Disrupted Body Clocks and Heart Disease Risk: The Important Role of Melatonin

At the cellular level, circadian rhythms are governed by a transcriptional–translational feedback loop (TTFL) composed of core clock genes and proteins that generate rhythmic oscillations in gene expression with an approximately 24 h periodicity. The central components of this loop include the CLOCK (circadian locomotor output cycles kaput) and BMAL1 (brain and muscle aryl hydrocarbon receptor nuclear translocator (Arnt)-like protein 1) proteins, which heterodimerize and bind to enhancer (E)-box elements in the promoter regions of target genes, activating the transcription of Period (PER1, PER2, and PER3) and Cryptochrome (CRY1 and CRY2) genes [18,19,20,21,22,23]. As PER and CRY proteins accumulate in the cytoplasm, they form inhibitory complexes that translocate into the nucleus and suppress their transcription by interacting with the CLOCK–BMAL1 complex. This negative feedback loop is delayed by time-dependent processes of transcription, translation, and protein degradation, allowing the system to maintain approximately 24 h stable rhythms [18,19,22,24].

This core loop is further regulated by secondary interlocking feedback mechanisms. Nuclear receptors, such as reverse orientation c-erbA gene α (REV-ERBα), known as nuclear receptor subfamily 1 group D member 1 (NR1D1), and retinoic acid receptor-related orphan receptor alpha (RORα), modulate the transcription of BMAL1 itself, forming stabilizing loops that fine-tune the amplitude and phase of oscillations [18,19,21,22,23]. These interconnected circuits collectively establish the molecular architecture of circadian rhythmicity, operating not only in the SCN but also in peripheral tissues, including the heart, vasculature, kidney, and liver. The precise timing of gene expression orchestrated by these mechanisms is crucial for synchronizing metabolic and physiological processes with daily environmental cycles [25].

The cardiovascular system exhibits robust circadian oscillations that influence a wide range of physiological parameters, including BP, heart rate (HR), vascular tone, and thrombotic potential [26]. BP typically follows a biphasic daily pattern, characterized by a nocturnal decline (“dipping”) during sleep and a marked surge in the early morning upon waking. This daily rhythm reflects the interplay between endogenous circadian regulation and behavioral cues such as physical activity, posture, and feeding cycles [27]. Laboratory protocols that isolate circadian influence, such as constant routine and forced desynchrony studies, confirm the presence of an intrinsic rhythm in BP, independent of behavioral states, with peak levels occurring in the late evening circadian phase [5,28].

Peripheral clocks expressed in cardiovascular tissues, including the heart, vasculature, kidney, and autonomic nervous system, contribute to the temporal control of cardiovascular functions [26]. These clocks regulate genes involved in vascular reactivity, ion channel expression, and hormonal signaling. Disruption of peripheral clock gene expression, especially BMAL1, has been shown to impair normal circadian variation in vascular resistance, reduce baroreflex sensitivity, and promote pathological BP profiles [29,30]. Importantly, a loss of the nocturnal dipping pattern or the emergence of a “reverse dipping” phenotype is strongly associated with increased risk of cardiovascular events, target organ damage, and mortality [29,31].

Blood vessels are under circadian control at both the structural and functional levels. Vascular smooth muscle cells (VSMCs) and endothelial cells express core clock genes that regulate rhythmic gene transcription involved in vasomotor tone, extracellular matrix remodeling, and cell cycle progression [32]. Experimental deletion of BMAL1 in VSMCs in murine models results in blunted circadian variation in systolic and diastolic BP, as well as loss of pulse pressure rhythmicity, highlighting the importance of local clocks in maintaining vascular homeostasis [33].

Endothelial-derived factors such as nitric oxide (NO) and endothelin-1 (ET-1) exhibit pronounced circadian patterns, contributing to time-of-day-dependent fluctuations in vascular tone. NO levels are typically lowest during the early morning hours, coinciding with the peak incidence of cardiovascular events, and highest in the late afternoon or evening [34]. Conversely, ET-1, a potent vasoconstrictor, follows a rhythmic secretion profile that aligns with sympathetic activity and modulates diurnal BP variability [35]. Circadian variations in peripheral blood flow, vascular resistance, and endothelial function underscore the role of the internal clock in optimizing cardiovascular efficiency and minimizing hemodynamic stress throughout the 24 h cycle [22].

HR follows a well-characterized circadian pattern, typically exhibiting lower values during nocturnal rest and higher values during daytime wakefulness [36]. This rhythm is governed not only by behavioral factors but also by endogenous circadian mechanisms that modulate the autonomic nervous system (ANS) [37]. Sympathetic activity tends to peak in the morning, contributing to the post-awakening surge in BP and HR. Meanwhile, parasympathetic (vagal) tone predominates during nighttime sleep, supporting cardiovascular recovery and energy conservation [38,39].

The circadian regulation of HR and HR variability (HRV) is mediated in part by oscillations in the expression of adrenergic receptors, ion channels, and autonomic regulatory genes, many of which are under the control of CLOCK and BMAL1 [40]. In experimental models, disrupting these clock genes in cardiac tissue alters chronotropic responsiveness, reduces vagal modulation, and predisposes to arrhythmogenicity [41]. Interestingly, endogenous rhythms in circulating catecholamines, particularly norepinephrine and epinephrine, reach peak concentrations during midday. At the same time, vagal activity shows its highest levels in the early morning, revealing a phase difference that may have functional implications for cardiovascular risk timing [42].

Modern societal demands have led to a growing proportion of the workforce, estimated at 15–27% in industrialized countries, engaging in nonstandard work schedules, including night shifts, rotating shifts, and extended-hour shifts [43]. Such shift work leads to chronic circadian misalignment, whereby behavioral cycles (e.g., sleep, activity, and feeding) are desynchronized from the endogenous circadian system. A large body of epidemiological evidence has demonstrated a significant association between shift work and increased risk of cardiovascular diseases (CVDs), including coronary heart disease (CHD) and stroke [44,45,46,47,48]. Shift work has been increasingly associated with adverse cardiovascular and metabolic health outcomes, as well as adverse psychological effects. Experimental and epidemiological studies highlight potential links between circadian disruption and increased risk of atherosclerosis, endothelial dysfunction, and impaired glucose metabolism. Moreover, prospective and mechanistic studies support the role of shift work as a contributor to long-term cardiovascular vulnerability and mental health burden [45,46,49,50].

The pathophysiological mechanisms linking shift work to CVD are multifactorial and involve complex interactions between sleep disruption, autonomic imbalance, metabolic dysregulation, and chronic low-grade inflammation [51,52,53]. Repeated alterations of the sleep–wake cycle impair sleep quality and duration, leading to increased sympathetic nervous system activity, elevated night-time BP, and reduced HRV, a marker of impaired parasympathetic tone [54]. Chronic misalignment between behavioral and circadian rhythms also disrupts glucose and lipid metabolism, promoting insulin resistance, hyperglycemia, and dyslipidemia [55]. Elevated levels of circulating inflammatory markers, such as C-reactive protein (CRP) and interleukin-6 (IL-6), have been observed in shift workers, further implicating inflammation as a mediator of vascular dysfunction [56]. Together, these alterations contribute to the development of atherosclerosis, hypertension, and other CVD risk factors.

Numerous longitudinal and meta-analytic studies demonstrate a dose–response relationship between the duration of shift work and cardiovascular risk. For example, each additional five years of shift work exposure has been associated with approximately a 5–7% increased risk of CVD overall, and a 4% increase in ischemic stroke risk in rotating night shift nurses. Moreover, individuals with long-term exposure (>15 years) show significantly higher incidences of both CHD and ischemic stroke [57,58,59]. This effect appears cumulative and progressive, particularly among individuals with rotating night shifts and irregular schedules. Notably, several large-scale cohort studies have shown that the association between shift work and CVD persists after adjustment for conventional risk factors such as hypertension, dyslipidemia, and type 2 diabetes [44,47,48]. These findings support the hypothesis that circadian misalignment, independently of other comorbidities, is causal in promoting CVD.

Given that a substantial proportion of the global workforce is regularly engaged in shift work, the public health implications of circadian disruption are profound. The increased cardiovascular risk observed in shift workers is not confined to clinical endpoints. Still, it is also reflected in a higher prevalence of intermediate risk factors, including obesity, metabolic syndrome, and elevated BP [15,45]. Importantly, the modifiability of work schedules, sleep hygiene, and behavioral timing offers potential avenues for intervention. Preventive strategies, such as optimizing shift rotations, limiting extended night shifts, and incorporating circadian-aware policies in occupational settings, may help mitigate the health burden associated with shift work [60]. Recognizing circadian misalignment as a distinct and targetable risk factor is essential for improving cardiovascular outcomes in this vulnerable population.

Beyond occupational influences, a wide range of lifestyle and environmental factors have emerged as potent disruptors of the circadian system. Among them, ALAN, including exposure to dim light at night (dLAN) and blue-enriched wavelengths from electronic devices, has gained increasing attention due to its pervasiveness in modern society [61,62]. ALAN acts directly on the retinohypothalamic tract, suppressing melatonin synthesis via stimulation of the SCN and thereby altering circadian phase and amplitude [63]. Experimental and epidemiological studies have shown that nighttime light exposure reduces the normal day–night variability of BP and HR, largely by increasing nocturnal sympathetic activity and impairing parasympathetic recovery [28,64].

In both animal models and humans, ALAN exposure has been associated with higher resting BP, increased HR, and attenuated dipping patterns, which are all established risk factors for cardiovascular morbidity [65]. These physiological effects appear to be independent of sleep duration or quality, suggesting a direct circadian mechanism involving the ANS. Importantly, even low-intensity or short-duration light exposure, such as light from bedside screens or urban light pollution, can significantly impair circadian rhythmicity, emphasizing the need to consider ALAN as a modifiable cardiovascular risk factor [65,66].

In addition to light, feeding time is a critical external cue (zeitgeber) for synchronizing peripheral clocks in metabolic tissues, including the liver, pancreas, adipose tissue, and vasculature [25]. While the central circadian pacemaker in the SCN is primarily entrained by light, peripheral oscillators are highly responsive to meal timing and caloric intake. Disruption of this coordination, such as eating during the biological rest phase, can lead to desynchronization between central and peripheral clocks, a phenomenon linked to impaired glucose tolerance, altered lipid metabolism, and increased cardiometabolic risk [67].

Experimental studies in rodents have shown that feeding during the rest phase can shift peripheral clock gene expression, uncouple it from the SCN, and induce metabolic derangements even without changes in diet composition or caloric load [68]. In humans, late-night eating has been associated with higher BP, elevated postprandial glucose levels, and increased incidence of obesity and coronary artery disease (CAD). Conversely, time-restricted eating (TRE), limiting food intake to the active (light) phase of the circadian cycle, has demonstrated beneficial effects on body mass, BP, insulin sensitivity, and lipid profiles, even in the absence of caloric restriction [69,70].

Psychosocial stress, a ubiquitous feature of modern life, is another potent modulator of circadian rhythmicity and cardiovascular function. Acute and chronic stressors activate the hypothalamic–pituitary–adrenal axis (HPA), leading to rhythmic secretion of glucocorticoids such as cortisol in humans (or corticosterone in rodents), which themselves exhibit strong circadian variation, typically peaking in the early morning [71]. Disruption of circadian organization, for example, through shift work, ALAN, or jet lag, can disturb this glucocorticoid rhythm, leading to sustained hypercortisolemia, impaired feedback regulation, and elevated allostatic load, a physiological state associated with increased cardiovascular risk [72,73,74].

Moreover, stress interacts dynamically with circadian phase: identical stressors may produce markedly different cardiovascular responses depending on the time of day. Studies have shown that sympathetic activation and parasympathetic withdrawal are more pronounced in the early biological morning, a time when HRV is lowest and cardiovascular vulnerability is heightened [75]. Individuals experiencing high levels of occupational or emotional stress, especially shift workers, demonstrate blunted vagal tone, elevated baseline HR, and increased inflammatory cytokine levels, which collectively promote vascular dysfunction and atherogenesis [76].

The cumulative effects of ALAN exposure, mistimed feeding, and chronic stress converge on a state of circadian disruption, often referred to as circadian disruption. This condition is characterized by a persistent misalignment between endogenous circadian rhythms and environmental or behavioral timing cues [77]. Circadian disruption affects a wide array of biological systems, including the ANS, metabolic pathways, and vascular function, thereby facilitating the development of cardiometabolic and cardiovascular disorders [78]. This disruption plays a pivotal role in the pathogenesis of hypertension, metabolic syndrome, and obesity, forming a mechanistic link between lifestyle patterns and long-term cardiovascular risk.

As it was mentioned above, circadian disruption refers to a sustained disturbance of a natural internal 24 h rhythm, often resulting from factors such as shift work, irregular sleep–wake schedules, nighttime light exposure, and mistimed food intake [79]. This disruption compromises the temporal coordination of biological processes, leading to a breakdown in synchronization between the central clock in the SCN and peripheral clocks in key metabolic tissues such as the liver, pancreas, adipose tissue, and vasculature [6]. Over time, this internal desynchrony contributes to metabolic inflexibility, promoting pathological states such as insulin resistance, dyslipidemia, visceral adiposity, and low-grade inflammation, which are hallmarks of cardiometabolic syndrome [79].

Epidemiological studies consistently show that individuals exposed to chronodisruptive conditions, particularly shift workers, late chronotypes, or those with irregular eating and sleeping habits, have a significantly increased risk of developing obesity, hypertension, type 2 diabetes, and metabolic syndrome [80,81]. These risks persist even when controlling for traditional lifestyle factors, suggesting that circadian misalignment itself is an independent contributor to cardiometabolic pathology [82].

The relationship between obesity and circadian disruption is bidirectional: while misaligned circadian rhythms can promote weight gain and metabolic dysfunction, obesity itself further impairs circadian regulation at both systemic and cellular levels [83]. Adipose tissue possesses autonomous circadian clocks that regulate the transcription of genes involved in lipogenesis, adipokine secretion, and insulin sensitivity [84]. Disruption of clock gene expression, particularly of BMAL1 and CLOCK, has been associated with increased adiposity, impaired glucose tolerance, and altered lipid profiles in both animal and human studies [19].

Experimental models have demonstrated that mice subjected to chronic light–dark cycle perturbations or fed during the rest phase develop significant weight gain, hepatic steatosis, and insulin resistance, even under isocaloric conditions. Similarly, clinical data show that individuals with late chronotypes, irregular sleep patterns, or nighttime eating habits exhibit a higher prevalence of visceral obesity and metabolic syndrome [85,86]. These findings highlight the role of circadian disruption not merely as a consequence, but as an active driver of metabolic disease.

In light of the strong link between circadian disruption and metabolic dysfunction, TRE has emerged as a promising non-pharmacological intervention to restore circadian alignment and improve cardiometabolic outcomes. TRE involves confining daily caloric intake to a limited window, typically 8–12 h, during the active (daylight) phase, without necessarily altering the quantity or quality of food consumed [19,87]. This feeding pattern reinforces peripheral clock gene oscillations and re-establishes synchrony between the central and peripheral circadian systems.

Both animal and human studies have shown that TRE can lead to reductions in body mass, waist circumference, BP, and atherogenic lipid levels, as well as improvements in insulin sensitivity and inflammatory markers, even in the absence of caloric restriction or increased physical activity [88,89]. These benefits are thought to arise from the reorganization of metabolic timing, improved mitochondrial function, and enhanced rhythmic gene expression [88]. As such, TRE represents a simple yet effective chronotherapeutic strategy to mitigate the adverse metabolic effects of circadian misalignment.

Circadian disruption plays a central role in the pathogenesis and progression of cardiometabolic disorders, acting through mechanisms that include endocrine imbalance, autonomic dysregulation, oxidative stress, and inflammatory activation [90]. The recognition that “when” physiological processes occur is as important as “what” occurs has led to a paradigm shift in cardiometabolic research and clinical practice. Understanding the biological consequences of sleep disturbances, mistimed feeding, and light-at-night exposure is essential for identifying at-risk individuals and designing targeted lifestyle interventions.

Realignment of circadian rhythms through strategies such as TRE, improved sleep hygiene, and light environment optimization offers promising avenues for preventing and managing conditions such as hypertension, obesity, and metabolic syndrome. Integrating chronobiological principles into cardiovascular prevention frameworks could enhance therapeutic efficacy and reduce long-term disease burden.

Melatonin (N-acetyl-5-methoxytryptamine) is an evolutionarily conserved indoleamine derived from the essential amino acid tryptophan [91]. Although this molecule is synthesized across diverse taxa, including plants, bacteria, and fungi, it plays a particularly vital role in vertebrates as a hormonal signal of darkness [91]. In mammals, melatonin secretion displays a robust circadian rhythm, with low daytime levels and peak nocturnal concentrations that convey information about the light–dark cycle to peripheral tissues. By acting as a systemic cue of circadian phase, melatonin helps coordinate internal biological rhythms with external environmental conditions [92].

In mammals, the pineal gland is the principal source of circulating melatonin, and its activity is tightly regulated by the central circadian pacemaker located in the SCN of the hypothalamus [2]. The SCN receives photic input from intrinsically photosensitive retinal ganglion cells via the retinohypothalamic tract and transmits this information to the pineal gland through a multisynaptic sympathetic pathway involving the paraventricular nucleus, intermediolateral cell column, and superior cervical ganglion [93]. During darkness, sympathetic stimulation of the pineal gland triggers norepinephrine release, which activates arylalkylamine N-acetyltransferase (AANAT), the rate-limiting enzyme in melatonin synthesis, resulting in a nocturnal surge in melatonin levels [94].

Exposure to light at night, particularly short-wavelength blue light (450 nm), suppresses melatonin synthesis by inhibiting this neural pathway, leading to attenuated nocturnal secretion and phase shifts in circadian rhythms [93]. Even low-intensity artificial light can significantly disrupt melatonin production, underscoring its sensitivity to environmental illumination [95].

Melatonin production exhibits a clear age-related decline, with peak nocturnal levels diminishing progressively over the human lifespan. In older individuals, this reduction is attributed to both functional deterioration of the pineal gland and structural changes within the SCN, including neuronal loss and reduced responsiveness to photic input [96]. As melatonin plays a central role in synchronizing circadian rhythms, its age-related decline may contribute to the flattening of hormonal and physiological rhythms, fragmentation of sleep, and increased susceptibility to cardiometabolic dysfunction in older adults.

Lifestyle and environmental factors also exert a strong modulatory influence on melatonin secretion. Nocturnal exposure to artificial light, especially blue-enriched light from electronic devices and light-emitting diode (LED) sources, suppresses endogenous melatonin release by interfering with the SCN-mediated sympathetic signaling to the pineal gland [97]. Moreover, irregular sleep–wake schedules, shift work, and insufficient exposure to natural daylight exacerbate circadian misalignment, leading to blunted melatonin rhythms and promoting circadian disruption [24]. These alterations are increasingly recognized as contributing factors in the pathogenesis of cardiovascular and metabolic diseases. An overview of the SCN–melatonin pathway and its influence on cardiovascular regulation is presented in Figure 1.

The most extensively studied cardioprotective mechanisms of melatonin include its potent antioxidant capacity, which it exerts through both direct and indirect pathways. Melatonin is capable of directly scavenging highly reactive ROS and RNS, including hydroxyl radicals, peroxynitrite, and singlet oxygen [98]. In addition, melatonin stimulates the expression and activity of endogenous antioxidant enzymes, such as SODs, GPxs, and catalases, enhancing the cellular defense system against oxidative stress [99].

Melatonin’s antioxidant cascade is its distinctive feature. The metabolic byproducts generated during melatonin scavenging retain radical-neutralizing properties, thereby prolonging and amplifying the antioxidant effect. Moreover, those byproducts have stronger antioxidant properties than melatonin. This multi-layered defense system is particularly relevant in the cardiovascular system, where oxidative stress contributes to endothelial dysfunction, lipid peroxidation, vascular inflammation, and atherogenesis [99].

In addition to its antioxidant properties, melatonin exerts significant anti-inflammatory effects, which contribute to its cardioprotective profile. One of the primary mechanisms involves inhibition of the nuclear factor kappa B (NF-κB) signaling pathway, a central regulator of pro-inflammatory gene expression [100]. By suppressing NF-κB activation, melatonin reduces the transcription of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), IL-6, and interleukin-1beta (IL-1β), thereby mitigating vascular inflammation and preventing the progression of atherogenic processes [101].

Interestingly, melatonin modulates immune system function by influencing the activity of macrophages, T lymphocytes, and other immune effector cells. This immunomodulatory effect helps maintain immune homeostasis, promoting adequate host defense while limiting chronic low-grade inflammation, a key driver of endothelial dysfunction, plaque instability, and cardiovascular events [12].

Melatonin also plays a critical role in the regulation of BP and vascular tone, acting through both central nervous system mechanisms and direct vascular effects. Centrally, melatonin modulates the ANS activity, notably by reducing sympathetic outflow, which leads to decreased vascular resistance and lower resting BP [102]. Peripherally, melatonin binds to melatonin receptor subtypes 1 (MT1) and 2 (MT2) expressed on VSMCs and endothelial cells, promoting vasodilation through increased NO bioavailability and reduced ROS generation [103].

Both MT1 and MT2 receptors are expressed in cardiovascular tissues, including endothelial cells, vascular smooth muscle cells, and cardiomyocytes [7]. MT1 activation has been associated with vasoconstrictive effects in certain vascular beds, mediated through Gi/o-protein-coupled inhibition of adenylate cyclase, reduced cAMP production, and increased intracellular Ca²⁺ in smooth muscle cells. In contrast [104], MT2 activation is more frequently linked to vasodilatory responses, in part by stimulating endothelial nitric oxide synthase activity, enhancing NO bioavailability, and promoting opening of large-conductance Ca²⁺-activated K⁺ channels [7,105]. Both receptors also modulate oxidative stress and autonomic balance, contributing to the circadian regulation of vascular tone and blood pressure. These complementary and sometimes opposing effects underscore the importance of receptor-specific pathways in mediating melatonin’s cardiovascular actions [7].

These vascular actions contribute to the preservation of endothelial function, a key determinant of cardiovascular health. By counteracting oxidative stress and inhibiting inflammatory signaling, melatonin protects the endothelial glycocalyx, supports arterial elasticity, and limits early vascular remodeling. The cumulative effects of these actions include a reduction in arterial stiffness, improved baroreflex sensitivity, and stabilization of circadian BP rhythms, particularly beneficial in hypertensive patients with a blunted nocturnal dip. The key molecular targets and physiological mechanisms underlying the cardioprotective actions of melatonin are summarized in Table 1.

Chronotherapy refers to the strategic timing of treatment administration in alignment with the body’s biological rhythms to optimize therapeutic efficacy and minimize adverse effects. In cardiovascular medicine, this concept is particularly relevant, as the incidence of adverse events such as myocardial infarction, stroke, and sudden cardiac death exhibits marked circadian patterns, often peaking in the early morning hours [106]. Melatonin, as a central modulator of circadian timing and vascular homeostasis, has emerged as a promising candidate for circadian-targeted intervention in disorders such as hypertension and atherosclerosis [7].

By influencing multiple pathophysiological pathways, including oxidative stress, endothelial dysfunction, autonomic imbalance, and inflammatory activation, melatonin provides a multifaceted therapeutic profile. Importantly, the timing of melatonin administration determines its physiological impact, highlighting the relevance of chronobiological principles in its clinical use [114].

Clinical studies have demonstrated that evening supplementation with melatonin, typically administered 1–2 h before bedtime, can significantly reduce nocturnal BP, particularly in individuals with a non-dipping profile, those who fail to exhibit the normal nighttime decline in BP. This subgroup is at increased risk for target organ damage and cardiovascular events, making it a key target for chronotherapeutic interventions [115,116]. As it was presented above, melatonin can exert its antihypertensive effects through several mechanisms, including attenuation of sympathetic tone, enhancement of parasympathetic activity, and improvement of endothelial function [102]. Notably, studies comparing daytime vs. nighttime dosing have shown that evening administration results in greater reductions in systolic and diastolic BP, improved sleep quality, and better alignment with endogenous circadian rhythms [117].

Beyond its antihypertensive actions, melatonin has demonstrated atheroprotective effects in preclinical studies. It inhibits the oxidation of low-density lipoprotein (LDL) cholesterol, a key initiating step in atherogenesis, and reduces the formation of foam cells by preventing lipid accumulation in macrophages [109]. Additionally, melatonin suppresses the expression of adhesion molecules and pro-inflammatory cytokines in the vascular endothelium, thereby limiting monocyte infiltration and plaque development [110]. Animal studies using atherosclerosis-prone models have shown that melatonin supplementation reduces the size and number of atherosclerotic lesions, stabilizes plaque structure, and decreases markers of vascular inflammation [110]. These effects are largely attributed to the inhibition of NF-κB-dependent signaling, reduction in oxidative stress, and restoration of endothelial integrity [118]. Although human data remain limited, these findings highlight the potential of melatonin as an adjunctive agent in atherosclerosis prevention and management.

The timing of melatonin administration plays a pivotal role in determining its therapeutic efficacy, particularly in cardiovascular applications. Administering melatonin in synchrony with the endogenous circadian rhythm, typically during the biological night, enhances its ability to regulate BP, reduce oxidative stress, and restore endothelial function [111]. In contrast, daytime supplementation appears less effective and may even disrupt circadian homeostasis. These observations support the concept of melatonin-based chronotherapy, in which treatment is aligned with diurnal variations in cardiovascular risk [112]. By targeting periods of increased vulnerability, such as the early morning surge in sympathetic activity, chronotherapeutic use of melatonin holds promise for reducing cardiovascular events, particularly in high-risk populations. While further clinical trials are needed to establish optimal dosing regimens and long-term outcomes, current evidence suggests that melatonin may serve as a safe, low-cost, and physiologically compatible adjunct in the prevention and management of hypertension and atherosclerosis, especially when administered with circadian precision.

Although several clinical trials and meta-analyses have reported reductions in nocturnal blood pressure and improvements in sleep quality following evening melatonin supplementation, the overall evidence remains mixed. The meta-analysis by Grossman et al. [116] demonstrated that controlled-release melatonin (2–5 mg for 7–90 days) significantly lowered nocturnal systolic and diastolic blood pressure in hypertensive patients, whereas immediate-release formulations generally showed no effect on 24 h ambulatory blood pressure. In contrast, some studies have not observed cardiovascular benefits, for example, a six-week randomized trial in older women with insomnia found no improvement in arterial stiffness or mitochondrial DNA markers despite within-group reductions in systolic blood pressure [119], and a high-dose (24 mg) crossover trial in African-American patients with hypertension reported no change in nocturnal blood pressure [120]. Mild and transient adverse effects, such as daytime somnolence, vivid dreams, or headache, have also been noted [116]. Variability in findings may be explained by differences in formulation, dosage, patient phenotyping, treatment duration, baseline dipping status, and outcome measurement methods.

Typical dosing regimens in cardiovascular studies involve evening administration of 2–5 mg melatonin, most often in controlled-release formulations, taken 1–2 h before habitual bedtime for intervention periods ranging from 2 weeks to 12 months [115,121]. Immediate-release preparations have shown less consistent effects on nocturnal blood pressure and other cardiovascular outcomes [121]. Short-term supplementation appears to be well tolerated, with mild adverse events such as daytime somnolence, vivid dreams, and headache reported in a minority of participants, and no serious cardiovascular complications observed in the available literature [122]. However, data on long-term safety in cardiovascular populations remain limited, and potential drug interactions—particularly with sedative agents or anticoagulant/antiplatelet medications—should be considered [122]. At present, the optimal dose, formulation, and duration of melatonin therapy for cardiovascular indications remain to be determined and require confirmation in well-powered, rigorously phenotyped, randomized controlled trials.

Taken together, the current body of evidence on melatonin chronotherapy for cardiovascular disease is constrained by important methodological limitations. Preclinical data are extensive and consistent in demonstrating antihypertensive and vasoprotective effects via multiple mechanisms [7], but translation into clinical benefit relies on relatively few human studies. Most clinical trials to date have been small (n ≈ 16–47), short-term (≤4 weeks), and often single-center, with only a minority at low risk of bias [115]. Meta-analyses pooling these trials indicate that the nocturnal BP-lowering effect is observed primarily with controlled-release melatonin, whereas immediate-release preparations show no benefit [115,116]. The certainty of evidence has been rated low to very low owing to imprecision and quality limitations [115]. Variability in study design, dosing regimens, patient selection, and outcome measures further limits comparability and generalizability [115]. These factors underscore the need for adequately powered, long-duration randomized controlled trials, particularly in well-characterized patient subgroups, to confirm efficacy, optimize treatment parameters, and determine long-term cardiovascular outcomes [115,116].