Michael F. Hilton

Adverse metabolic and cardiovascular consequences of circadian misalignment

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 ≈1,000 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 ≈12 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.

Impact of the human circadian system, exercise, and their interaction on cardiovascular function

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.

Endogenous circadian rhythm in an index of cardiac vulnerability independent of changes in behavior.

There exists a robust day/night pattern in the incidence of adverse cardiac events with a peak at ≈10 a.m. This peak traditionally has been attributed to day/night patterns in behaviors affecting cardiac function in vulnerable individuals. However, influences from the endogenous circadian pacemaker independent from behaviors may also affect cardiac control. Heartbeat dynamics under healthy conditions exhibit robust complex fluctuations characterized by self-similar temporal structures, which break down under pathologic conditions. We hypothesize that these dynamical features of the healthy human heartbeat have an endogenous circadian rhythm that brings the features closer to those observed under pathologic conditions at the endogenous circadian phase corresponding to ≈10 a.m. We investigate heartbeat dynamics in healthy subjects recorded throughout a 10-day protocol wherein the sleep/wake and behavior cycles are desynchronized from the endogenous circadian cycle, enabling assessment of circadian factors while controlling for behavior-related factors. We demonstrate that the scaling exponent characterizing temporal correlations in heartbeat dynamics does exhibit a significant circadian rhythm (with a sharp peak at the circadian phase corresponding to ≈10 a.m.), which is independent from scheduled behaviors and mean heart rate. Cardiac dynamics under pathologic conditions such as congestive heart failure also are associated with a larger value of the scaling exponent of the interbeat interval. Thus, the sharp peak in the scaling exponent at the circadian phase coinciding with the period of highest cardiac vulnerability observed in epidemiological studies suggests that endogenous circadian-mediated influences on cardiac control may be involved in the day/night pattern of adverse cardiac events in vulnerable individuals.

The Prevalence of Psychological Distress in Employees and Associated Occupational Risk Factors

Objective: There is limited occupational health industry data pertaining to 1) the prevalence of psychological distress in various employee subtypes and 2) risk factors for employee psychological distress. Method: The employees of 58 large public and private sector employers were invited to complete the Kessler 6 (K6) as part of the Health and Performance at Work Questionnaire. A K6 score of ≥13 was chosen to indicate high psychological distress. Results: Data on 60,556 full-time employees indicate that 4.5% of employees have high psychological distress of which only 22% were in current treatment. Occupational risk factors identified include long working hours, sales staff and non-traditional gender roles. Conclusion: High psychological distress is pervasive across all employee subtypes and remains largely untreated. Risk factors identified will guide the targeting of mental health promotion, prevention and screening programs.

An Endogenous Circadian Rhythm in Sleep Inertia Results in Greatest Cognitive Impairment upon Awakening during the Biological Night

Sleep inertia is the impaired cognitive performance immediately upon awakening, which decays over tens of minutes. This phenomenon has relevance to people who need to make important decisions soon after awakening, such as on-call emergency workers. Such awakenings can occur at varied times of day or night, so the objective of the study was to determine whether or not the magnitude of sleep inertia varies according to the phase of the endogenous circadian cycle. Twelve adults (mean, 24 years; 7 men) with no medical disorders other than mild asthma were studied. Following 2 baseline days and nights, subjects underwent a forced desynchrony protocol composed of seven 28-h sleep/wake cycles, while maintaining a sleep/wakefulness ratio of 1:2 throughout. Subjects were awakened by a standardized auditory stimulus 3 times each sleep period for sleep inertia assessments. The magnitude of sleep inertia was quantified as the change in cognitive performance (number of correct additions in a 2-min serial addition test) across the first 20 min of wakefulness. Circadian phase was estimated from core body temperature (fitted temperature minimum assigned 0°). Data were segregated according to: (1) circadian phase (60° bins); (2) sleep stage; and (3) 3rd of the night after which awakenings occurred (i.e., tertiary 1, 2, or 3). To control for any effect of sleep stage, the circadian rhythm of sleep inertia was initially assessed following awakenings from Stage 2 (62% of awakening occurred from this stage; n = 110). This revealed a significant circadian rhythm in the sleep inertia of cognitive performance (p = 0.007), which was 3.6 times larger during the biological night (circadian bin 300°, ~2300—0300 h in these subjects) than during the biological day (bin 180°, ~1500—1900 h). The circadian rhythm in sleep inertia was still present when awakenings from all sleep stages were included (p = 0.004), and this rhythm could not be explained by changes in underlying sleep drive prior to awakening (changes in sleep efficiency across circadian phase or across the tertiaries), or by the proportion of the varied sleep stages prior to awakenings. This robust endogenous circadian rhythm in sleep inertia may have important implications for people who need to be alert soon after awakening.

Endogenous circadian rhythm in human motor activity uncoupled from circadian influences on cardiac dynamics

The endogenous circadian pacemaker influences key physiologic functions, such as body temperature and heart rate, and is normally synchronized with the sleep/wake cycle. Epidemiological studies demonstrate a 24-h pattern in adverse cardiovascular events with a peak at ≈10 a.m. It is unknown whether this pattern in cardiac risk is caused by a day/night pattern of behaviors, including activity level and/or influences from the internal circadian pacemaker. We recently found that a scaling index of cardiac vulnerability has an endogenous circadian peak at the circadian phase corresponding to ≈10 a.m., which conceivably could contribute to the morning peak in cardiac risk. Here, we test whether this endogenous circadian influence on cardiac dynamics is caused by circadian-mediated changes in motor activity or whether activity and heart rate dynamics are decoupled across the circadian cycle. We analyze high-frequency recordings of motion from young healthy subjects during two complementary protocols that decouple the sleep/wake cycle from the circadian cycle while controlling scheduled behaviors. We find that static activity properties (mean and standard deviation) exhibit significant circadian rhythms with a peak at the circadian phase corresponding to 5–9 p.m. (≈9 h later than the peak in the scale-invariant index of heartbeat fluctuations). In contrast, dynamic characteristics of the temporal scale-invariant organization of activity fluctuations (long-range correlations) do not exhibit a circadian rhythm. These findings suggest that endogenous circadian-mediated activity variations are not responsible for the endogenous circadian rhythm in the scale-invariant structure of heartbeat fluctuations and likely do not contribute to the increase in cardiac risk at ≈10 a.m.

Mental Ill-Health and the differential effect of employee type on absenteeism and presenteeism

Objective: Mental ill-health results in substantial reductions in employee productivity (absenteeism and presenteeism). This paper examines the relationship between employee psychological distress, employee type and productivity. Method: Utilizing the Health and Performance at Work Questionnaire, in a sample of 60,556 full-time employees, the impact that psychological distress (Kessler 6) imposes on employee productivity by occupation type is examined. Results: Comparison of white-collar workers absenteeism rates by low and high psychological distress reveals no statistically significant difference. Nevertheless, the same comparison for blue-collar workers reveals that high psychological distress results in an 18% increase in absenteeism rates. High K6 score resulted in a presenteeism increase of 6% in both blue and white-collar employees. Conclusion: The novel finding is that mental ill-health produces little to no absenteeism in white-collar workers yet a profound absenteeism increase in the blue-collar sector.

Patterns of multimorbidity in working Australians

BackgroundMultimorbidity is becoming more prevalent. Previously-used methods of assessing multimorbidity relied on counting the number of health conditions, often in relation to an index condition (comorbidity), or grouping conditions based on body or organ systems. Recent refinements in statistical approaches have resulted in improved methods to capture patterns of multimorbidity, allowing for the identification of nonrandomly occurring clusters of multimorbid health conditions. This paper aims to identify nonrandom clusters of multimorbidity.MethodsThe Australian Work Outcomes Research Cost-benefit (WORC) study cross-sectional screening dataset (approximately 78,000 working Australians) was used to explore patterns of multimorbidity. Exploratory factor analysis was used to identify nonrandomly occurring clusters of multimorbid health conditions.ResultsSix clinically-meaningful groups of multimorbid health conditions were identified. These were: factor 1: arthritis, osteoporosis, other chronic pain, bladder problems, and irritable bowel; factor 2: asthma, chronic obstructive pulmonary disease, and allergies; factor 3: back/neck pain, migraine, other chronic pain, and arthritis; factor 4: high blood pressure, high cholesterol, obesity, diabetes, and fatigue; factor 5: cardiovascular disease, diabetes, fatigue, high blood pressure, high cholesterol, and arthritis; and factor 6: irritable bowel, ulcer, heartburn, and other chronic pain. These clusters do not fall neatly into organ or body systems, and some conditions appear in more than one cluster.ConclusionsConsiderably more research is needed with large population-based datasets and a comprehensive set of reliable health diagnoses to better understand the complex nature and composition of multimorbid health conditions.

The sleep apnoea/hypopnoea syndrome depresses waking vagal tone independent of sympathetic activation

The modest daytime hypertension and sympathetic upregulation associated with the sleep apnoea/hypopnoea syndrome (SAHS), does not explain the relatively large increased risk of cardiac morbidity and mortality in the SAHS patients population. Therefore, efferent vagal and sympathetic activity was evaluated during wakefulness in SAHS subjects and matched healthy controls, in order to determine if vagal downregulation may play a role in the aetiology of cardiac disease in the SAHS. The awake autonomic nervous system function of 15 male subjects, with mild-to-moderate SAHS was compared to that of 14 healthy controls matched for age, body mass index, gender and blood pressure. All subjects were free from comorbidity. Vagal activity was estimated from measurements of heart rate variability high frequency power (HF) and sympathetic activity was measured from urine catecholamine excretion. The %HF power was significantly (p < 0.03) reduced in SAHS patients (10+/-1.6 (mean+/-SEM)) as compared to controls (17 +/- 3). In addition, HF power correlated with the apnoea/hypopnoea index in the SAHS subjects (R = -0.592, p = 0.02). There was no statistically significant difference in the daytime excretion of nonadrenaline between control (242 +/- 30 nmol x collection(-1)) and SAHS (316 +/- 46 nmol x collection(-1)) subjects (p = 0.38). In these sleep apnoea/hypopnoea syndrome patients there was limited evidence of increased waking levels of urine catecholamines. The principal component altering waking autonomic nervous system function, in the sleep apnoea/hypopnoea syndrome subjects, was a reduced daytime efferent vagal tone.

Using the interaction of mental health symptoms and treatment status to estimate lost employee productivity

Objective: In Australia it has been estimated that mental health symptoms result in a loss of