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The molecular mechanism of the circadian clock in mammals. Constituting the core circadian clock is an autoregulatory transcriptional feedback loop involving the activators CLOCK and BMAL1 and their target genes Per1, Per2, Cry1, and Cry2, whose gene products form a negative-feedback repressor complex.
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Circadian rhythms are internal 24-h intrinsic oscillations that are present in essentially all mammalian cells and can influence numerous biological processes. Cardiac function is known to exhibit a circadian rhythm and is strongly affected by the day/night cycle. Many cardiovascular variables, including heart rate, heart rate variability (HRV), el...
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Context 1
... such loop is the Reverba (Nr1d1) and RORa that coordinates CLOCK-BMAL1 functions. REV-ERBa and RORa individually bind to retinoic acidrelated orphan receptor response elements (RORE) to regulate (Figure 1). This loop affects the transcription of Bmal1 (and partially CLOCK) triggering the antiphase oscillation of BMAL1. ...
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Sleep is a fundamental physiological process that not only supports immune function but also contributes significantly to overall well-being. Because of the established decline in the average amount of sleep due to lifestyle and rise in shift work over the past few decades, exploring the relationship between sleep and immunity has become crucial. M...
Citations
... e circadian rhythm additionally a ects blood ow, arterial exibility, and blood clotting patterns, which can raise cardiovascular risk depending on the time of day. Disturbances to these natural rhythms, whether from lifestyle choices, shi work, sleep disorders, or underlying health issues, have been linked to a heightened risk of cardiovascular problems, as a disconnect between internal rhythms and external demands can create precarious periods [3]. ...
... This disruption is believed to stem from altered regulation of the hypothalamic-pituitary-adrenal (HPA) axis, which plays a central role in coordinating circadian signals with immune and endocrine functions. This is consistent across several studies demonstrating significant alterations in cortisol levels including an increase during nighttime shifts and sleep deprivation periods (5, 6,7,8,9,10,11). ...
Background: Circadian disruptions, such as shift work, sleep irregularity, and chronic circadian misalignment, have been increasingly linked to adverse health outcomes, particularly affecting cardiovascular health. These disruptions alter inflammatory and neuroendocrine pathways, which may accelerate cardiovascular disease risk. This meta-analysis aimed to synthesize evidence on the association between circadian misalignment, inflammatory markers, neuroendocrine dysregulation, and cardiovascular outcomes. Methods: A systematic literature search was conducted using PubMed, Web of Science, PsycINFO, Cochrane Library, and Scopus databases, covering studies published between 2015 and 2024. Eligible studies included observational and experimental designs assessing the impact of documented circadian disruptions on inflammatory markers (CRP, IL-6, TNF-α), neuroendocrine biomarkers (cortisol, melatonin), and cardiovascular outcomes (coronary heart disease, cardiovascular events, metabolic risk). Quality assessment was performed using the Cochrane Risk of Bias Tool for experimental studies and the Newcastle-Ottawa Scale (NOS) for observational studies. Due to substantial heterogeneity across studies, a narrative synthesis supported by descriptive statistics, correlation analysis, and visual comparative techniques was applied, rather than a formal pooled effect size calculation. Results: Eight studies (n=744) reported increased inflammatory markers (CRP, IL-6, TNF-α) in circadian disruptions (p < 0.05–0.01). Misalignment was linked to altered cortisol rhythms and increased secretion (p < 0.05). Correlation analysis showed a moderate positive association between neuroendocrine dysregulation and cardiovascular risk. Shift work and chronic misalignment had the highest cardiovascular risk, with stronger effects in longer studies. Most studies had low-to-moderate bias. Conclusions: Circadian disruptions contribute to inflammation, neuroendocrine dysregulation, and cardiovascular risk. Maintaining circadian stability is crucial, particularly for shift workers. High-quality studies are needed for targeted interventions.
... These findings highlight the importance of identifying modifiable risk factors. The correlations among sleep, circadian rhythm, and risk of cardiovascular disease have been studied [7,8]. Insomnia has been found to be associated with cardiovascular and metabolic disease risk and mortality [9]. ...
... We followed these patients for 6 months after discharge to evaluate their prognosis. Considering the crucial role of circadian rhythm in cardiovascular function [8], actigraphy data were further analyzed with different mathematical algorithms to assess the circadian rhythm of patients. ...
Background
Myocardial infarction (MI) is a medical emergency resulting from coronary artery occlusion. Patients with acute MI often experience disturbed sleep and circadian rhythm. Most previous studies assessed the premorbid sleep and circadian rhythm of patients with MI and their correlations with cardiovascular disease. However, little is known about post-MI sleep and circadian rhythm and their impacts on prognosis. The use of actigraphy with different algorithms to evaluate sleep and circadian rhythm after acute MI has the potential for predicting outcomes and preventing future disease progression.
Objective
We aimed to evaluate how sleep patterns and disrupted circadian rhythm affect the prognosis of MI, using actigraphy and heart rate variability (HRV). Nonparametric analysis of actigraphy data was performed to examine the circadian rhythm of patients.
Methods
Patients with MI in the intensive care unit (ICU) were enrolled alongside age- and gender-matched healthy controls. Actigraphy was used to evaluate sleep and circadian rhythm, while HRV was monitored for 24 hours to assess autonomic nerve function. Nonparametric indicators were calculated to quantify the active-rest patterns, including interdaily stability, intradaily variability, the most active 10 consecutive hours (M10), the least active 5 consecutive hours (L5), the relative amplitude, and the actigraphic dichotomy index. Follow-ups were conducted at 3 and 6 months after discharge to evaluate prognosis, including the duration of current admission, the number and duration of readmission and ICU admission, and catheterization. Independent sample t tests and analysis of covariance were used to compare group differences. Pearson correlation tests were used to explore the correlations of the parameters of actigraphy and HRV with prognosis.
Results
The study included 34 patients with MI (mean age 57.65, SD 9.03 years) and 17 age- and gender-matched controls. MI patients had significantly more wake after sleep onset, an increased number of awakenings, and a lower sleep efficiency than controls. Circadian rhythm analysis revealed significantly lower daytime activity in MI patients. Moreover, these patients had a lower relative amplitude and dichotomy index and a higher intradaily variability and midpoint of M10, suggesting less sleep and wake activity changes, more fragmentation of the rest-activity patterns, and a more delayed circadian rhythm. Furthermore, significant correlations were found between the parameters of circadian rhythm analysis, including nighttime activity, time of M10 and L5, and daytime and nighttime activitySD, and patient prognosis.
Conclusions
Patients with acute MI experienced significantly worse sleep and disturbed circadian rhythm compared with healthy controls. Our actigraphy-based analysis revealed a disturbed circadian rhythm, including reduced daytime activities, greater fluctuation in hourly activities, and a weak rest-activity rhythm, which were correlated with prognosis. The evaluation of sleep and circadian rhythm in patients with acute MI can serve as a valuable indicator for prognosis and should be further studied.
... Circadian rhythm-related genes (CRGs) play a crucial role in coordinating the regulation of circadian rhythms, the body's endogenous timing system. Emerging evidence has well established the impact of circadian rhythms on cardiovascular function and myocardial ischemia injury, strongly supporting CRGs as candidate diagnostic biomarkers 34,35 . Simultaneously, a study reveals a potentially complex relationship between CRGs and immune infiltration in heart failure 19 . ...
Current diagnostic biomarkers for acute myocardial infarction (AMI), such as troponins, often lack specificity, leading to false positives under non-cardiac conditions. Recent studies have implicated circadian rhythm and immune infiltration in the pathogenesis of AMI. This study hypothesizes that analyzing the interplay between circadian rhythm-related gene expression and immune infiltration identify highly specific diagnostic biomarkers for AMI. Our results demonstrated differential expression of 15 circadian rhythm-related genes (CRGs) between AMI patients and healthy individuals, with five key genes—JUN, NAMPT, S100A8, SERPINA1, and VCAN identified as key contributors to this process. Functional enrichment analyses suggest these genes significantly influence cytokine and chemokine production in immune responses. Immune infiltration assessments using ssGSEA indicated elevated levels of neutrophils, macrophages, and eosinophils in AMI patients. Additionally, we identified potential therapeutic implications with 13 pivotal miRNAs and 10 candidate drugs targeting these genes. The Benjamini–Hochberg method was employed to adjust for multiple testing, and the results retained statistical significance. RT-qPCR analysis further confirmed the upregulation of these five genes under hypoxic conditions, compared to controls. Collectively, our findings highlight the critical role of CRGs in AMI, providing a foundation for improved diagnostic approaches and novel therapeutic targets.
... Otherwise, most physiological processes, including heart rate, heart rate variability, blood pressure, platelet activity, vagal modulation, cardiomyocyte function, and endothelial cells display a circadian rhythm regulated mainly by sleep/wake and fasting/feeding cycles [15]. A clear link between human synchronization of the circadian clock and CV health has been established [16]. In this line, the daily light/dark pattern was considered a new modifiable lifestyle and a synchronizer of the circadian clock [17]. ...
Background
Endothelial function (EndFx) is a core component of cardiovascular (CV) health and cardioprotection following acute myocardial infarction (AMI) treated with primary percutaneous coronary intervention (PCI).
Hypothesis
AMI patients experience endothelial dysfunction (EndDys), associated with traditional CV risk factors and sleep patterns. EndFx may also predict short and mid‐term outcomes.
Methods
EndFx was assessed in 63 patients (56.2 ± 7.6 years) using the Endothelium Quality Index (EQI). Sleep quality and quantity were evaluated using objective (actigraphy) and subjective (Pittsburgh Sleep Quality Index questionnaire) measures. Cardiorespiratory fitness was quantified through the 6‐min walking test. Cardiac function was assessed using the left ventricular ejection fraction.
Results
Following AMI, patients tended to experience EndDys (EQI = 1.4 ± 0.7). A severe EndDys was observed in 23.8% of patients (n = 15), while a mild EndDys was present in 63.49% (n = 40). Furthermore, EndDys was significantly associated with traditional CV risk factors (i.e., low physical activity level [12.8%], age [−4.2%], and smoking [−0.7%]) (R² adjusted = 0.50, p < 0.001). Patients with EndDys had poor sleep quality (p = 0.001) and sleep efficiency (p = 0.016) compared to healthy persons. Patients with severe EndDys exhibited lower cardiorespiratory fitness compared to those with healthy EndFx (p = 0.017). Furthermore, during a follow‐up period (nearly 4 months) following PCI, major adverse cardiac events were observed in four patients with severe EndDys.
Conclusions
Our results emphasize the importance of adequate sleep and an active lifestyle, notably physical activity practice, as modifiable elements to enhance EndFx, which is regarded as a predictive tool following AMI. However, other factors remain to be elucidated as predictors of CV risk.
Trial Registration
The study protocol was registered in the Pan African Clinical Trial Registry under the trial ID: PACTR202208834230748.
... Such disruptions not only lead to chronic sleep deprivation, but also trigger a cascade of physiological changes, including altered circadian central nervous system activity, hormonal imbalances, and heightened cortisol levels [41,42]. These changes contribute to systemic inflammation and endothelial dysfunction, both of which are critical pathways in the development of cardiovascular diseases, including myocardial infarction [43]. Moreover, chronic stress, another common issue faced by shift workers, can induce a range of physiological and behavioral changes that are closely linked to cardiovascular disease [44]. ...
Cardiovascular disease continues to be a major contributor to global morbidity and mortality, with environmental and occupational factors such as air pollution, noise, and shift work increasingly recognized as potential contributors. Using a two-sample Mendelian randomization (MR) approach, this study investigates the causal relationships of these risk factors with the risks of unstable angina (UA) and myocardial infarction (MI). Leveraging single nucleotide polymorphisms (SNPs) as genetic instruments, a comprehensive MR study was used to assess the causal influence of four major air pollutants (PM2.5, PM10, NO2, and NOx), noise, and shift work on unstable angina and myocardial infarction. Summary statistics were derived from large genome-wide association studies (GWASs) from the UK Biobank and the FinnGen consortium (Helsinki, Finland), with replication using an independent GWAS data source for myocardial infarction. The inverse-variance weighted (IVW) approach demonstrated a significant positive correlation between shift work and the increased risk of both unstable angina (OR with 95% CI: 1.62 [1.12–2.33], p = 0.010) and myocardial infarction (OR with 95% CI: 1.46 [1.00–2.14], p = 0.052). MR-PRESSO analysis identified outliers, and after correction, the association between shift work and myocardial infarction strengthened (OR with 95% CI: 1.58 [1.11–2.27], p = 0.017). No notable causal associations were identified for air pollution or noise with either outcome. The replication of myocardial infarction findings using independent data supported a possible causal link between shift work and myocardial infarction (OR with 95% CI: 1.41 [1.08–1.84], p = 0.012). These results provide novel evidence supporting shift work as a likely causal risk factor for unstable angina and myocardial infarction, underscoring the need for targeted public health strategies to mitigate its cardiovascular impact. However, further investigation is necessary to elucidate the role of air pollution and noise in cardiovascular outcomes.
... Studies on mouse models lacking clock genes have revealed that the circadian rhythm genes influence the regulation of up to 10% of the cardiac transcriptome [80] associated with preload, contractility, and rate [81]. The involvement of circadian rhythm regulators in the pathogenesis of cardiac arrhythmias, myocardial infarction, cardiomyopathy, and heart failure has been extensively documented [82][83][84]. Circadian genes play a key role in regulating inflammatory processes and lipid metabolism, and their dysregulation can lead to the development of atherosclerosis and thrombosis [85]. Recent studies have emphasized the significance of peripheral circadian clock dysregulation in controlling local tissue function [86]. ...
Background
Long-term consumption of Western Diet (WD) is a well-established risk factor for the development of cardiovascular disease (CVD); however, there is a paucity of studies on the long-term effects of WD on the pathophysiology of CVD and sex-specific responses.
Methods
Our study aimed to investigate the sex-specific pathophysiological changes in left ventricular (LV) function using transthoracic echocardiography (ECHO) and LV tissue transcriptomics in WD-fed C57BL/6 J mice for 125 days, starting at the age of 300 through 425 days.
Results
In female mice, consumption of the WD diet showed long-term effects on LV structure and possible development of HFpEF-like phenotype with compensatory cardiac structural changes later in life. In male mice, ECHO revealed the development of an HFrEF-like phenotype later in life without detectable structural alterations. The transcriptomic profile revealed a sex-associated dichotomy in LV structure and function. Specifically, at 530-day, WD-fed male mice exhibited differentially expressed genes (DEGs), which were overrepresented in pathways associated with endocrine function, signal transduction, and cardiomyopathies. At 750 days, WD-fed male mice exhibited dysregulation of several genes involved in various lipid, glucagon, and glutathione metabolic pathways. At 530 days, WD-fed female mice exhibited the most distinctive set of DEGs with an abundance of genes related to circadian rhythms. At 640 days, altered DEGs in WD-fed female mice were associated with cardiac energy metabolism and remodeling.
Conclusions
Our study demonstrated distinct sex-specific and age-associated differences in cardiac structure, function, and transcriptome signature between WD-fed male and female mice.
Graphical Abstract
... For example, using a mouse model of induced cardiac hypertrophy, it has been found that exposure to 10 h L: 10 h D cycles adversely affects cardiac structure and function reflected in the altered expression of clock genes and remodeling genes 51 . Thus, restoring a normal diurnal rhythm could rescue these changes, indicating that a normal daily rhythm is crucial for cardiovascular health 52 . Indeed, chronic jet lag and shift work have been linked to CVD disease 53 . ...
... Sleep-related BP variation can be described by a square wave function with changes at sleep onset and offset and relatively constant values over the course of sleep. This drop in BP during sleep is important for cardiovascular health 52 . ...
... Circadian rhythm-related genes (CRGs) play a crucial role in coordinating the regulation of circadian rhythms, the body's endogenous timing system. Emerging evidence has well established the impact of circadian rhythms on cardiovascular function and myocardial ischemia injury, strongly supporting CRGs as candidate diagnostic biomarkers 31,32 . Simultaneously, a study reveals a potentially complex relationship between CRGs and immune in ltration in heart failure 19 . ...
Current diagnostic biomarkers for acute myocardial infarction (AMI), such as troponins, often lack specificity, leading to false positives under non-cardiac conditions. Recent studies have implicated circadian rhythm and immune infiltration in the pathogenesis of AMI. This study hypothesizes that analyzing the interplay between circadian rhythm-related gene expression and immune infiltration can pinpoint more accurate diagnostic biomarkers for AMI. Our results demonstrated differential expression of 15 circadian rhythm-related genes (CRGs) between AMI patients and healthy individuals, with five key genes—JUN, NAMPT, S100A8, SERPINA1, and VCAN—emerging as central to this process. Functional enrichment analyses suggest these genes significantly influence cytokine and chemokine production in immune responses. Immune infiltration assessments using ssGSEA indicated elevated levels of neutrophils, macrophages, and eosinophils in AMI patients. Additionally, we identified potential therapeutic implications with 13 pivotal miRNAs and 10 candidate drugs targeting these genes. RT-qPCR analysis further confirmed the upregulation of these five genes under hypoxic conditions, compared to controls. Collectively, our findings highlight the critical role of CRGs in AMI, offering new insights into its diagnosis and potential therapeutic targets.
... Regional, cultural and perhaps ethnic variations in this rhythm have also been described [9,10]. The main determinant of the rhythm set by the central nervous system is thought to be light [11]. Light affects the frequency of neuronal discharges and modifies both the expression of circadian genes [12] and the activity of the au-tonomic nervous system, thereby altering fundamental factors of circulatory regulation such as blood pressure, endothelial response, and platelet aggregation [11]. ...
... The main determinant of the rhythm set by the central nervous system is thought to be light [11]. Light affects the frequency of neuronal discharges and modifies both the expression of circadian genes [12] and the activity of the au-tonomic nervous system, thereby altering fundamental factors of circulatory regulation such as blood pressure, endothelial response, and platelet aggregation [11]. The activation of the autonomic nervous system during waking hours may explain the increased incidence of AMI in the morning. ...
... In mammals, there is a daily rhythm of increased activity that precedes the availability of food, called the food-entrainable oscillator or food-anticipatory activity [14]. Disruption of the circadian rhythm by these factors modifies circulatory variables [15] and could act as a trigger for cardiovascular events such as AMI, both through changes in heart rate and vascular reactivity or through rupture of the atheroma plaque [11]. Previous studies have demonstrated a diurnal cycle in AMI, but there is limited evidence in relation to type I infarctions due to atheroma plaque rupture [16] and the potential relation of circadian patterns with seasons and months. ...
Background
A circadian rhythm of myocardial infarction has been described but there is little data on its relation with seasons and months.
Methods
From June 2013 to June 2018, we analyzed the alerts for acute ST-segment elevation myocardial infarction (STEMI) in a Spanish region with 6.64 million inhabitants, universal health coverage, and an organized STEMI reperfusion network. We selected those patients which an identifiable culprit plaque.
Results
We recruited 6765 cases of STEMI due to type I acute myocardial infarction (type-I AMI), with mean age of 63.2 years (range 17–101, standard deviation [SD] 13.7), 5238 were males (77.4%) and 2801 (41.9%) were 65 years or older. The hourly distribution followed a fixed pattern in all months, with most of the events occurring between 6:00 AM and 4:00 PM, a peak at approximately 01:00 PM and a valley between 10:00 PM and 06:00 AM. No significant difference was found when comparing the mean time to first medical contact between July (the month with more daylight hours) and December (the month with shortest days). No significant differences were found between male and female patients, or between patients aged 65 years or older and younger patients. There was a close correlation between the number of events per month and the number of events occurring during the day (6 AM to 6 PM, r = 0.988, p = 0.001) and during the night (6 PM to 6 AM, r = 0.944, p < 0.001), with different slopes of the regression lines (t-test, p < 0.001), so that the difference between day-night occurrences increased with the total incidence.
Conclusions
There is a circadian pattern in the presentation of STEMI that is not influenced by sex and age. The different incidence of STEMI at different times of the year does not affect the circadian pattern in terms of the shape of the curve or the mean time of presentation, although diurnal events increase more than nocturnal events, suggesting that triggers are most likely to act during vulnerable periods as determined by a circadian-based rhythm.
