Circadian rhythm in QT interval is preserved in mice deficient of potassium channel interacting protein 2

Potassium Channel Interacting Protein 2 (KChIP2) is suggested to be responsible for the circadian rhythm in repolarization duration, ventricular arrhythmias, and sudden cardiac death. We investigated the hypothesis that there is no circadian rhythm in QT interval in the absence of KChIP2. Implanted telemetric devices recorded electrocardiogram continuously for 5 days in conscious wild-type mice (WT, n = 9) and KChIP2^?/? mice (n = 9) in light:dark periods and in complete darkness. QT intervals were determined from all RR intervals and corrected for heart rate (QT₁₀₀ = QT/(RR/100)^1/2). Moreover, QT intervals were determined from complexes within the RR range of mean-RR ± 1% in the individual mouse (QT_mean-RR). We find that RR intervals are 125 ± 5 ms in WT and 123 ± 4 ms in KChIP2^?/? (p = 0.81), and QT intervals are 52 ± 1 and 52 ± 1 ms, respectively(p = 0.89). No ventricular arrhythmias or sudden cardiac deaths were observed. We find similar diurnal (light:dark) and circadian (darkness) rhythms of RR intervals in WT and KChIP2^?/? mice. Circadian rhythms in QT₁₀₀ intervals are present in both groups, but at physiological small amplitudes: 1.6 ± 0.2 and 1.0 ± 0.3 ms in WT and KChIP2^?/?, respectively (p = 0.15). A diurnal rhythm in QT₁₀₀ intervals was only found in WT mice. QT_mean-RR intervals display clear diurnal and circadian rhythms in both WT and KChIP2^?/?. The amplitude of the circadian rhythm in QT_mean-RR is 4.0 ± 0.3 and 3.1 ± 0.5 ms in WT and KChIP2^?/?, respectively (p = 0.16). In conclusion, KChIP2 expression does not appear to underlie the circadian rhythm in repolarization duration.     

Circadian Phase,Sleepiness, and Light Exposure Assessment in Night Workers With and Without Shift Work Disorder

Most night workers are unable to adjust their circadian rhythms to the atypical hours of sleep and wake. Between 10% and 30% of shiftworkers report symptoms of excessive sleepiness and/or insomnia consistent with a diagnosis of shift work disorder (SWD). Difficulties in attaining appropriate shifts in circadian phase, in response to night work, may explain why some individuals develop SWD. In the present study, it was hypothesized that disturbances of sleep and wakefulness in shiftworkers are related to the degree of mismatch between their endogenous circadian rhythms and the night-work schedule of sleep during the day and wake activities at night. Five asymptomatic night workers (ANWs) (3 females; [mean?±?SD] age: 39.2?±?12.5 yrs; mean yrs on shift?=?9.3) and five night workers meeting diagnostic criteria (International Classification of Sleep Disorders [ICSD]-2) for SWD (3 females; age: 35.6?±?8.6 yrs; mean years on shift?=?8.4) participated. All participants were admitted to the sleep center at 16:00?h, where they stayed in a dim light (<10 lux) private room for the study period of 25 consecutive hours. Saliva samples for melatonin assessment were collected at 30-min intervals. Circadian phase was determined from circadian rhythms of salivary melatonin onset (dim light melatonin onset, DLMO) calculated for each individual melatonin profile. Objective sleepiness was assessed using the multiple sleep latency test (MSLT; 13 trials, 2-h intervals starting at 17:00?h). A Mann-Whitney U test was used for evaluation of differences between groups. The DLMO in ANW group was 04:42?±?3.25?h, whereas in the SWD group it was 20:42?±?2.21?h (z = 2.4; p?<?.05). Sleep did not differ between groups, except the SWD group showed an earlier bedtime on off days from work relative to that in ANW group. The MSLT corresponding to night work time (01:00–09:00?h) was significantly shorter (3.6?±?.90?min: [M?±?SEM]) in the SWD group compared with that in ANW group (6.8?±?.93?min). DLMO was significantly correlated with insomnia severity (r = ?.68; p < .03), indicating that the workers with more severe insomnia symptoms had an earlier timing of DLMO. Finally, SWD subjects were exposed to more morning light (between 05:00 and 11:00?h) as than ANW ones (798 vs. 180 lux [M?±?SD], respectively z?=??1.7; p?<?.05). These data provide evidence of an internal physiological delay of the circadian pacemaker in asymptomatic night-shift workers. In contrast, individuals with SWD maintain a circadian phase position similar to day workers, leading to a mismatch/conflict between their endogenous rhythms and their sleep-wake schedule. (Author correspondence: vgumeny1@hfhs.org)     

An observational study on disturbed peripheral circadian rhythms in hemodialysis patients

The quality of life of hemodialysis (HD) patients is hampered by reduced nocturnal sleep quality and excessive daytime sleepiness. In addition to the sleep/wake cycle, levels of circadian biomarkers (e.g. melatonin) are disturbed in end-stage renal disease (ESRD). This suggests impaired circadian clock performance in HD patients, but the underlying mechanism is unknown. In this observational study, diurnal rhythms of sleep, serum melatonin and cortisol concentrations and clock gene mRNA expression are compared between HD patients (n?=?9) and healthy control subjects (n?=?9). In addition, the presence of circulating factors that might affect circadian rhythmicity is tested in vitro with cell culture experiments. Reduced sleep quality (median sleep onset latency [interquartile range] of 23.9 [17.3]?min for patients versus 5.0 [10] minutes for controls, p?<?0.01; mean (± SD) sleep efficiency 70.2?±?8.1% versus 82.9?±?10.9%, p?=?0.02 and mean awake minutes after sleep onset 104.8?±?27.9 versus 54.6?±?41.6 minutes, p?= 0.01) and increased daytime sleepiness (mean Epworth Sleepiness Score of 10.0?±?4.8 versus 3.9?±?2.0, p?<?0.01) were confirmed in HD patients. Reduced nocturnal melatonin concentrations (1 AM: 98.1 [122.9] pmol/L versus 12.5 [44.2] pmol/L, p?= 0.019; 5 AM: 114.0 [131.6] pmol/L versus 11.8 [86.8] pmol/L, p?= 0.031) and affected circadian control of cortisol rhythm and circadian expression of the clock gene REV-ERBα were found. HD patient serum had a higher capacity to synchronize cells in vitro, suggesting an accumulated level of clock resetting compounds in HD patients. These compounds were not cleared by hemodialysis treatment or related to frequently used medications. In conclusion, the abovementioned results strongly suggest a disturbance in circadian timekeeping in peripheral tissues of HD patients. Accumulation of clock resetting compounds possibly contributes to this. Future studies are needed for a better mechanistic understanding of the interaction between renal failure and perturbation of the circadian clock.     

Consistent Changes in the Circadian Rhythms of Blood Pressure and Atrial Natriuretic Peptide in Congestive Heart Failure

We demonstrated in previous works that the circadian rhythms of blood pressure (BP) and atrial natriuretic peptide (ANP) are antiphasic in normal subjects and in essential hypertension. The aim of the present study was to assess the circadian rhythms of BP and ANP in 20 patients with stable congestive heart failure (CHF), divided into two groups of 10 according to their New York Heart Association functional class. A matched control group of 10 normal volunteers was also studied. Noninvasive BP monitoring at 15-min intervals was performed for 24 h. Peripheral blood samples were also obtained at 4-h intervals starting from 08:OO h. The mean (±SEM) circadian mesors of ANP plasma levels were 13.4 ± 1.7 pmol/L in the control group, 28.6 ± 2.4 pmol/L in the group of 10 patients in class 11, and 81.5 ± 12 pmol/L in the group of 10 patients in class 111-IV. In normal subjects, plasma ANP concentration was highest at 04:OO h (21.5 ± 2.7 pmol/L) and lowest at 16:OO h (8.8 ± 2.4 pmol/L; p < 0.01). Both groups of patients with CHF showed no significant circadian change in the plasma levels of ANP and also a significantly blunted circadian rhythm of BP. Cosinor analysis confirmed the loss of the circadian rhythms of ANP and BP in CHF patients. Our findings support the existence of a causal relationship between the circadian rhythms of ANP and BP.     

Circadian Rhythms of Embryonic Development and Hatching in Fish: A Comparative Study of Zebrafish (Diurnal), Senegalese Sole (Nocturnal), and Somalian Cavefish (Blind)

During early development, most organisms display rhythmic physiological processes that are shaped by daily changes in their surrounding environment (i.e., light and temperature cycles). In fish, the effects of daily photocycles and their interaction with temperature during early developmental stages remain largely unexplored. We investigated the existence of circadian rhythms in embryonic development and hatching of three teleost species with different daily patterns of behavior: diurnal (zebrafish), nocturnal (Senegalese sole), and blind, not entrained by light (Somalian cavefish). To this end, fertilized eggs were exposed to three light regimes: 12 h of light: 12 h of darkness cycle (LD), continuous light (LL), or continuous darkness (DD); and three species-appropriate temperature treatments: 24°C, 28°C, or 32°C for zebrafish and cavefish and 18°C, 21°C, or 24°C for sole. The results pointed to the existence of daily rhythms of embryonic development and hatching synchronized to the LD cycle, with different acrophases, depending on the species: zebrafish embryos advanced their developmental stage during the light phase, whereas sole did so during the dark phase. In cavefish, embryogenesis occurred within 24 h post fertilization (hpf) at the same pace during day or night. The hatching rhythms appeared to be controlled by a clock mechanism that restricted or “gated” hatching to a particular time of day/night (window), so that embryos that reached a certain developmental state by that time hatch, whereas those that have not wait until the next available window. Under LL and DD conditions, hatching rhythms and the gating phenomenon persisted in cavefish, in zebrafish they split into ultradian bouts of hatching occurring at 12–18-h intervals, whereas in sole DD and LL produced a 24-h delay and advance, respectively. Hatching rates were best under the LD cycle and the reported optimal temperature for each species (95.2?±?2.7% of the zebrafish and 83.3?±?0.1% of the cavefish embryos hatched at 28°C, and 93.1?±?2.9% of the sole embryos hatched at 21°C). In summary, these results revealed that hatching rhythms in fish are endogenously driven by a time-keeping mechanism, so that the day and time of hatching are determined by the interplay between the developmental state (temperature-sensitive) and the circadian clock (temperature-compensated), with the particular phasing being determined by the diurnal/nocturnal behavior of the species. (Author correspondence: javisan@um.es)     

Evening physical activity alters wrist temperature circadian rhythmicity

The adequate time to perform physical activity (PA) to maintain optimal circadian system health has not been defined. We studied the influence of morning and evening PA on circadian rhythmicity in 16 women with wrist temperature (WT). Participants performed controlled PA (45?min continuous-running) during 7 days in the morning (MPA) and evening (EPA) and results were compared with a no-exercise-week (C). EPA was characterized by a lower amplitude (evening: 0.028?±?0.01?°C versus control: 0.038?±?0.016?°C; p?<?0.05) less pronounced second-harmonic (power) (evening: 0.41?±?0.47 versus morning: 1.04?±?0.59); and achrophase delay (evening: 06:35?±?02:14?h versus morning: 04:51?±?01:11?h; p?<?0.05) as compared to MPA and C. Performing PA in the late evening might not be as beneficial as in the morning.     

EFFECTS OF AEROBIC EXERCISE ON THE CIRCADIAN RHYTHM OF HEART RATE AND BLOOD PRESSURE

Although the effects of aerobic exercise on resting heart rate, heart rate variability, and blood pressure have been investigated, there are scant data on the effects of aerobic exercise on the circadian rhythm of such cardiovascular parameters. In this study, we investigated the effects of aerobic exercise on the 24?h rhythm of heart rate and ambulatory blood pressure in the morning, when cardiovascular events are more common. Thirty-five healthy young subjects were randomized to control and aerobic exercise groups. Subjects in the latter group participated in their respective exercise program for two months, while those in the former group did not exercise. Twenty-four-hour electrocardiogram and ambulatory blood pressure monitoring data were obtained at baseline and at the end of the exercise intervention. The control group showed no changes, while the aerobic exercise group showed a significant decrease in heart rate (73.7?±?6.6?bpm to 69.5?±?5.1?bpm, p?<?0.005) and sympathetic activity such as LF/HF ratio (2.0?±?0.7 to 1.8?±?0.6, p?<?0.05) throughout the 24?h period, particularly in the daytime. The decrease in the heart rate was most prominent in the morning. However, heart rate and LF/HF ratio showed no statistical changes during the night. No significant changes were observed in blood pressure. These findings suggest aerobic exercise exerts beneficial effects on the circadian rhythm of heart rate, especially in the morning. (Author correspondence: hshio@kobe-u.ac.jp)     

Stability and Fragmentation of the Activity Rhythm Across the Sleep-Wake Cycle: The Importance of Age,Lifestyle, and Mental Health

The rhythms of activity across the 24-h sleep-wake cycle, determined in part by the circadian clock, change with aging. Few large-scale studies measured the activity rhythm objectively in the general population. The present population-based study in middle-aged and elderly persons evaluated how activity rhythms change with age, and additionally investigated sociodemographics, mental health, lifestyle, and sleep characteristics as determinants of rhythms of activity. Activity rhythms were measured objectively with actigraphy. Recordings of at least 96?h (138?±?14?h, mean?±?SD) were collected from 1734 people (age: 62?±?9.4?yrs) participating in the Rotterdam Study. Activity rhythms were quantified by calculating interdaily stability, i.e., the stability of the rhythm over days, and intradaily variability, i.e., the fragmentation of the rhythm relative to its 24-h amplitude. We assessed age, gender, presence of a partner, employment, cognitive functioning, depressive symptoms, body mass index (BMI), coffee use, alcohol use, and smoking as determinants. The results indicate that older age is associated with a more stable 24-h activity profile (β?=?0.07, p?=?0.02), but also with a more fragmented distribution of periods of activity and inactivity (β?=?0.20, p?<?0.001). Having more depressive symptoms was related to less stable (β?=??0.07, p?=?0.005) and more fragmented (β?=?0.10, p?<?0.001) rhythms. A high BMI and smoking were also associated with less stable rhythms (BMI: β?=??0.11, p?<?0.001; smoking: β?=??0.11, p?<?0.001) and more fragmented rhythms (BMI: β?=?0.09, p?<?0.001; smoking: β?=?0.11, p?<?0.001). We conclude that with older age the 24-h activity rhythm becomes more rigid, whereas the ability to maintain either an active or inactive state for a longer period of time is compromised. Both characteristics appear to be important for major health issues in old age.     

CARDIOVASCULAR RHYTHMS AND CARDIAC BAROREFLEX SENSITIVITY IN AT1A RECEPTOR GAIN-OF-FUNCTION MUTANT MICE

A mutant mouse expressing a gain-of-function of the AT_1A angiotensin II receptor was engineered to study the consequences of a constitutive activation of this receptor on blood pressure (BP). Cardiovascular rhythms and spontaneous cardiac baroreflex sensitivity (BRS) were evaluated using telemetric BP recordings of five transgenic (AT_1AMUT) and five wild (AT_1AWT) mice. The circadian rhythms were described with the Chronos-Fit program. The gain of the transfer function between systolic BP (SBP) and pulse intervals used to estimate the spontaneous BRS (ms/mmHg) was calculated in the low frequency (0.15–0.60?Hz) band. Transgenic AT_1AMUT exhibited higher BP and heart rate (HR) levels compared to controls (SBP AT_1AMUT 134.6?±?5.9?mmHg vs. AT_1AWT 110.5?±?5.9; p?<?0.05; HR AT_1AMUT 531.0?±?14.9 vs. AT_1AWT 454.8?±?5.4 beats/min; p?=?0.001). Spontaneous BRS was diminished in transgenic mice (AT_1AMUT 1.23?±?0.17?ms/mmHg vs. AT_1AWT 1.91?±?0.18?ms/mmHg; p?<?0.05). Motor activity did not differ between groups. These variables exhibited circadian changes, and the differences between the strains were maintained throughout the cycle. The highest values for BP, HR, and locomotor activity were observed at night. Spontaneous BRS varied in the opposite direction, with the lowest gain estimated when BP and HR were elevated (i.e., at night, when the animals were active). It is likely the BP elevation of the mutant mice results from the amplification of the effects of AngII at different sites. Future studies are necessary to explore whether AT_1A receptor activation at the central nervous system level effectively contributed to the observed differences. (Author correspondence: jean-luc.elghozi@nck.aphp.fr)     

Dim Light Melatonin Onset in Alcohol-Dependent Men and Women Compared with Healthy Controls

Sleep disturbances in alcohol-dependent (AD) individuals may persist despite abstinence from alcohol and can influence the course of the disorder. Although the mechanisms of sleep disturbances of AD are not well understood and some evidence suggests dysregulation of circadian rhythms, dim light melatonin onset (DLMO) has not previously been assessed in AD versus healthy control (HC) individuals in a sample that varied by sex and race. The authors assessed 52 AD participants (mean?±?SD age: 36.0?±?11.0 yrs of age, 10 women) who were 3–12 wks since their last drink (abstinence: 57.9?±?19.3 d) and 19 age- and sex-matched HCs (34.4?±?10.6 yrs, 5 women). Following a 23:00–06:00?h at-home sleep schedule for at least 5 d and screening/baseline nights in the sleep laboratory, participants underwent a 3-h extension of wakefulness (02:00?h bedtime) during which salivary melatonin samples were collected every 30?min beginning at 19:30?h. The time of DLMO was the primary measure of circadian physiology and was assessed with two commonly used methodologies. There was a slower rate of rise and lower maximal amplitude of the melatonin rhythm in the AD group. DLMO varied by the method used to derive it. Using 3 pg/mL as threshold, no significant differences were found between the AD and HC groups. Using 2 standard deviations above the mean of the first three samples, the DLMO in AD occurred significantly later, 21:02?±?00:41?h, than in HC, 20:44?±?00:21?h (t?=??2.4, p?=?.02). Although melatonin in the AD group appears to have a slower rate of rise, using well-established criteria to assess the salivary DLMO did not reveal differences between AD and HC participants. Only when capturing melatonin when it is already rising was DLMO found to be significantly delayed by a mean 18?min in AD participants. Future circadian analyses on alcoholics should account for these methodological caveats. (Author correspondence: daconroy@med.umich.edu)     

A comparison of the prognostic value of BNP versus NT-proBNP after hospitalisation for heart failure

Aims

Concentrations of circulating B?type natriuretic peptides provide important prognostic information in heart failure (HF) patients. We directly compared the prognostic performance of brain natriuretic peptide (BNP) versus N?terminal-proBNP (NT-proBNP) measurements in a large population of HF patients at hospital discharge after an admission for decompensated HF.

Methods and results

BNP and NT-proBNP were measured in 563 stable HF patients before discharge. All patients were followed for a fixed period of 18 months. The primary endpoint was time to first major event (HF hospitalisation or death).Patients were in NYHA class II (47%) or III/IV (53%) at discharge and the mean age of the patients was 71?±?11 years, 217 (39%) females, mean left ventricular ejection fraction was 0.32?±?0.14 and 234 (42%) had an ischaemic aetiology of HF. During the study, 236 patients (42%) reached the primary endpoint. Multivariate odds ratios of the primary endpoint for doubling of baseline levels of BNP and NT-proBNP were 1.46 (95% CI 1.19–1.80, p?<?0.001) and 1.45 (95% CI 1.18–1.78, p?<?0.001), respectively. The multivariable adjusted areas under the receiver-operating characteristic curve for prediction of the primary endpoint for doubling of BNP and NT-proBNP were 0.69 and 0.68, respectively. Direct comparison of the prognostic value of BNP and NT-proBNP did not reveal significant differences.

Conclusions

BNP and NT-proBNP at discharge for hospitalisation for HF are powerful, and equally strong and independent predictors of all-cause death and HF rehospitalisation.

     

Effect of sleep deprivation on rhythms of clock gene expression and melatonin in humans

This study investigated the impact of sleep deprivation on the human circadian system. Plasma melatonin and cortisol levels and leukocyte expression levels of 12 genes were examined over 48?h (sleep vs. no-sleep nights) in 12 young males (mean?±?SD: 23?±?5 yrs). During one night of total sleep deprivation, BMAL1 expression was suppressed, the heat shock gene HSPA1B expression was induced, and the amplitude of the melatonin rhythm increased, whereas other high-amplitude clock gene rhythms (e.g., PER1-3, REV-ERBα) remained unaffected. These data suggest that the core clock mechanism in peripheral oscillators is compromised during acute sleep deprivation.     

Comparative Antiapoptotic Effects of KB-R7943 and Ischemic Postconditioning During Myocardial Ischemia Reperfusion

We examined whether KB-R7943 reduced infarct size by attenuating apoptosis during reperfusion and also compared antiapoptotic effects of KB-R7943 and IPost. For this purpose, isolated rat hearts underwent 30-min global ischemia and 120-min reperfusion. Ischemic postconditioning (IPost) (n?=?15; three cycles of 10-s reperfusion/10-s ischemia or three cycles of 30-s reperfusion/30-s ischemia) and KB-R7943 (n?=?15; 1???M KB-R at the onset of reperfusion or before ischemia) were compared with controls (n?=?12; ischemia?Creperfusion only). Myocardial injury was determined by TTC staining, TUNEL assay and caspase-3 activity. AKT and eNOS phosphorylation were measured by immunoblotting. We found that IPost (10?s), Pre KB-R, and Reperf KB-R reduced infarct size (29?±?4.1, 35?±?5.0, 28.6?±?3.4?%, respectively, vs. controls 46?±?8.7?%; P?<?0.05) and attenuated cell apoptosis (TUNEL-positive cardiomyocyte nuclei) in the myocardium (P?<?0.01). Moreover, IPost (10?s), Pre KB-R and Reperf KB-R significantly decreased caspase-3 activation caused by myocardial ischemia?Creperfusion. However, IPost (30?s) did not show any effect on necrosis and apoptosis. Akt, eNOS phosphorylation, at 30?min of reperfusion/IPost-10?s was significantly higher than other groups. In conclusion, KB-R7943 was as effective as IPost in reducing necrosis and inhibiting apoptosis and it might be an ideal pharmacological agent to provide a more amenable approach to cardioprotection.     

PHASE RELATIONSHIP BETWEEN SKIN TEMPERATURE AND SLEEP-WAKE RHYTHMS IN WOMEN WITH VASCULAR DYSREGULATION AND CONTROLS UNDER REAL-LIFE CONDITIONS

The aim of the study was to investigate whether women with primary vascular dysregulation (VD; main symptoms of thermal discomfort with cold extremities) and difficulties initiating sleep (DIS) exhibit a disturbed phase of entrainment (Ψ) under everyday life conditions. The authors predicted a phase delay of the distal-proximal skin temperature gradient and salivary melatonin rhythms with respect to the sleep-wake cycle in women with VD and DIS (WVD) compared to controls (CON), similar to that found in their previous constant-routine laboratory data. A total of 41 young healthy women, 20 with WVD and 21 matched CON without VD and normal sleep onset latency (SOL), were investigated under ambulatory conditions (following their habitual bedtimes) during 7 days of continuous recording of skin temperatures, sleep-wake cycles monitored by actimetry and sleep-wake diaries, and single evening saliva collections for determining the circadian marker of dim light melatonin onset (DLMO). Compared to CON, WVD showed increased distal vasoconstriction at midday and in the evening, as indicated by lower distal (DIST; hands and feet) and foot-calf skin temperatures, and distal-proximal skin temperature gradients (p?<?.05). WVD manifested distal vasoconstriction before lights-off that also lasted longer after lights-off than in CON. In parallel, WVD exhibited a longer SOL (p?<?.05). To define internal phase-relationships, cross-correlation analyses were performed using diurnal rhythms of wrist activity and foot skin temperature. WVD showed a phase delay in foot skin temperature (CON versus WVD: 3.57?±?17.28?min versus 38.50?±?16.65?min; p?<?.05) but not in wrist activity. This finding was validated by additional within-subject cross-correlation analyses using the diurnal wrist activity pattern as reference. DLMO and habitual sleep times did not differ between CON and WVD. The authors conclude that WVD exhibit a phase delay of distal vasodilatation with respect to their habitual sleep-wake cycle and other circadian phase markers, such as DLMO. A full factorial design will have to show whether the finding is specific to primary vascular dysregualtion, to DIS, or to their interaction. (Author correspondence: Kurt.kraeuchi@upkbs.ch)     

Irregular 24-hour activity rhythms and the metabolic syndrome in older adults

Circadian rhythms – near 24?h intrinsic biological rhythms – modulate many aspects of human physiology and hence disruption of circadian rhythms may have an important impact on human health. Experimental work supports a potential link between irregular circadian rhythms and several key risk factors for cardiovascular disease including hypertension, obesity, diabetes and dyslipidemia, collectively termed the metabolic syndrome. While several epidemiological studies have demonstrated an association between shift-work and the components of the metabolic syndrome in working-age adults, there is a relative paucity of data concerning the impact of non-occupational circadian irregularity in older women and men. To address this question, we studied 7 days of actigraphic data from 1137 older woman and men participating in the Rush Memory and Aging Project, a community-based cohort study of the chronic conditions of aging. The regularity of activity rhythms was quantified using the nonparametric interdaily stability metric, and was related to the metabolic syndrome and its components obesity, hypertension, diabetes and dyslipidemia. More regular activity rhythms were associated with a lower odds of having the metabolic syndrome (OR?=?0.69, 95% CI?=?0.60–0.80, p?=?5.8?×?10^?7), being obese (OR?=?0.73, 95% CI?=?0.63–0.85, p?=?2.5?×?10^?5), diabetic (OR?=?0.76, 95% CI?=?0.65–0.90, p?=?9.3?×?10^?4), hypertensive (OR?=?0.78, 95% CI?=?0.66–0.91, p?=?2.0?×?10^?3) or dyslipidemic (OR?=?0.82, 95% CI?=?0.72–0.92, p?=?1.2?×?10^?3). These associations were independent of differences in objectively measured total daily physical activity or rest, and were not accounted for by prevalent coronary artery disease, stroke or peripheral artery disease. Moreover, more regular activity rhythms were associated with lower odds of having cardiovascular disease (OR?=?0.83; 95% CI?=?0.73–0.95, p?=?5.7?×?10^?3), an effect that was statistically mediated by the metabolic syndrome. We conclude that irregular activity rhythms are associated with several key components of the metabolic syndrome in older community-dwelling adults, and that the metabolic syndrome statistically partially mediates the association between activity rhythms and prevalent cardiovascular disease. Although additional longitudinal and experimental studies are needed to conclusively delineate the causal relationships underlying these associations, these findings are consistent with preclinical data, and add further support for investigations of the irregularity of activity rhythms as a potential therapeutic target to decrease the burden of cardiovascular disease in older adults.     

HABITUAL MODERATE ALCOHOL CONSUMPTION DESYNCHRONIZES CIRCADIAN PHYSIOLOGIC RHYTHMS AND AFFECTS REACTION-TIME PERFORMANCE

The authors studied longitudinally four healthy young adults to explore if habitual evening intake of a “moderate” amount of wine alters parameters, including period (τ) of circadian rhythms. Subjects, synchronized by diurnal activity from 07.30?h?±?60?min to 23.00?h?±?90?min and nocturnal rest, were studied during a continuous 22-day span: 11 days without alcohol (control) and 11 days with a glass (200?mL) of wine nightly at supper (alcohol). The amount of alcohol ingested with dinner ranged from 0.28 to 0.42?g/kg/24?h/participant and the estimated evening blood alcohol level ranged from 0.02 to 0.10?g/L/participant. Single reaction time (SRT; yellow light signal), three-choice reaction time (CRT) (red, green, and yellow signals) of both hands, related cumulated errors (c-errors), as well as oral temperature (OT) and grip strength (GS) were measured four to seven times/24?h. Time series were analyzed individually to quantify 24-h means (M), circadian τ (power spectra), and cosinor, and correlation, χ², and t tests were performed. The sleep-wake τ (actography) was 24?h in every subject for both conditions. With alcohol, all subjects showed an OT circadian τ shorter than the control one. The SRT circadian M was longer (poorer performance) with wine versus control in three subjects, while CRT was longer with wine versus control in only one subject. Correlation analyses also showed the detrimental effect of alcohol on the same variables. Number of days with <2 c-errors was predominant in control and decreased with alcohol, especially for SRT. The desynchronization of the 10 different documented rhythms was greater with alcohol with reference to control in two of the four studied subjects. This work shows that habitual "moderate" wine drinking at supper reduces the performance of subjects, increases the level of c-errors/24?h, especially for SRT, suggesting a “moderate” amount of alcohol has the potential to increase accident risk, and it can also desynchronize circadian time organization. (Author correspondence: bergarein@yahoo.fr)     

FREE-RUNNING RHYTHMS OF COCAINE SELF-ADMINISTRATION IN RATS HELD UNDER CONSTANT LIGHTING CONDITIONS

Using a discrete trials (DT) procedure, we have previously shown that rats exhibit variations in their pattern of cocaine self-administration relative to the time-of-day, often producing a daily rhythm of intake in which the majority of infusions occur during the dark phase of the 24?h light-dark cycle. We have sought to determine if cocaine self-administration demonstrates free-running circadian characteristics under constant-lighting conditions in the absence of external environmental cues. Rats self-administering cocaine (1.5?mg/kg/infusion) under a DT3 procedure (three trials/h) were kept in constant-dim (<2 lux, DIM) conditions, and the pattern of intake was analyzed for free-running behavior. We show that cocaine self-administration has a period length (τ) of 24.14?±?0.07?h in standard 12?h light:12?h dark conditions, which is maintained for at least five days in constant-dim conditions. With longer duration DIM exposure, cocaine self-administration free-runs with a τ of approximately 24.92?±?0.16?h. Exposure to constant-light conditions (1000 lux, LL) lengthened τ to 26.46?±?0.23?h; this was accompanied by a significant decrease in total cocaine self-administered during each period. The pattern of cocaine self-administration, at the dose and availability used in this experiment, is circadian and is likely generated by an endogenous central oscillator. The DT procedure is therefore a useful model to examine the substrates underlying the relationship between circadian rhythms and cocaine intake. (Author correspondence: cbass@wfubmc.edu)     

Seasonal changes in entrainment cues for the circadian rhythm of the supratidal amphipod Talorchestia longicornis

The supratidal amphipod Talorchestia longicornis Say has a circadian rhythm in activity, in which it is active on the substrate surface at night and inactive in burrows during the day. The present study determined: (1) the circadian rhythms in individual versus groups of amphipods; (2) the range of temperature cycles that entrain the circadian rhythm; (3) entrainment by high-temperature cycles versus light?:?dark cycles, and (4) seasonal substrate temperature cycles. The circadian rhythm was determined by monitoring temporal changes in surface activity using a video system. Individual and groups of amphipods have similar circadian rhythms. Entrainment occurred only to temperature cycles that included temperatures below 20°C (10–20, 15–20, 17–19, 15–25°C) but not to temperatures above 20°C (20–25, 20–30°C), and required only a 2°C temperature cycle (17–19°C). Diel substrate temperatures were above 20°C in the summer and below 20°C during the winter. Upon simultaneous exposure to a diel high-temperature cycle (20–30°C) and a light?:?dark cycle phased differently, amphipods entrained to the light?:?dark cycle. Past studies found that a temperature cycle below 20°C overrode the light?:?dark cycle for entrainment. The functional significance of this change in entrainment cues may be that while buried during the winter, the activity rhythm remains in phase with the day?:?night cycle by the substrate temperature cycles. During the summer, T. longicornis switches to the light?:?dark cycle for entrainment, perhaps as a mechanism to phase activity precisely to the short summer nights.     

Letter from the President: Expectations and Needs of Members of the International Society of Chronobiology

The focus of the reported work is investigation of disopyramide chronopharmacokinetics in the mouse. Different groups of male NMRI mice maintained under controlled environmental conditions (LD: 0600-1800) received a single intraperitoneal injection of disopyramide (30mg per kg of body weight) at one of four different fixed time points of a 24-h period, i.e. 1000, 1600, 2200 or 0400. Blood samples were taken 0.5,1,2,3,4 and 6 hr after drug administration and total and free plasma levels of disopyramide were measured by an immunoenzymatic method.

Our data showed statistically significant circadian rhythms in the following pharmacokinetic parameters: highest volume of distribution = 3.91 ± 0.211kg^?1 at 2200 (circadian amplitude, half the peak-to-trough difference relative to the 24-hr mean multiplied by 100, is 34%); highest area under concentration curves = 16.06 ± 1.03μgml^?1hr^?1 at 0400 (circadian amplitude = 43%) and highest clearance = 3.04 ± 0.191hr“kg”¹ at 2200 (circadian amplitude = 21%). Protein binding of the drug was shown to ^he circadian time dependent. Alpha and beta phase elimination half-lives were not found to be significantly circadian phase-dependent. Thus circadian changes in disopyramide clearance may represent circadian changes in the drug's volume of distribution.     

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.