Heart rate circadian rhythm as a biological marker of desynchronization in major depression: a methodological and preliminary report

Heart rate (HR) was continuously monitored during successive 24-hr periods in 19 healthy subjects and 26 major depressed patients (DSM III-R). Recordings were performed after a 2-week wash-out period and the morningness or eveningness typology of each subject was determined. The chronobiological parameters and rhythm percentage (RP) were calculated by the single cosinor method from the smoothed HR curves of each subject. In normal subjects, HR follows a circadian rhythm (RP greater than 65%) with the lowest values at night. Morning type subjects have an earlier peak time (13:30) than evening type subjects (17:30). Major depressive patients were split into two groups; in the first one HR circadian rhythm was still present (RP greater than 63%) with a decrease in amplitude (24%) while in the second group, no circadian rhythm of HR could be detected (RP less than 25%, decrease in amplitude greater than 70%). In the group of patients with a persisting HR circadian rhythm, no veritable phase advance was observed. Our results suggest that circadian HR rhythm, which can be easily studied with non-invasive methods, might represent a chronobiological marker of some depressions. Given the lag that exists between the rhythms of morning type and evening type subjects, our study also stresses the importance of taking into account this behavioural trait in chronobiological studies.     

24-Hour Profiles of Blood Pressure and Heart Rate in Cushing's Syndrome: Relationship Between Cortisol and Cardiovascular Rhythmicities

We monitored the circadian profiles of Cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P< 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P < 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.     

Comparison of circadian rhythm characteristics of blood pressure and heart rate in patients before and after elective coronary artery bypass surgery

Coronary artery bypass grafting surgery (CABGS) is done to reperfuse the ischemic myocardium of coronary disease patients. This study was designed to analyze the circadian rhythm characteristics of blood pressure (BP) and heart rate (HR) of patients before and after CABGS. Fifty-one patients undergoing elective CABGS were studied; 21 patients received one, 12 two and 18 three or more grafts. BP was monitored for 24h before and after CABGS while patients were recumbent in the hospital. Systolic (S) and diastolic (D) BP and HR were assessed every 30 min. Of the 51 patients, 37 (73%) had nondipper 24h BP patterns (nocturnal decline in BP < 10% of daytime mean level) in the preoperative baseline assessment. The peak and MESOR (rhythm-adjusted 24h mean) values of the circadian rhythm in SBP, DBP, and pulse pressure (PP) significantly declined following surgery, while HR and rate-pressure product (RPP = SBP x HR) markedly increased. The double amplitude (peak-to-trough variation) of the circadian rhythm in SBP and DBP was significantly reduced postoperatively, and that of the rhythm in HR and RPP significantly increased. The slopes of the morning rise and evening dip in the 24h SBP profile were reduced significantly after bypass grafting. The corresponding slopes of the HR profile, in contrast, were markedly increased.     

Circadian Rhythm of Gastric Acid Secretion in Active Duodenal Ulcer: Chronobiological Statistical Characteristics and Comparison of Acid Secretory and Plasma Gastrin Patterns with Healthy Subjects and Post-Vagotomy and Pyloroplasty Patients

Twenty-one male patients with active duodenal ulcer underwent hourly 24-hr gastric acid collections under controlled, calorically deprived conditions. The 24-hr hourly acid secretory output for the group displayed a statistically significant (p < 0.001) rhythm, with peak rates occurring during the evening hours and low rates during the early morning hours, by population-mean cosinor statistical analysis. Population-mean cosinor analysis also verified the occurrence of a significant (p=0.034) circadian rhythm in unstimulated acid secretion in a group (N=14) of healthy male subjects similarly studied and reported previously. In contrast, population-mean cosinor analysis confirmed the absence of any detectable circadian rhythm in unstimulated acid secretion in a group (N=17) of post-vagotomy and pyloroplasty patients studied 2-11 years after surgery. Population-mean cosinor analysis of 4-hr plasma gastrin determinations, obtained in all groups during the 24-hr gastric acid collection, revealed an absence of any detectable circadian rhythm in plasma gastrin. This latter finding is compatible with the interpretation that the circadian rhythm of unstimulated gastric acid secretion, observed in the clinically healthy and active ulcer groups, is unrelated to changes in plasma gastrin levels. The employment of quantitative chronobiological inferential statistical techniques is important to the analysis of any time-dependent measurement in gastrointestinal function, of which gastric acidity is one example.     

The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

The Circadian Rhythm of Plasma Thyrotropin in Depression and Recovery

The 24-hr patterns of plasma thyrotropin have been observed in 12 endogenous depressed patients in both depressed and recovered states and in 13 normal subjects. A clear circadian rhythm was detected in controls with high values at night. In depression, the circadian rhythm was altered with amplitude reduction and blunted nocturnal secretion, abnormalities particularly relevant in bipolar patients. This flattened profile could be linked to the blunted response of TSH to TRH administration reported in depressed patients. Normal nyctohemeral patterns have been restored after recovery. These chronobiological abnormalities as well as their normalization under antidepressant drugs seem to be similar to those reported for various parameters (e.g. temperature, Cortisol, etc) in depression which could support the chronobiological hypothesis for affective disorders.     

Features of the circadian rhythm of skin temperature in eight- to nine-year-old children and young adults

The age-related features of the circadian rhythm of skin temperature were studied using the Termochron iButton method in two age groups of subjects: eight-to nine-year-old boys and girls and young men and women aged 20–22 years. For this purpose, the temperature was monitored for 48 h at a recording interval of 10 min. The following authentic chronobiological differences were revealed: the temperature mesor was higher in the girls than in the boys and in the young men it was higher than in the young women. The circadian rhythm’s amplitude was higher in the boys and the young women. Studies of the chronological values in different 24-h periods showed that the average level of temperature at night was lower in all subjects. The amplitude in the adults did not differ in different 24-h periods, whereas it was higher in the children at night.     

Circadian rhythm of gastric acid secretion in active duodenal ulcer: chronobiological statistical characteristics and comparison of acid secretory and plasma gastrin patterns with healthy subjects and postvagotomy and pyloroplasty patients

Twenty-one male patients with active duodenal ulcer underwent hourly 24-hr gastric acid collections under controlled, calorically deprived conditions. The 24-hr hourly acid secretory output for the group displayed a statistically significant (p less than 0.001) rhythm, with peak rates occurring during the evening hours and low rates during the early morning hours, by population-mean cosinor statistical analysis. Population-mean cosinor analysis also verified the occurrence of a significant (p = 0.034) circadian rhythm in unstimulated acid secretion in a group (N = 14) of healthy male subjects similarly studied and reported previously. In contrast, population-mean cosinor analysis confirmed the absence of any detectable circadian rhythm in unstimulated acid secretion in a group (N = 17) of postvagotomy and pyloroplasty patients studied 2-11 years after surgery. Population-mean cosinor analysis of 4-hr plasma gastrin determinations, obtained in all groups during the 24-hr gastric acid collection, revealed an absence of any detectable circadian rhythm in plasma gastrin. This latter finding is compatible with the interpretation that the circadian rhythm of unstimulated gastric acid secretion, observed in the clinically healthy and active ulcer groups, is unrelated to changes in plasma gastrin levels. The employment of quantitative chronobiological inferential statistical techniques is important to the analysis of any time-dependent measurement in gastrointestinal function, of which gastric acidity is one example.     

Chronobiological study of several enzymes of lysosomal origin in human plasma

The possible occurrence of circadian and circannual rhythms in the plasma concentrations of the following enzymes of lysosomal origin was assessed: beta-D-N-acetylglucosaminidase (EC 3.2.1.30) beta-D-glucuronidase (EC 3.2.1.31), beta-D-glucosidase (EC 3.2.1.21), beta-D-galactosidase (EC 3.2.1.22), alpha-D-galactosidase (EC 3.2.1.23), alpha-L-fucosidase (EC 3.2.1) and alpha-D-mannosidase (EC 3.2.1.24). The circadian rhythm was studied in 16 women (aged: 17-24 years) and 13 men (age: 23 years) volunteers; the circannual rhythm, in 10 women and 8 men (age: 20-25 years). The circadian rhythm was detected in all the tested enzymes of women, and only in alpha-D-galactosidase, beta-D-glucosidase, alpha-D-mannosidase and beta-D-acetylglucosaminidase of men. A statistically significant difference between genders in the circadian rhythm was exhibited by beta-D-galactosidase (MESOR; amplitude) beta-D-glucosidase (MESOR; amplitude; acrophase) beta-D-N-acetylglucosaminidase, beta-D-glucuronidase and alpha-D-galactosidase (MESOR) and alpha-L-fucosidase (amplitude, acrophase). A circannual rhythm was detected in all the tested enzymes with the exception of beta-D-glucuronidase and beta-D-N-acetylglucosaminidase; no statistically significant difference between genders was detected. The group rhythms of some of the enzymes (alpha-D-galactosidase, beta-D-glucosidase, beta-D-galactosidase) showed similar values of both circadian and circannual acrophases, suggesting that they may subjected as a group to the same chronobiological coordination, possibly mediated by hormones. The chronobiological rhythms of lysosomal enzymes were different from those of lactate dehydrogenase and alpha 1-antitrypsin, indicating that these rhythms are not merely reflecting fluctuations of the water content of plasma. No in-phase relationship was observed between the circadian and circannual rhythms of plasma cortisol and those of the tested lysosomal enzymes, excluding a direct chronobiological and possibly functional relationship between this hormone and lysosomal enzymes.     

24-hour profiles of blood pressure and heart rate in Cushing's syndrome: relationship between cortisol and cardiovascular rhythmicities

We monitored the circadian profiles of cortisol, systolic and diastolic blood pressure (SBP and DBP) and heart rate (HR) in 33 matched normotensive subjects, 32 patients with essential hypertension and 16 patients with Cushing's Syndrome (8 pituitary adenomas, 6 adrenal adenomas and 2 adrenal carcinomas). Each subject underwent serial blood drawings at 4-hr intervals along the 24-hr cycle. BP and HR were automatically recorded every 30 min. Data were analyzed by conventional statistics and by chronobiological procedures (cosinor rhythmometry). Both the control subjects and essential hypertensives showed a circadian profile of BP and HR characterized by a peak in the early afternoon and a clear nocturnal fall (rhythm detection: P less than 0.001). The rhythmicity of BP was disrupted in patients affected by Cushing's Syndrome, whereas the 24-hr oscillation of HR was preserved (P less than 0.001). Our data are compatible with the view that glucocorticoids are involved in the control of BP circadian rhythm, whereas HR is not under their control.     

The influence of short-term sedentary behavior on circadian rhythm of heart rate and heart rate variability

The notion that sedentary behavior is harmful to human health is widespread. Little is known about the short term influence of sedentary behavior on heart rate (HR) and heart rate variability (HRV) circadian rhythms. Therefore the purpose of the present study was to examine the influence of short term sedentary behavior on the circadian rhythms of HR and HRV using cosine periodic regression analysis. Sixteen healthy young students were included in a randomized crossover study. All subjects underwent 24-h ECG Holter monitoring in two different states of physical activity, an active condition (more than 15,000 steps per day) and a sedentary condition (less than 1,000 steps per day). Hourly mean values were calculated for HR and HRV, and then were evaluated using cosine periodic regression analysis. The circadian rhythm parameters, amplitude, mesor, and acrophase for HR and HRV variables were obtained. As a result, the significance of the circadian rhythm was confirmed for all variables in each condition. The measure of fit R2 value was decreased in sedentary condition. The amplitude of the sedentary condition was significantly smaller than that of the active condition with respect to HR (7.94 ± 1.91 bpm vs. 15.4 ± 3.93 bpm, p < 0.001), natural log of the high frequency measurement (lnHF) (0.38 ± 0.21 ms2 vs. 0.80 ± 0.28 ms2, p < 0.001), and low frequency/high frequency ratio (LF/HF) (0.75 ± 0.54 vs. 1.24 ± 0.69, p = 0.008). We found that sedentary behavior not only significantly lowered the amplitude of HR and HRV variables, but also might have led to weakness of the circadian rhythm of the HR and HRV variables.     

Blunting of circadian rhythms and increased acrophase variability in sleep-time hypertensive subjects

24 h and ultradian rhythms of blood pressure (BP) have been previously shown to be disorganized in nocturnal hypertensive subjects. The present study was undertaken to further analyze the ultradian and circadian BP rhythm structure in sleep-time hypertensive subjects with normal or elevated awake-time BP levels. Fourier analysis was used to fit 24, 12, 8, and 6 h curves to mean BP as well as heart rate (HR) time series data derived from 24 h ambulatory blood pressure monitoring. Awake and sleep periods were defined according to individual sleep diaries. Awake-time hypertension was defined as diurnal systolic (SBP) and/or diastolic BP (DBP) means ≥135/85 mmHg. Sleep-time hypertension was defined as nocturnal SBP and/or DBP means ≥120/70 mmHg. The sample included 240 awake-time normotensive subjects (180 sleep-time normotensives and 60 sleep-time hypertensives) and 138 untreated awake-time hypertensive subjects (31 sleep-time normotensives and 107 sleep-time hypertensives). The amplitude and integrity (i.e., percent rhythm) of the 24 and 12 h BP rhythms were lower in the sleep-time hypertensive subjects and higher in the awake-time hypertensive subjects. However, no differences were detected when the integrity and amplitude of the 6 and 8 h mean BP rhythms were analyzed. The sleep-time hypertensive group showed significantly higher 24 h BP rhythm acrophase variability. No differences could be found in any of the HR rhythm parameters. Altogether, the findings suggest a disorganization of the BP circadian rhythm in sleep-time hypertensives that results in reduced 24 h rhythm amplitude and integrity that could be related to cardiovascular risk.     

Effects of 24-Hour Shift Work with Nighttin Napping on Circadian Rhythm Characteristi in Ambulance Personnel

Forty-two ambulance personnel engaged in a 24-h shift system participated in a chronobiological field study to study the effects of 24-h shift work on circadian rhythm characteristics. Autorhythmometry of circadian rhythms of oral temperature, right and left grip strengths, and heart rate plus subjective assessment of drowsiness, fatigue, and attention was performed every ～ 4 h except during sleep for 7 days. Cosinor and power spectral analyses were applied to the longitudinal data of each individual. Changes in circadian period different from 24 h of oral temperature, grip strengths, and heart rate plus subjective drowsiness, fatigue, and attention were observed in ambulance personnel. The incidence of circadian periodicity different from 24 h in oral temperature and right and left grip strength was 28.6%, 35.7%, and 47.6%, respectively. The incidence was relatively lower than that of shift workers engaged in a discontinuous 8-h shift system we reported on previously. Working conditions allowing ambulance personnel to nap when not called for emergency (for > 4 h) might contribute to a stabilization of circadian rhythms. Furthermore, long nighttime ambulance service amounting to >100 min was significantly associated with a high incidence of at least one prominent circadian period among oral temperature and right and left grip strength rhythms different from 24 h. In conclusion, 24-h shift work altered the characteristics of circadian rhythms of ambulance personnel; nighttime naps seemed to have a favorable effect on averting changes in circadian rhythms.     

CIRCADIAN PATTERN OF BLOOD PRESSURE,HEART RATE,AND DOUBLE PRODUCT IN LIVER GLYCOGEN STORAGE DISEASE

The objective of this study was to determine systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), heart rate (HR), double-product (DP: SBP×HR), and activity levels and their 24h pattern in liver glycogen storage disease (LGSD) patients. A case series of 12 (11 pediatric and one adult) diurnally active LGSD (seven type I, three type III, and two type IX) subjects were simultaneously assessed by 24h ambulatory blood pressure monitoring and wrist actigraphy. Nine subjects were judged to be hypertensive based on the criterion of an elevated 24h mean SBP and/or DBP being elevated beyond reference standards or the SBP and/or DBP load (percentage of time BP exceeds normal values) being greater than 25%. Two of the three other subjects, not viewed as hypertensive based on their 24h average SBP or DBP, exhibited daytime or nighttime SBP and/or DBP load hypertension. Each study variables displayed statistically significant (p<0.001) group circadian rhythmicity. The SBP, DBP, and MAP displayed comparable 24h patterns of appreciable amplitude (total peak–trough variation equal to 17.7, 23.6, and 19.6%, respectively, of the 24h mean) with highest values (orthophase) occurring ～11 h after the commencement of daytime activity. The sleep-time trough (bathyphase) occurred ～4.5 h before morning awakening. The statistically significant (p<0.006) circadian rhythms of HR (amplitude equal to 33.2% of the 24h mean) and DP (amplitude equal to 49.4% of the 24h mean) peaked earlier, ～7.4 h into the daytime activity span. The sleep-time trough occurred ～3 h before morning awakening. The 24h pattern in the cardiovascular variables was correlated with the 24h pattern of activity, with r ranging from 0.50 for DBP to 0.39 for HR.     

Chronotypes of Bipolar Patients in Remission: Validation of the French Version of the Circadian Type Inventory in the FACE-BD Sample

Circadian rhythm disturbances have been associated with bipolar disorder (BD) during both the mood episodes and the periods of remission. Circadian phase preferences for the evening have been reported for remitted patients, whereas the amplitude and stability of their rhythms have never been assessed using questionnaires. The primary aim of our study was the validation of a French version of the Circadian Type Inventory (CTI), whereas its secondary aim was the comparison between remitted patients with BD and healthy controls for rhythm stability and amplitude and for phase preference. For this purpose, we used the CTI and the Composite Scale of Morningness (CSM) that assesses phase preference (“morning” or “evening” type). First, we report here on the validation of the French version of the 11-item Circadian Type Inventory in a sample of 140 remitted patients with BD and 156 healthy controls. Principal components analysis revealed a two-factor structure (FR: flexibility/rigidity scale corresponding to rhythm stability; LV: languid/vigorous scale corresponding to rhythm amplitude) explaining 52% of the variance in the control group and 47% in the bipolar group. Cronbach’s alpha was 0.75 for FR and 0.73 for LV. The test-retest reliability was 0.74 for FR and 0.86 for LV (3 wks) and 0.62 for FR and 0.72 for LV (6 mos). LV and FR scores correlated with the Composite Scale of Morningness score (p?<?0.00001 and p?=?0.0002, respectively). Second, as compared with controls, patients with BD were more languid (p?<?0.00001) and showed an evening preference (p?=?0.0003), but they did not differ from the controls with regard to flexibility/rigidity. The French version of the CTI appeared to have satisfactory psychometrics characteristics. Bipolar patients exhibited not only abnormalities in phase preference but also in amplitude as measured by languidity. Since circadian rhythm dysfunction has been shown to predict poor functioning and mood relapses in interepisodic patients with BD, this tool would appear to be a promising, easy-to-use, measure of the amplitude and flexibility of circadian rhythms that could enrich the arsenal of assessments used in clinical settings.     

Circadian Rhythm of Blood Pressure and Heart Rate in Cardiopathic Patients Before and After Heart Transplantation

The aim of this study was to investigate the natural history of the circadian rhythm of blood pressure (BP) and heart rate (HR) in 10 patients with heart failure (class IV of the New York Heart Association), who underwent heart transplantation because of primary congestive cardiomyopathy. The control group was 10 age-matched clinically healthy subjects. The BP and HR monitor-ings were performed before and after transplantation. Preoperatively, analysis of variance and cosinor methods validated the occurrence of a statistically significant BP and HR circadian rhythm in cardiopathic patients. Over the 4 days after surgery, both the cosinor method and serial section analysis were unable to validate a 24-h periodicity for BP and HR in patients with heart transplants. Six months after surgery, the BP and HR circadian rhythm was not detected as well. One year after transplantation. the BP and HR circadian rhythm was statistically validated. The recovery of the BP and HR circadian rhythm 1 year after heart transplantation can be regarded as a clinical sign of a reacquired susceptibility to neurovegetative chronoregulation.     

Human cone light sensitivity and melatonin rhythms following 24-hour continuous illumination

This study investigates the possibility of an endogenous circadian rhythm in retinal cone function in humans. A full-field cone electroretinogram (ERG) was performed every 2 h for 24 h under continuous rod-saturating ambient white light (53 ± 30 lux; pupils dilated) in nine healthy subjects. Distinct circadian variations were superimposed upon a gradual decrease in cone responsiveness to light, demonstrated most reliably in the implicit times of b-wave and oscillatory potentials, and to a lesser extent in amplitude and a-wave implicit times. After mathematical correction of the linear trend, the cone response was found to be greatest around 20:00 h and least around 06:00 h. The phase of the ERG circadian rhythm was not synchronized with the phase of the salivary melatonin rhythm measured the previous evening. Melatonin levels measured under constant light on the day of ERG assessments were suppressed by 53% on average compared to melatonin profiles obtained previously under near-total darkness in seven participants. The progressive decline in cone responsiveness to light over the 24 h may reflect an adaptation of the cone-driven retinal system to constant light, although the mechanism is unclear. The endogenous rhythm of cone responsiveness to light may be used as an additional index of central or retinal circadian clock time.     

Circadian pattern of blood pressure,heart rate,and double product in liver glycogen storage disease

The objective of this study was to determine systolic, diastolic, and mean arterial blood pressure (SBP, DBP, and MAP), heart rate (HR), double-product (DP: SBP x HR), and activity levels and their 24h pattern in liver glycogen storage disease (LGSD) patients. A case series of 12 (11 pediatric and one adult) diurnally active LGSD (seven type I, three type III, and two type IX) subjects were simultaneously assessed by 24h ambulatory blood pressure monitoring and wrist actigraphy. Nine subjects were judged to be hypertensive based on the criterion of an elevated 24h mean SBP and/or DBP being elevated beyond reference standards or the SBP and/or DBP load (percentage of time BP exceeds normal values) being greater than 25%. Two of the three other subjects, not viewed as hypertensive based on their 24h average SBP or DBP, exhibited daytime or nighttime SBP and/or DBP load hypertension. Each study variables displayed statistically significant (p < 0.001) group circadian rhythmicity. The SBP, DBP, and MAP displayed comparable 24h patterns of appreciable amplitude (total peak-trough variation equal to 17.7, 23.6, and 19.6%, respectively, of the 24h mean) with highest values (orthophase) occurring approximately 11 h after the commencement of daytime activity. The sleep-time trough (bathyphase) occurred approximately 4.5 h before morning awakening. The statistically significant (p < 0.006) circadian rhythms of HR (amplitude equal to 33.2% of the 24h mean) and DP (amplitude equal to 49.4% of the 24h mean) peaked earlier, approximately 7.4 h into the daytime activity span. The sleep-time trough occurred approximately 3 h before morning awakening. The 24h pattern in the cardiovascular variables was correlated with the 24h pattern of activity, with r ranging from 0.50 for DBP to 0.39 for HR.     

Serum angiotensin-converting enzyme activity in pre-eclamptic pregnancy: evidence for a relative hypermesorACEemia

The circadian rhythm of serum angiotensin-converting enzyme (ACE) activity was investigated in pregnant women with normal and pre-eclamptic gestation. The chronobiological approach was able to document the occurrence of a circadian rhythm for serum ACE activity in normal pregnancy. Such a rhythm is characterized by a decreased mesor and amplitude and a shifted crest. The circadian rhythm for serum ACE activity was not detectable in pre-eclamptic pregnancy. Such an abrogation is accompanied by a negligible decrease of mesor suggesting the occurrence of a relative hyperACEemia. This disorder could play a role in pregnancy-induced hypertension.     

Melatonin rhythm observed throughout a three-cycle bright-light stimulus designed to reset the human circadian pacemaker.

Exposure to light and darkness can rapidly induce phase shifts of the human circadian pacemaker. A type 0 phase response curve (PRC) to light that has been reported for humans was based on circadian phase data collected from constant routines performed before and after a three-cycle light stimulus, but resetting data observed throughout the entire resetting protocol have not been previously reported. Pineal melatonin secretion is governed by the hypothalamic circadian pacemaker via a well-defined neural pathway and is reportedly less subject to the masking effects of sleep and activity than body temperature. The authors reasoned that observation of the melatonin rhythm throughout the three-cycle light resetting trials could provide daily phase-resetting information, allowing a dynamic view of the resetting response of the circadian pacemaker to light. Subjects (n = 12) living in otherwise dim light (approximately 10-15 lux) were exposed to a noncritical stimulus of three cycles of bright light (approximately 9500 lux for 5 h per day) timed to phase advance or phase delay the human circadian pacemaker; control subjects (n = 11) were scheduled to the same protocols but exposed to three 5-h darkness cycles instead of light. Subjects underwent initial and final constant routine phase assessments; hourly melatonin samples and body temperature data were collected throughout the protocol. Average daily phase shifts of 1 to 3 h were observed in 11 of 12 subjects receiving the bright light, supporting predictions obtained using Kronauer's phase-amplitude model of the resetting response of the human circadian pacemaker. The melatonin rhythm in the 12th subject progressively attenuated in amplitude throughout the resetting trial, becoming undetectable for >32 hours preceding an abrupt reappearance of the rhythm at a shifted phase with a recovered amplitude. The data from control subjects who remained in dim lighting and darkness delayed on average -0.2 h per day, consistent with the daily delay expected due to the longer than 24-h intrinsic period of the human circadian pacemaker. Both temperature and melatonin rhythms shifted by equivalent amounts in both bright light-treated and control subjects (R = 0.968; p<0.0001; n = 23). Observation of the melatonin rhythm throughout a three-cycle resetting trial has provided a dynamic view of the daily phase-resetting response of the human circadian pacemaker. Taken together with the observation of strong type 0 resetting in humans in response to the same three-cycle stimulus applied at a critical phase, these data confirm the importance of considering both phase and amplitude when describing the resetting of the human circadian pacemaker by light.