Role of the circadian system in cardiovascular disease Thosar, Saurabh S; Butler, Matthew P; Shea, Steven A
The Journal of clinical investigation,
2018-Jun-01, 2018-6-1, 20180601, Letnik:
128, Številka:
6
Journal Article
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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.
Significance It is established that glucose tolerance decreases from the morning to the evening, and that shift work is a risk factor for diabetes. However, the relative importance of the endogenous ...circadian system, the behavioral cycle (including the sleep/wake and fasting/feeding cycles), and circadian misalignment on glucose tolerance is unclear. We show that the magnitude of the effect of the endogenous circadian system on glucose tolerance and on pancreatic β-cell function was much larger than that of the behavioral cycle in causing the decrease in glucose tolerance from morning to evening. Also, independent from circadian phase and the behavioral cycle, circadian misalignment resulting from simulated night work lowered glucose tolerance—without diminishing effects upon repeated exposure—with direct relevance for shift workers.
Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show—by using two 8-d laboratory protocols—in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.
Serious adverse cardiovascular events peak in the morning, possibly related to increased thrombosis in critical vessels. Plasminogen activator inhibitor-1 (PAI-1), which inhibits fibrinolysis, is a ...key circulating prothrombotic factor that rises in the morning in humans. We tested whether this morning peak in PAI-1 is caused by the internal circadian system or by behaviors that typically occur in the morning, such as altered posture and physical activity. Twelve healthy adults underwent a 2-week protocol that enabled the distinction of endogenous circadian effects from behavioral and environmental effects. The results demonstrated a robust circadian rhythm in circulating PAI-1 with a peak corresponding to ∼6:30 am. This rhythm in PAI-1 was 8-times larger than changes in PAI-1 induced by standardized behavioral stressors, including head-up tilt and 15-minute cycle exercise. If this large endogenous morning peak in PAI-1 persists in vulnerable individuals, it could help explain the morning peak in adverse cardiovascular events.
•The human circadian system causes a morning peak in circulating levels of PAI-1, independent of any behavioral or environmental influences.•The circadian system determines to a large extent the PAI-1 rhythm observed during a regular sleep/wake cycle.
There is considerable epidemiological evidence that shift work is associated with increased risk for obesity, diabetes, and cardiovascular disease, perhaps the result of physiologic maladaptation to ...chronically sleeping and eating at abnormal circadian times. To begin to understand underlying mechanisms, we determined the effects of such misalignment between behavioral cycles (fasting/feeding and sleep/wake cycles) and endogenous circadian cycles on metabolic, autonomic, and endocrine predictors of obesity, diabetes, and cardiovascular risk. Ten adults (5 female) underwent a 10-day laboratory protocol, wherein subjects ate and slept at all phases of the circadian cycle--achieved by scheduling a recurring 28-h "day." Subjects ate 4 isocaloric meals each 28-h "day." For 8 days, plasma leptin, insulin, glucose, and cortisol were measured hourly, urinary catecholamines 2 hourly (totaling almost equal to1,000 assays/subject), and blood pressure, heart rate, cardiac vagal modulation, oxygen consumption, respiratory exchange ratio, and polysomnographic sleep daily. Core body temperature was recorded continuously for 10 days to assess circadian phase. Circadian misalignment, when subjects ate and slept almost equal to12 h out of phase from their habitual times, systematically decreased leptin (-17%, P < 0.001), increased glucose (+6%, P < 0.001) despite increased insulin (+22%, P = 0.006), completely reversed the daily cortisol rhythm (P < 0.001), increased mean arterial pressure (+3%, P = 0.001), and reduced sleep efficiency (-20%, P < 0.002). Notably, circadian misalignment caused 3 of 8 subjects (with sufficient available data) to exhibit postprandial glucose responses in the range typical of a prediabetic state. These findings demonstrate the adverse cardiometabolic implications of circadian misalignment, as occurs acutely with jet lag and chronically with shift work.
Objective:
Despite the extended overnight fast, paradoxically, people are typically not ravenous in the morning and breakfast is typically the smallest meal of the day. We assessed whether this ...paradox could be explained by an endogenous circadian influence on appetite with a morning trough, while controlling for sleep/wake and fasting/feeding effects.
Design and Methods:
Twelve healthy non‐obese adults (six males; age, 20‐42 years) were studied throughout a 13‐day laboratory protocol that balanced all behaviors, including eucaloric meals and sleep periods, evenly across the endogenous circadian cycle. Participants rated their appetite and food preferences by visual analog scales.
Results:
There was a large endogenous circadian rhythm in hunger, with the trough in the biological morning (8 AM) and peak in the biological evening (8 PM; peak‐to‐trough amplitude = 17%; P = 0.004). Similarly‐phased significant endogenous circadian rhythms were present in appetites for sweet, salty and starchy foods, fruits, meats/poultry, food overall, and for estimates of how much food participants could eat (amplitudes 14‐25%; all P < 0.05).
Conclusions:
In people who sleep at night, the intrinsic circadian evening peak in appetite may promote larger meals before the fasting period necessitated by sleep, whereas the circadian morning trough would theoretically facilitate the extended overnight fast. Furthermore, the circadian decline in hunger across the night would theoretically counteract the fasting‐induced hunger increase that could otherwise disrupt sleep.
Adequate sleep timed appropriately during the circadian night is important for numerous biological processes and systems. New evidence suggests that both sleep timing and duration may be important ...for optimal bone health as well. This review examines the diurnal variation of bone turnover markers (BTMs) and the importance of circadian clock genes in regulating bone mass. In addition, this review explores the evidence for a link between shift work (and its associated disturbances in sleep duration/quality and circadian alignment) and alterations in bone metabolism and bone health. Finally, we review how commonly used medications and over-the-counter substances (e.g. caffeine, melatonin) complicate the relationship between sleep and circadian disorders and bone health.
Sleep Disorders, Health, and Safety in Police Officers Rajaratnam, Shantha M. W; Barger, Laura K; Lockley, Steven W ...
JAMA : the journal of the American Medical Association,
12/2011, Letnik:
306, Številka:
23
Journal Article
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CONTEXT Sleep disorders often remain undiagnosed. Untreated sleep disorders among police officers may adversely affect their health and safety and pose a risk to the public. OBJECTIVE To quantify ...associations between sleep disorder risk and self-reported health, safety, and performance outcomes in police officers. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional and prospective cohort study of North American police officers participating in either an online or an on-site screening (n=4957) and monthly follow-up surveys (n=3545 officers representing 15 735 person-months) between July 2005 and December 2007. A total of 3693 officers in the United States and Canada participated in the online screening survey, and 1264 officers from a municipal police department and a state police department participated in the on-site survey. MAIN OUTCOME MEASURES Comorbid health conditions (cross-sectional); performance and safety outcomes (prospective). RESULTS Of the 4957 participants, 40.4% screened positive for at least 1 sleep disorder, most of whom had not been diagnosed previously. Of the total cohort, 1666 (33.6%) screened positive for obstructive sleep apnea, 281 (6.5%) for moderate to severe insomnia, 269 (5.4%) for shift work disorder (14.5% of those who worked the night shift). Of the 4608 participants who completed the sleepiness scale, 1312 (28.5%) reported excessive sleepiness. Of the total cohort, 1294 (26.1%) reported falling asleep while driving at least 1 time a month. Respondents who screened positive for obstructive sleep apnea or any sleep disorder had an increased prevalence of reported physical and mental health conditions, including diabetes, depression, and cardiovascular disease. An analysis of up to 2 years of monthly follow-up surveys showed that those respondents who screened positive for a sleep disorder vs those who did not had a higher rate of reporting that they had made a serious administrative error (17.9% vs 12.7%; adjusted odds ratio OR, 1.43 95% CI, 1.23-1.67); of falling asleep while driving (14.4% vs 9.2%; adjusted OR, 1.51 95% CI, 1.20-1.90); of making an error or safety violation attributed to fatigue (23.7% vs 15.5%; adjusted OR, 1.63 95% CI, 1.43-1.85); and of exhibiting other adverse work-related outcomes including uncontrolled anger toward suspects (34.1% vs 28.5%; adjusted OR, 1.25 95% CI, 1.09-1.43), absenteeism (26.0% vs 20.9%; adjusted OR, 1.23 95% CI, 1.08-1.40), and falling asleep during meetings (14.1% vs 7.0%; adjusted OR, 1.95 95% CI, 1.52-2.52). CONCLUSION Among a group of North American police officers, sleep disorders were common and were significantly associated with increased risk of self-reported adverse health, performance, and safety outcomes.
Obstructive sleep apnea is a risk factor for mortality, but its diagnostic metric-the apnea-hypopnea index-is a poor risk predictor. The apnea-hypopnea index does not capture the range of ...physiological variability within and between patients, such as degree of hypoxemia and sleep fragmentation, that reflect differences in pathophysiological contributions of airway collapsibility, chemoreceptive negative feedback loop gain, and arousal threshold.
To test whether respiratory event duration, a heritable sleep apnea trait reflective of arousal threshold, predicts all-cause mortality.
Mortality risk as a function of event duration was estimated by Cox proportional hazards in the Sleep Heart Health Study, a prospective community-based cohort. Gender-specific hazard ratios were also calculated.
Among 5,712 participants, 1,290 deaths occurred over 11 years of follow-up. After adjusting for demographic factors (mean age, 63 yr; 52% female), apnea-hypopnea index (mean, 13.8; SD, 15.0), smoking, and prevalent cardiometabolic disease, individuals with the shortest-duration events had a significant hazard ratio for all-cause mortality of 1.31 (95% confidence interval, 1.11-1.54). This relationship was observed in both men and women and was strongest in those with moderate sleep apnea (hazard ratio, 1.59; 95% confidence interval, 1.11-2.28).
Short respiratory event duration, a marker for low arousal threshold, predicts mortality in men and women. Individuals with shorter respiratory events may be predisposed to increased ventilatory instability and/or have augmented autonomic nervous system responses that increase the likelihood of adverse health outcomes, underscoring the importance of assessing physiological variation in obstructive sleep apnea.
Endogenous circadian rhythms prepare the cardiovascular (CV) system for optimal function to match the daily anticipated behavioral and environmental cycles, including variable activities when awake ...during the day and recuperation when sleeping at night. The overall day-night patterns in most CV variables result from the summation of predictable circadian effects with variable behavioral and environmental effects on the CV system. The circadian system has also been implicated in the morning peak in the incidence of adverse CV events, including myocardial infarction, stroke, and sudden cardiac death. We discuss the resting and stress-reactive circadian control of CV physiology in humans and suggest future research opportunities, including improving CV therapy by optimally timing therapy relative to a person’s internal body clock time.
•The suprachiasmatic nuclei are the seat of the central circadian clock.•Peripheral circadian clocks exist throughout the cardiovascular (CV) system.•Together, these clocks orchestrate resting and responsive rhythms in CV physiology.•Day-night CV patterns result from the summation of circadian and behavioral effects.•Timing drugs to specific circadian phases is a new opportunity to optimize therapy.
The risk of adverse cardiovascular events peaks in the morning (≈9:00 AM) with a secondary peak in the evening (≈8:00 PM) and a trough at night. This pattern is generally believed to be caused by the ...day/night distribution of behavioral triggers, but it is unknown whether the endogenous circadian system contributes to these daily fluctuations. Thus, we tested the hypotheses that the circadian system modulates autonomic, hemodynamic, and hemostatic risk markers at rest, and that behavioral stressors have different effects when they occur at different internal circadian phases. Twelve healthy adults were each studied in a 240-h forced desynchrony protocol in dim light while standardized rest and exercise periods were uniformly distributed across the circadian cycle. At rest, there were large circadian variations in plasma cortisol (peak-to-trough ≈85% of mean, peaking at a circadian phase corresponding to ≈9:00 AM) and in circulating catecholamines (epinephrine, ≈70%; norepinephrine, ≈35%, peaking during the biological day). At ≈8:00 PM, there was a circadian peak in blood pressure and a trough in cardiac vagal modulation. Sympathetic variables were consistently lowest and vagal markers highest during the biological night. We detected no simple circadian effect on hemostasis, although platelet aggregability had two peaks: at ≈noon and ≈11:00 PM. There was circadian modulation of the cardiovascular reactivity to exercise, with greatest vagal withdrawal at ≈9:00 AM and peaks in catecholamine reactivity at ≈9:00 AM and ≈9:00 PM. Thus, the circadian system modulates numerous cardiovascular risk markers at rest as well as their reactivity to exercise, with resultant profiles that could potentially contribute to the day/night pattern of adverse cardiovascular events.
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