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Cited by 443Circadian rhythm and melatoninHeart Rate Variability and Autonomic ControlSleep and Work-Related Fatigue

Role of the circadian system in cardiovascular disease

Open access
Thosar, Saurabh S., Butler, Matthew P., Shea, Steven A.·2018·Journal of Clinical Investigation
DOI 10.1172/jci80590PMC PMC5983320
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Abstract

All species organize behaviors to optimally match daily changes in the environment, leading to pronounced activity/rest cycles that track the light/dark cycle. Endogenous, approximately 24-hour circadian rhythms in the brain, autonomic nervous system, heart, and vasculature prepare the cardiovascular system for optimal function during these anticipated behavioral cycles. Cardiovascular circadian rhythms, however, may be a double-edged sword. The normal amplified responses in the morning may aid the transition from sleep to activity, but such exaggerated responses are potentially perilous in individuals susceptible to adverse cardiovascular events. Indeed, the occurrence of stroke, myocardial infarction, and sudden cardiac death all have daily patterns, striking most frequently in the morning. Furthermore, chronic disruptions of the circadian clock, as with night-shift work, contribute to increased cardiovascular risk. Here we highlight the importance of the circadian system to normal cardiovascular function and to cardiovascular disease, and identify opportunities for optimizing timing of medications in cardiovascular disease.

AI snapshot

Written from the paper’s full text.

TL;DR

This review describes how endogenous circadian clocks drive day/night rhythms in cardiovascular physiology and reactivity, contributing to the morning peak in myocardial infarction, stroke, and sudden cardiac death. It argues that circadian disruption increases cardiovascular risk and that chronotherapy—timing medications relative to circadian phase—may improve outcomes, though evidence in diseased populations remains limited.

Key findings

  • Adverse cardiovascular events, including myocardial infarction, ischemic stroke, ventricular arrhythmias, and sudden cardiac death, show a robust morning increase; morning behaviors raise sympathetic tone, blood pressure, heart rate, platelet aggregability, and vasoconstriction while reducing thrombolytic activity and endothelial function.
  • Endogenous circadian rhythms affect blood pressure, autonomic function, hemostasis, and endothelial function. For example, PAI-1 peaks in the biological morning with a circadian rhythm approximately 8 times larger than behavior-induced changes; epinephrine and norepinephrine have circadian peak-to-trough amplitudes of 70% and 34% of the mean; and in tilt-table tests, presyncope occurred in 15% of tests, with 81% during the biological night.
  • Circadian disruption from night-shift work and social jet lag is linked to increased cardiovascular risk. Approximately 70% of the population has social jet lag greater than 1 hour; weekly 12-hour light/dark phase shifts reduced longevity in cardiomyopathic hamsters by 11%; and circadian misalignment increased 24-hour blood pressure and inflammatory markers including IL-6, C-reactive protein, and TNF-α.
  • Chronotherapy trials suggest timing matters: in the MAPEC study of over 2,000 individuals with resistant hypertension, evening dosing reduced all cardiovascular events and cardiovascular mortality over 5.6 years; low-dose aspirin reduced the morning myocardial infarction peak by approximately 60%; and bedtime aspirin reduced 24-hour systolic/diastolic blood pressure by 7/5 mmHg, whereas awakening aspirin increased it by 3/2 mmHg.

Methods

  • Narrative review with no new primary data; it synthesizes epidemiological, animal, human physiological, and clinical trial literature on circadian rhythms and cardiovascular disease.
  • Human circadian protocols discussed include constant routine and forced desynchrony, with imposed behavioral cycles such as 5 hours 20 minutes, 20 hours, and 28 hours, to dissociate endogenous circadian effects from behavioral and environmental effects.
  • Main analysis is qualitative synthesis and conceptual modeling; no systematic search strategy or meta-analysis is stated.

Limitations

  • Stated in the paper: most experiments have been performed in healthy participants, and a critical gap exists in identifying mechanisms by which cardiovascular circadian rhythms in healthy people translate to those with existing cardiovascular disease.
  • Stated in the paper: modelling circadian disruption in humans is difficult; mechanisms of the MAPEC results are not understood; double-blind placebo-controlled trials with specific antihypertensive medications are warranted; and estimating internal circadian phase is presently slow and expensive, with no inexpensive, accurate, instantaneous biomarker available.
  • Evident from the text: as a narrative review, it does not use a systematic search or meta-analysis and presents no new experimental data, so causal claims and chronotherapy recommendations are inferential.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci80590

Cites

184 of 184 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 119 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Exercise-induced increases in epinephrine were twice as large in the morning (0830 hours) than in the middle of the night (0430 hours).

    “Notably, exercise-induced increases in epinephrine were twice as large in the morning (0830 hours) than in the middle of the night (0430 hours) (90).”
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  • Findingcitation

    Using three stringently controlled constant routine and forced desynchrony protocols that overcame limitations of earlier studies, robust endogenous circadian rhythms in blood pressure were discovered.

    “In contrast, using three stringently controlled constant routine and forced desynchrony protocols that overcame these limitations, robust endogenous circadian rhythms in BP were discovered (83,90).”
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  • Findingcitation

    Sympathetic tone (circulating epinephrine and norepinephrine) has large endogenous circadian rhythms (peak-to-trough amplitudes of 70% and 34% of the mean, respectively) that peak at a circadian phase equivalent to midday.

    “Sympathetic tone (circulating epinephrine and norepinephrine) had large endogenous circadian rhythms (peakto-trough amplitudes of 70% and 34% of the mean, respectively) that peaked at a circadian phase equivalent to midday.”
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    • cites [90] source

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    • cites [106] Hilton, 2000, Endogenous circadian control of the human autonomic nervous system, Comput Cardiol

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  • Findingcitation

    The endogenous circadian resting blood pressure rhythm has an evening peak and a morning trough.

    “The endogenous circadian resting BP rhythm has an evening peak and a morning trough.”
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  • Findingcitation

    The reactivities to exercise of both epinephrine and norepinephrine exhibited 12-hour rhythms with large peaks at circadian phases corresponding to 0700-1030 and 2000-2200 hours.

    “Rather than a simple 24-hour rhythm, the reactivities to exercise of both epinephrine and norepinephrine exhibited 12-hour rhythms with large peaks at circadian phases corresponding to 0700-1030 and 2000-2200 hours.”
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    Findingcitation

    There were significant circadian rhythms in the reactivity of parasympathetic markers, with the greatest cardiac vagal withdrawal during exercise across the morning period.

    “There were also significant circadian rhythms in the reactivity of parasympathetic markers, with the greatest cardiac vagal withdrawal during exercise across the morning period.”
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    Findingcitation

    A forced desynchrony protocol revealed that PAI-1 is rhythmic and peaks in the biological morning, suggesting a role for the circadian clock in reducing fibrinolytic activity in the morning, especially since this circadian rhythm was approximately 8 times larger than changes in PAI-1 induced by behaviors such as mild exercise.

    “A forced desynchrony protocol revealed that PAI-1 is rhythmic and peaks in the biological morning, suggesting a role for the circadian clock in reducing fibrinolytic activity in the morning, especially since this circadian rhythm was approximately 8 times larger than changes in PAI-1 induced by behaviors such as mild exercise (111).”
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    Findingcitation

    A 20-hour forced desynchrony in healthy individuals with tilt table tests across all phases of the circadian cycle revealed presyncope in 15% of all tests, with almost all cases (81%) occurring during the half of the circadian cycle corresponding to the biological night (2230-1030 hours).

    “A 20-hour forced desynchrony in healthy individuals with tilt table tests (60° head-up for 15 minutes) across all phases of the circadian cycle revealed presyncope in 15% of all tests, with almost all cases (81%) occurring during the half of the circadian cycle corresponding to the biological night (2230-1030 hours) (91).”
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    Findingcitation

    The amplitudes of basal resting blood pressure rhythms are small in healthy people (group average 3- to 6-mmHg peak-to-trough amplitudes) but may have clinical relevance, as they doubled upon exercise.

    “The amplitudes of basal resting rhythms are small in healthy people (group average 3-to 6-mmHg peak-to-trough amplitudes) but may have clinical relevance, as they doubled upon exercise (90).”
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    Findingcitation

    Efferent cardiac vagal tone (estimated from heart rate variability) has a circadian peak at approximately 8 am, coincident with the circadian basal blood pressure trough, suggesting that circadian rhythms of blood pressure and parasympathetic nervous system activity may be mechanistically related in resting healthy individuals.

    “On the other hand, the efferent cardiac vagal tone (estimated from HR variability) had a circadian peak at approximately 8 am, coincident with the circadian basal BP trough (90), suggesting that circadian rhythms of BP and parasympathetic nervous system activity may be mechanistically related in resting healthy individuals.”
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    Premisecitation

    Approximately 5% of all genes in the aorta are rhythmic.

    “For example, approximately 5% of all genes in the aorta are rhythmic (68).”
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    Targeted deletion of Bmal1 in murine vascular smooth muscle cells blunts the circadian amplitudes and advances the circadian phases of systolic and diastolic blood pressure, and abolishes the circadian variation of pulse pressure.

    “Functionally, targeted deletion of Bmal1 in murine vascular smooth muscle cells blunts the circadian amplitudes and advances the circadian phases of systolic and diastolic BP, and abolishes the circadian variation of pulse pressure (70).”
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    Premisecitation

    Cardiomyocyte-specific deletion of Bmal1 results in loss of normal circadian expression of the Na+ and K+ channels resulting in decreased heart rate and increased risk of arrhythmias, which could contribute to sudden cardiac death.

    “Cardiomyocyte-specific deletion of Bmal1 results in loss of normal circadian expression of the Na + and K + channels resulting in decreased HR and increased risk of arrhythmias (66), which could contribute to sudden cardiac death (67).”
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    Premisecitation

    Approximately 13% of protein-coding genes in the kidney are rhythmic.

    “The kidney is essential to long-term regulation of BP and approximately 13% of protein-coding genes in the kidney are rhythmic (41).”
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    Premisecitation

    The suprachiasmatic nucleus is an autonomous oscillator and cycles even in vitro almost indefinitely.

    “The SCN is an autonomous oscillator and cycles even in vitro almost indefinitely (26).”
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    • cites [26] Yamazaki, 2005, Real-time luminescence reporting of circadian gene expression in mammals, Meth Enzymol source

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    Premisecitation

    In any given mammalian tissue, approximately 5%-15% of gene transcripts are rhythmic, with some differences in the specific cycling genes between tissues, with 43% of protein-coding genes being rhythmic in at least one tissue.

    “In any given mammalian tissue, approximately 5%-15% of gene transcripts are rhythmic, with some differences in the specific cycling genes between tissues, with 43% of protein-coding genes being rhythmic in at least one tissue (41).”
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    Premisecitation

    In all nucleated cells, four families of core clock genes (Clock, Bmal1, Period, and Cryptochrome) form a transcription-translation feedback loop that cycles every approximately 24 hours.

    “In all nucleated cells, four families of core clock genes (Clock, Bmal1, Period [Per], and Cryptochrome [Cry]) form a transcriptiontranslation feedback loop that cycles every approximately 24 hours (reviewed in refs.[28][29][30][31][32][33][34][35].”
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    • cites [28] Takahashi, 2015, Molecular components of the circadian clock in mammals, Diabetes Obes Metab source

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    Premisecitation

    Selective Bmal1 knockout in cardiomyocytes eliminates much of the rhythmic transcriptome, reduces stroke volume and ejection fraction, and causes heart failure and early mortality in mice.

    “For instance, Bmal1 knockout in mice causes dilated cardiomyopathy (62) and selective Bmal1 knockout in cardiomyocytes eliminates much of the rhythmic transcriptome (63), reduces stroke volume and ejection fraction, and causes heart failure and early mortality in mice (63,64).”
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    Premisecitation

    Typical morning behaviors cause increases in sympathetic tone, vasoconstriction, peripheral arterial resistance, heart rate, blood pressure, and platelet aggregability.

    “Typical morning behaviors (e.g., arousal from sleep, sudden change in posture after overnight recumbency, increased activity, and psychological stress) cause increases in sympathetic tone, vasoconstriction, peripheral arterial resistance, HR, BP, and platelet aggregability, and decreases in thrombolytic activity, parasympathetic tone, and vascular endothelial function (14).”
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    Premisecitation

    Blood pressure is usually lower in sleep than in wakefulness and has a characteristic surge after awakening.

    “BP is usually lower in sleep than in wakefulness and has a characteristic surge after awakening, drawing parallels with the daily pattern of adverse CV events (refs.94-97 and Figure 1).”
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    • cites [97] Hodgkinson, 2011, Relative effectiveness of clinic and home blood pressure monitoring compared with ambulatory blood pressure monitoring in diagnosis of hypertension: systematic review, BMJ source

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    Premisecitation

    PER1 plays an important role in blood pressure maintenance by regulating aldosterone levels and affecting sodium retention.

    “PER1 plays an important role in BP maintenance by regulating aldosterone levels and affecting sodium retention (71)(72)(73).”
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    Premisecitation

    Dissociated suprachiasmatic nucleus cells remain rhythmic in culture, showing that rhythmicity is a cellular property.

    “Moreover, dissociated SCN cells also remain rhythmic in culture, showing that rhythmicity is a cellular property (27).”
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    Interpretationcitation

    Cardiovascular changes in the morning may be advantageous in healthy individuals, but could be implicated in precipitating an adverse cardiovascular event in susceptible individuals.

    “Such CV changes in the morning may be advantageous in healthy individuals, but could be implicated in precipitating an adverse CV event in susceptible individuals (14)(15)(16)(17).”
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    Premisecitation

    Typical morning behaviors cause decreases in thrombolytic activity, parasympathetic tone, and vascular endothelial function.

    “Typical morning behaviors (e.g., arousal from sleep, sudden change in posture after overnight recumbency, increased activity, and psychological stress) cause increases in sympathetic tone, vasoconstriction, peripheral arterial resistance, HR, BP, and platelet aggregability, and decreases in thrombolytic activity, parasympathetic tone, and vascular endothelial function (14).”
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    • cites [14] source

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    Premisecitation

    In rodents, lesions of the suprachiasmatic nucleus abolish or attenuate daily rhythms in locomotor activity, body temperature, blood pressure, and heart rate, showing that these rhythms are endogenous rather than resulting from daily changes in behavior or environment.

    “In rodents, lesions of the SCN abolish or attenuate daily rhythms in locomotor activity, body temperature, BP, and HR (22)(23)(24), showing that these rhythms are endogenous rather than resulting from daily changes in behavior or environment.”
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    Premisecitation

    Highest platelet aggregability and highest concentration of plasminogen activator inhibitor-1 (PAI-1) occur in the morning.

    “For instance, highest platelet aggregability and highest concentration of plasminogen activator inhibitor-1 (PAI-1) occur in the morning (109, 110).”
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    Premisecitation

    In humans, transient misalignment of behaviors and the circadian clock increases inflammation and impairs glucose regulation, with potential relevance to cardiovascular disease.

    “In humans, transient misalignment of behaviors and the circadian clock increases inflammation and impairs glucose regulation (137-140), with potential relevance to CV disease (141).”
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    • cites [137] Buxton, 2012, Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption, Sci Transl Med source

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    • cites [139] Spiegel, 2005, Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes, J Appl Physiol source

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    Premisecitation

    In people with severe heart failure, endothelial function is impaired at all times, with loss of daily variation in endothelial function.

    “Interestingly, in people with severe heart failure, endothelial function is impaired at all times, with loss of daily variation in endothelial function (128).”
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    Interpretationreasoning

    Healthy people exhibit greatest sympathetic activation and greatest parasympathetic withdrawal during stresses in the biological morning, which corresponds to the time of the greatest risk of adverse events based on epidemiological data.

    “In summary, healthy people exhibit greatest sympathetic activation and greatest parasympathetic withdrawal during stresses in the biological morning, which corresponds to the time of the greatest risk of adverse events based on epidemiological data.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In humans, vascular endothelial function is relatively impaired in the morning, and therefore potentially implicated in the morning increase in adverse cardiovascular events.

    “In humans, vascular endothelial function is relatively impaired in the morning (6, 123-126), and therefore potentially implicated in the morning increase in adverse CV events (127).”
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    • cites [124] Elherik, 2002, Circadian variation in vascular tone and endothelial cell function in normal males, Clin Sci source

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    Premisecitation

    Aspirin reduces the morning peak in myocardial infarction, suggesting that the prothrombotic milieu in the morning is partly responsible for increased cardiovascular risk during that period.

    “Indeed, aspirin reduces the morning peak in myocardial infarction (116), suggesting that the prothrombotic milieu in the morning is partly responsible for increased CV risk during that period.”
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    Premisecitation

    High nighttime blood pressure (lack of nocturnal blood pressure dipping) is a sensitive indicator for cardiovascular mortality, with 21% greater risk for each 10-mmHg increase in nighttime systolic blood pressure and 9% greater risk for each 5-mmHg increase in nighttime diastolic blood pressure.

    “The morning BP surge is not the only risk, as high nighttime BP (lack of nocturnal BP dipping) is a sensitive indicator for CV mortality, with 21% greater risk for each 10-mmHg increase in nighttime systolic BP and 9% greater risk for each 5-mmHg increase in nighttime diastolic BP (99).”
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    Premisecitation

    Greater social jet lag is associated with increased heart rate and higher cortisol levels.

    “The effects of social jet lag on the CV system have not been well studied, though it is reported that greater social jet lag is associated with increased HR and higher cortisol levels (155).”
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    Premisecitation

    Another study of the ACE inhibitor captopril showed that it reduced blood pressure in mice at all times of day, but improved cardiac function only when administered at sleep time, potentially owing to captopril administration being in phase with increased ACE in the heart, and a consequent time-gated cardiac remodeling.

    “Another study of the ACE inhibitor captopril showed that it reduced BP in mice at all times of day, but improved cardiac function only when administered at sleep time, potentially owing to captopril administration being in phase with increased ACE in the heart, and a consequent time-gated cardiac remodeling (179).”
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    Premisecitation

    The goal of medication dosing is to optimize effectiveness without causing serious adverse side effects, both of which may depend on circadian time.

    “The goal of medication dosing is to optimize effectiveness without causing serious adverse side effects, both of which may depend on circadian time (170, 171).”
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    • cites [171] Zang, 2010, Effect on blood pressure of a continued nursing intervention using chronotherapeutics for adult Chinese hypertensive patients, J Clin Nurs source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Dosing according to internal circadian phase is presently somewhat impractical because estimation of internal phase (e.g., from serial salivary melatonin assays) is slow and expensive.

    “we acknowledge that dosing according to internal circadian phase is presently somewhat impractical because estimation of internal phase (e.g., from serial salivary melatonin assays) is slow and expensive.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    This interaction results in resting physiological rhythms (e.g., blood pressure) and reactivity of those rhythms in the presence of stressors.

    “This results in resting physiological rhythms (e.g., blood pressure) and reactivity of those rhythms in the presence of stressors.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Genetic manipulation of clock components impacts the ischemic tolerance of the heart, with some mutations worsening and some improving the response.

    “Genetic manipulation of clock components impacts the ischemic tolerance of the heart, with some mutations worsening (146) and some improving the response (147).”
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    Premisecitation

    In people with mild untreated hypertension, 100 mg aspirin at bedtime reduced 24-hour systolic blood pressure by an average of 7 mmHg and diastolic blood pressure by 5 mmHg, whereas a similar dose of aspirin upon awakening actually increased 24-hour systolic blood pressure by an average of 3 mmHg and diastolic blood pressure by 2 mmHg.

    “Interestingly, in people with mild untreated hypertension, 100 mg aspirin at bedtime reduced 24-hour systolic BP by an average of 7 mmHg and diastolic BP by 5 mmHg, whereas a similar dose of aspirin upon awakening actually increased 24-hour systolic BP by an average of 3 mmHg and diastolic BP by 2 mmHg (178).”
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    Premisecitation

    β-adrenoreceptor blockers can suppress normal melatonin release, which may affect sleep.

    “a minor concern for evening chronotherapy using β-adrenoreceptor blockers is that these medications can suppress normal melatonin release, which may affect sleep (182).”
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    • cites [182] Scheer, 2007, Decreased sleep in heart failure: are medications to blame?, Arch Intern Med source

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    Premisecitation

    Use of β-adrenoreceptor blockers reduces adverse cardiovascular events on an overall-population basis and abolishes the day/night pattern of such events.

    “Use of β-adrenoreceptor blockers reduces adverse CV events on an overall-population basis and abolishes the day/ night pattern of such events (9, 174).”
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    Premisecitation

    Pharmacokinetics are driven by the absorption, distribution, metabolism, and excretion of a medication, each of which may be modulated by circadian rhythms.

    “Furthermore, pharmacokinetics are driven by the absorption, distribution, metabolism, and excretion of a medication, each of which may be modulated by circadian rhythms (172).”
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    • cites [172] source

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    Premisecitation

    Recovery from experimentally induced myocardial ischemia is impaired in mice by rapidly shifting light/dark cycles, suggesting that sleep and circadian rhythm disruption that occurs in intensive care units may compromise recovery.

    “For instance, recovery from experimentally induced myocardial ischemia is impaired in mice by rapidly shifting light/dark cycles, suggesting that sleep and circadian rhythm disruption that occurs in intensive care units may compromise recovery (145).”
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    Premisecitation

    Approximately 70% of the population have noticeable social jet lag (i.e., their biological and social clocks differ by more than 1 hour).

    “Approximately 70% of the population have noticeable social jet lag (i.e., their biological and social clocks differ by more than 1 hour) (154), and the greater the social jet lag, the greater the risk for obesity and diabetes (154-156).”
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    Interpretationreasoning

    Considerations of internal circadian phase and its interaction with behavioral cycle can be important for prescribing medications.

    “These considerations can be important because internal circadian phase relative to external time or behavioral cycle varies between people, across ages, and depends on habitual light exposure (e.g., night-shift work).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Internal circadian phase relative to external time or behavioral cycle varies between people, across ages, and depends on habitual light exposure.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    In a healthy individual, resting physiological rhythms are within normal limits and reactivity to a stressor is modest, such that the theoretical risk threshold for an adverse cardiovascular event is not crossed.

    “In a healthy individual, the resting physiological rhythms are within normal limits and the reactivity to a stressor (upward-pointing arrows) is modest, such that the theoretical risk threshold for an adverse cardiovascular event is not crossed.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: There is a theoretical risk threshold for an adverse cardiovascular event that physiological rhythms can cross.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationcitation

    The magnitude of side effects of chronotherapy can depend on the time of dosing.

    “In any chronotherapeutic trial, it should be noted that the magnitude of side effects can also depend on the time of dosing.”
    Quote in the paperNot a substantial claim

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    Interpretationcitation

    Both external (light/dark cycle shifts) and internal (molecular clock disruption) impact cardiovascular health in mice.

    “Thus, both external (light/dark cycle shifts) and internal (molecular clock disruption) impact CV health in mice.”
    Quote in the paperSubstantial claim
43 of 43

  • The paper relies on this without support.

    Internal circadian phase relative to external time or behavioral cycle varies between people, across ages, and depends on habitual light exposure.

    “internal circadian phase relative to external time or behavioral cycle varies between people, across ages, and depends on habitual light exposure (e.g., night-shift work).”

  • The authors state this as an assumption.

    There is a theoretical risk threshold for an adverse cardiovascular event that physiological rhythms can cross.

    “the theoretical risk threshold for an adverse cardiovascular event is not crossed.”
    “can cross the theoretical risk threshold for an adverse cardiovascular event such as stroke.”
2 of 2

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Circadian oscillations have been reported for physiological CVD regulation including heart rate and blood pressure, for cardiac disorders including arrhythmias, and there is circadian variation in frequency of onset of myocardial infarction and sudden cardiac death.

    “Circadian oscillations have been reported for both physiological CVD regulation including heart rate and blood pressure 57, for cardiac disorders including arrythmias 58, 59, and there is circadian variation in frequency of onset of myocardial infarction and sudden cardiac death 19, 60.”

    From The Circadian Syndrome: is the Metabolic Syndrome and much more! (2019) · cites this paper as [58]

Cites

Flagged first, then by citations

Research works printed but not linked: 2

  1. 10.1007/s00109-003-0520-1 · DOI
  2. 10.1177/0748730414550199 · DOI · Paper page

Cited by

Sorted by citations

Related

Authors
Thosar, S. S., Butler, M. P., & Shea, S. A.
Affiliations
Oregon Health & Science University (US)
Corresponding author
Shea, Steven A.
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2018-06-01
Volume
128
Issue
6
Pages
2157-2167
ISSN
  • 0021-9738 (ISSN-L)
  • 1558-8238
DOI
10.1172/jci80590
PMC
PMC5983320
OpenAlex
W2807228974
Semantic Scholar
69b04cd62d7a1f62dfe89521d2d0de3988ffe4ff
Cited by
443
References
184
Citations by year
2026: 36 · 2025: 50 · 2024: 54 · 2023: 55 · 2022: 69 · 2021: 55 · 2020: 90 · 2019: 28 · 2018: 6
FWCI
6.26
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • American Sleep Medicine Foundation
  • National Space Biomedical Research Institute (NCC 9‐58)
  • National Institutes of Health (NCC9-58, UL1TR002369)
  • Oregon Institute of Occupational Health Sciences, Oregon Health and Science University
  • National Heart, Lung, and Blood Institute (R01HL140577, R21HL140377, R01HL142064, R01HL125893, F32HL131308)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Circadian rhythm and melatonin
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Social Sciences › Psychology › Experimental and Cognitive Psychology › Sleep and Work-Related Fatigue
Keywords
circadian rhythm, cardiovascular disease, circadian clock, morning surge, cardiovascular risk, stroke, myocardial infarction, sudden cardiac death, shift work, chronotherapy, autonomic nervous system, vascular system
MeSH terms
Animals, Circadian Rhythm, Heart, Humans, Myocardial Infarction, Myocardium, Sleep, Circadian Clocks

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

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