabetes mellitus, obesity and shift workers, in whom there is an elevated risk of cardiovascular disease [51, 52].

Specific links between the melatonin and cardiovascular disease

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References

The circadian pacemaker within the suprachiasmatic nucleus triggers the pineal gland to produce a melatonin increase at night [53]. The production of melatonin by the pineal gland in vertebrates exhibits an unambiguous circadian rhythm with its peak near the middle of the scotophase and basal levels during the photophase. The daily and seasonal melatonin rhythms are involved in ‘time of day’ and ‘time of year’ signaling, and it is for this reason that they are considered to serve as a bio-clock and bio-calendar [54].

The amount of melatonin produced by the pineal gland of mammals changes with the age of the animal. The production of melatonin wanes with the aging process [55, 56]. In humans, melatonin production not only diminishes with age [57] but is also significantly lower in many age-related diseases, including cardiovascular disease [58–61]. Mounting evidence reveals that the rhythmicity of melatonin has a crucial role in a variety of cardiovascular pathophysiological processes including anti-inflammatory, antioxidant, antihypertensive and possibly antilipidemic functions (Fig. 2).

image

Figure 2.  Photic regulation of human physiological melatonin biosynthesis. RHT, Retinohypothalamic tract; SCN, Suprachiasmatic nucleus; pre-GSN, preganglionic sympathetic neuron; SCG, superior cervical ganglia; post-GSN, postganglionic sympathetic neuron.

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Evidence gathered in the last 15 yr indicates that melatonin influences multiple factors of the cardiovascular function [62]. Patients with coronary artery disease have low melatonin production rates, and blood melatonin concentrations correlate with the severity of the disease, i.e. greater reductions in melatonin production are observed in patients with a higher risk of myocardial infarction and/or sudden death [9, 62]. In addition, the use of β-adrenoceptor blockers, which reduce melatonin synthesis in the pineal gland, may also be responsible for low melatonin levels in patients with coronary disease. Stoschitzky et al. [63] showed that beta-blockers decrease pineal melatonin synthesis via a specific inhibition of β1-receptors. Nathan et al. [64] demonstrated a dose-dependent relationship between β1-receptor blockade and the suppression of nocturnal plasma melatonin in humans. Unexpectedly, however, Girotti et al. [65] did not observe a significant difference in the urinary levels of 6-sulfatoxymelatonin (the chief hepatic metabolite of melatonin) excretion in patients treated with β-adrenoceptor blocker compared to levels in nontreated individuals. Lower nocturnal melatonin concentrations may be the cause of sleep disturbances which are well-known side effects of β-adrenergic antagonists [9]. Several studies indicate that sleep disorders occur more frequently in patients with coronary than in noncoronary or normal subjects. As low melatonin levels can be associated with sleep disturbances [66, 67], at least in elderly patients, the low melatonin secretion, reported in patients with coronary, could play a causal role in the sleep disorders they experience [9].

Hypercholesterolemia and hypertension are also common consequences of aging. Oxidized low-density lipoprotein is a critical factor in the initiation and progression of atherosclerosis and it contributes to endothelial dysfunction and plaque destabilization through multiple mechanisms [68]. People with high levels of low-density lipoprotein cholesterol typically have low levels of melatonin. It has been shown that melatonin suppresses the formation of cholesterol by 38% and reduces low-density lipoprotein accumulation by 42% in freshly isolated human mononuclear leukocytes [69]. Several in vitro studies have documented the antioxidant actions of melatonin on low-density lipoprotein oxidation. According to Kelly and Loo [70], melatonin inhibits oxidative low-density lipoprotein modification. Furthermore, Seegar et al. [71] demonstrated that although melatonin itself appears to have little anti-atherogenic activity, melatonin’s precursors and breakdown products inhibit low-density lipoprotein oxidation, comparable to vitamin E. Melatonin has been also shown to depress plasma levels of total cholesterol and very low-density lipoprotein cholesterol as well as the low-density lipoprotein cholesterol subfraction in hypercholesterolemic rats [72]. Melatonin may exert these effects by increasing endogenous cholesterol clearance. In contrast, Abuja et al. [73] claimed that melatonin did not prevent the oxidative modification of low-density lipoprotein. Because of its lipophilic nature, however, melatonin readily enters the lipid phase of the low-density lipoprotein particles and prevents lipid peroxidation [74]. Dominguez-Rodriguez et al. [75] showed an association between nocturnal elevated serum levels of oxidized low-density lipoprotein and reduced circulating melatonin levels in patients with acute myocardial infarction, while Tamura et al. [76] found that melatonin treatment of peri- and postmenopausal women cause a significant elevation of high-density lipoprotein cholesterol without influencing total cholesterol levels. These findings generally support the notion that melatonin may lower total cholesterol and stimulate high-density lipoprotein levels while reducing the oxidation of low-density lipoprotein, changes that would generally be protective against cardiovascular disease [77].

The administration of melatonin reduces blood pressure in normal [78], pinealectomized [79] and spontaneously hypertensive rats [80], whereas pinealectomy leads to hypertension in rats [81]. Individuals with hypertension have lower melatonin levels than those with normal blood pressure, and the administration of melatonin reduces blood pressure. It has been shown that melatonin reduces blood pressure in both normo- and hypertensive subjects [82–85]. Melatonin has been shown to reduce the resistance of the large arteries to blood flow in adult men [84] and young women [83]. The administration of melatonin reportedly reduces blood pressure as a consequence of various mechanisms including a direct hypothalamic effect, a reduction of catecholamine levels, relaxation of the smooth muscle wall and, most importantly, as a result of its antioxidant properties [9, 86, 87]. Additionally, it is known that nitric oxide plays a key role in the maintenance of vascular tone, which in turn influences blood pressure. A relative nitric oxide deficiency has been documented in different forms of hypertension [62]. Pechanova et al. [88] demonstrated that melatonin reduces blood pressure significantly and that this treatment enhanced nitric oxide synthase activity, reduced oxidative stress and decreased NF-κβ. Finally, melatonin was also shown to reduce some of the pathophysiological consequences of renovascular hypertension because of its ability to function as an antioxidant [89].

Several studies suggest that some immunological factors play an important role in the initiation of inflammatory processes that predispose to coronary artery disease. Moreover, interactions exist between the endocrine and the immune system [90]. In this context, melatonin plays an essential role as a modulator of a large number of inflammatory molecules [91, 92]. We have demonstrated that light/dark variations in the production of endogenous inflammatory markers in patients with coronary artery disease might be related, at least in part, to day/night fluctuations in melatonin circulating levels [93–96].

Melatonin and its metabolites have been widely tested for their ability to attenuate the tissue damage resulting from transient occlusion of the blood supply to organs [97–99]. Salie et al. [100] reported that melatonin, via inhibition of reactive oxygen species generation and intracellular Ca2+accumulation, protects rat ventricular myocytes against ischemia/reperfusion-induced morphologic damage. Using a Langendorff rat heart preparation, Tan et al. [101] found that when melatonin, infused throughout the period of coronary artery occlusion and after reopening of the vessel, highly significantly reduced both premature ventricular contractions and the ventricular fibrillation. Investigations have also confirmed the beneficial effects of pharmacological doses of melatonin on abnormal function and cardiac tissue damage resulting from ischemia/reperfusion injury [102–104]. A significant portion of melatonin’s antioxidant actions may derive from its stimulatory effect on antioxidative enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase and glucose-6 phosphate dehydrogenase as well as its ability to inhibit the pro-oxidative inducible nitric oxide synthase [105, 106]. Additionally, a number of early studies suggested that the reported protective effects of melatonin are mediated via melatonin’s receptor-independent actions as a radical scavenger [104, 107]. Recent investigations in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention confirmed a relationship between melatonin concentrations and ischemia-modified albumin, a marker of myocardial ischemia. Our data thus suggest that melatonin acts as a potent antioxidant agent, reducing myocardial damage induced by ischemia/reperfusion [108] (Fig. 3).

image

Figure 3.  As illustrated in this simplified figure, the events that lead to molecular damage and cell death during ischemia/reperfusion injury are complex. Considering the numerous intracellular actions of melatonin as a direct free radical scavenger, as an indirect antioxidant because of its ability to stimulate antioxidative enzymes and its effect on mitochondrial electron transport, this indole has a role in reducing molecular damage and cell death in patients with ST-segment elevation myocardial infarction.

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Melatonin and cardiovascular disease: genetic background

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References

That disturbances of circadian rhythmicity are associated with the risk of cardiovascular events is established [109], but addressing these issues is challenging as the major circadian hormone, i.e. melatonin, is modulated by several variables including genetic and especially environmental factors. A number of recent investigations have demonstrated how alterations in the circadian melatonin rhythm may be involved in adverse cardiovascular outcomes and possibly also influence common manifestations of metabolic disorders [110]. Up to 10% of the transcriptome might be under the control of the circadian clock [111]. Understanding the specific contribution that melatonin in this context may be assisted by the fact that costs of DNA analysis have been reduced recently [112, 113].

The marked variability of melatonin production by the pineal gland may be because of mutations in genes encoding for critical enzymes involved in melatonin biosynthesis [e.g. arylalkylamine N-acetyltransferase (AANAT) and tryptophan hydroxylase 1 (TPH1)]. In the case of the AANAT gene, eleven coding single-nucleotide polymorphisms (SNPs) have been described, with six of them having a similar function and five representing missense mutations with one amino acid substituted for another [114]. Hohjoh et al. [115] demonstrated a relationship between the SNP rs28936679 in the AANAT gene and the delayed sleep-phase syndrome. Also, the SNP rs10488682 located in the promoter region of TPH1 is related with the synthesis of melatonin [116]. An impaired maturation of the photoneuroendocrine system caused by a genetic absence or mutation of these enzymes may cause a lethal imbalance in the chemical interactions among serotonin, progesterone, catecholamines and intracellular calcium. This stresses the fact that a misfiring circadian release of melatonin can lead to cardiovascular disease because of abnormal levels of other hormones (e.g. abnormally high levels of aldosterone influence blood pressure through water retention) [117]. Melatonin levels were reported to be significantly reduced in victims of the sudden infant death syndrome compared to age-matched controls with nonsudden infant death syndrome victims [118]. It is hypothesized that a delayed ontogenesis of melatonin is a challenge facing newborns who are at risk for sudden infant death syndrome because of gene mutations or immature cardiac responses [119]. Melatonin deficiency may potentially increase electrical instability of the heart during the sleep period. These observations suggest that genetic screening in neonates at risk for cardiac disorders might be important in the design-protective strategies.

Two G protein-coupled membrane receptors for melatonin have been cloned and are identified as MTNR1A (MT1) and MTNR1B (MT2) [120]. In mammals, these melatonin receptors are expressed in the majority of the central and peripheral tissues including the cardiovascular system [121, 122]. These receptors share a high degree of sequence homology with the G protein-coupled receptor 50 (GPR50), which plays a pivotal role in mediating the intracellular effects of numerous neurotransmitters and hormones, including melatonin [123]. There are nine coding SNPs in the MTNR1A gene (5 missenses, 3 synonymous and 1 insertion) and another nine coding SNPs in the MTNR1B gene (7 missenses and 2 synonymous). These SNPs may be associated with less-effective melatonin receptors and specific patterns of expression, emphasizing the possibility of novel cardiovascular syndrome pathways and potential preventative therapies.

Two-stage approaches, genome-wide association followed by selective SNP genotyping, have been adopted as an efficient strategy for personalizing medicine by identifying high cardiovascular risk individuals. A major limitation is the modest number of melatonin-related markers included in ongoing independent analyses, especially when a large proportion of disease associations may well be population specific, or are likely to be because of chance. Finding genetic variants of the melatonin pathway linked to obesity and prediabetes traits are patently associated with cardiovascular disorders, including hypertension and atherosclerosis, as results from the effects of SNPs within the MTNR1B locus [124]. Recent studies on individuals carrying the minor G allele of SNP rs10830963 in the MTNR1B gene revealed that this melatonin receptor subtype is associated with higher glucose levels and increased diabetes risk [125–127]. Among a number of physiological variations, the SNP rs1562444 located in the 3′-untranslated region of MTNR1B could be associated with the rheumatoid arthritis by altering its appropriate expression or RNA folding [128]. In addition, three genome-wide association studies identified two SNPs in the MTNR1B (rs1387153, rs10830963) predicting susceptibility to type 2 diabetes. [129].

These may be good examples on how different genotypes affecting the production of melatonin or the function of its receptors could be useful to elicit cardiovascular disease risk given the modest effects of common variants that contribute to these complex traits.

The aim of ongoing studies is to identify gene polymorphisms that confer susceptibility to inflammation, variations in blood pressure or even those affecting the therapeutic efficacy of specific cardiovascular drugs [130, 131]. Recently, two SNPs (rs10455872 and rs3798220) have been identified at the locus encoding Lp(a) lipoprotein, which are strongly associated with both an increased level of Lp(a) lipoprotein and an elevated risk of coronary disease [132]. There are also results, however, indicating that SNPs in the melatonin-related receptor gene (GPR50) might be associated with circulating triglyceride and high-density lipoprotein levels [133], and additional findings suggest that melatonin may inhibit the activity of lipoprotein lipase [134].

Finally, it is worth stressing that we have been assessing the relationship between C-reactive protein polymorphisms, i.e. 1059G>C, rs1800947 and MTNR1A (G166E, rs28383653) to ascertain whether these two SNPs are associated with an increased risk for acute myocardial infarction. We have performed a case–control study in 300 consecutive patients with acute myocardial infarction and 250 healthy controls (unpublished data). For validation of this association, we are presently examining larger subject panels for an extended set of markers, including several genetic variants of the melatonin pathway. The information of the new SNPs could be linked to advance cardiovascular risk factors or at least to propose new ways to treat circadian clock–related cardiovascular events. Moreover, the relevance of the identified polymorphisms to protein structure or function will be required to provide some insights into the pathomechanism that might underpin various cardiovascular syndromes.

Conclusions

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References

Synchrony between external and internal circadian rhythms and harmony among molecular fluctuations within cells are essential for normal organ biology. Circadian clocks exist within multiple components of the cardiovascular system. These clocks have the potential of affecting multiple cellular processes and, therefore, hold promise of modulating various aspects of cardiovascular function over the course the 24-hr cycle. Many aspects of cardiovascular physiology are subject to diurnal variations, and serious adverse cardiovascular events appear to be conditioned by the time of day. The suprachiasmatic nucleus is responsible for the control of circadian rhythms in peripheral tissues, acting via neural and humoral signals such as melatonin.

Numerous cardiac conditions are a consequence of free radical damage and processes involving an inflammatory response [62, 74, 92, 135]. The beneficial effects of melatonin administration against these conditions are because of its direct free radical scavenger activity and its indirect antioxidant properties. Likewise, the results from many investigations documented a role of melatonin against inflammatory molecules in patients with acute coronary syndrome indicating that this indoleamine has significant beneficial immunomodulatory effects. Therefore, melatonin rhythmicity appears to have crucial roles in various cardiovascular functions as an antioxidant, an anti-inflammatory agent chronobiotic and possibly as an epigenetic regulator [136].

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Circadian rhythm and cardiovascular function
  5. Specific links between the melatonin and cardiovascular disease
  6. Melatonin and cardiovascular disease: genetic background
  7. Conclusions
  8. References