Wrist skin temperature, motor activity, and body position as determinants of the circadian pattern of blood pressure

Although the circadian blood pressure (BP) pattern has been extensively studied, the determinants of this rhythm are not fully understood. Peripheral vasodilatation is a regulatory mechanism for BP maintenance. However, it remains to be established whether the increase of nocturnal distal skin temperature associated with heat loss could also reflect the dipping status. For the first time, this paper investigates the relationship between BP and skin wrist temperature (WT), to evaluate whether the WT circadian rhythm can serve as screening procedure to detect dipping/non-dipping BP patterns. In addition, the authors compare the relationship between WT and other variables previously described as determinants of the BP pattern, such as physical activity and body position. Measurements of WT, motor activity, and body position for 5 d, plus ambulatory BP for 24-h during that span, were obtained from 28 diurnally active normotensive volunteers. WT was negatively correlated, whereas activity and body position were positively correlated, with systolic and diastolic BPs. However, these relationships were stronger during the rest than activity phase. In addition, a 78.6% concordance was detected between the observed dips in BP and the predicted BP pattern calculated based on the WT rhythm. Thus, these results suggest that the increase in WT produced by heat loss during the rest phase through peripheral skin blood vessels is the result of blood vessel vasodilatation reflexes in response to a shift from a standing to a supine position, together with shift in the circadian sympathetic/parasympathetic balance (nocturnal parasympathetic activation). In conclusion, WT could be considered as a potential new screening procedure to implement the diagnosis of non-dipping BP pattern.     

Crosstalk Between Environmental Light and Internal Time in Humans

Daily exposure to environmental light is the most important zeitgeber in humans, and all studied characteristics of light pattern (timing, intensity, rate of change, duration, and spectrum) influence the circadian system. However, and due to lack of current studies on environmental light exposure and its influence on the circadian system, the aim of this work is to determine the characteristics of a naturalistic regimen of light exposure and its relationship with the functioning of the human circadian system. Eighty-eight undergraduate students (18–23 yrs) were recruited in Murcia, Spain (latitude 38°01′N) to record wrist temperature (WT), light exposure, and sleep for 1 wk under free-living conditions. Light-exposure timing, rate of change, regularity, intensity, and contrast were calculated, and their effects on the sleep pattern and WT rhythm were then analyzed. In general, higher values for interdaily stability, relative amplitude, mean morning light, and light quality index (LQI) correlated with higher interdaily stability and relative amplitude, and phase advance in sleep plus greater stability in WT and phase advance of the WT circadian rhythm. On the other hand, a higher fragmentation of the light-exposure rhythm was associated with more fragmented sleep. Naturalistic studies using 24-h ambulatory light monitoring provide essential information about the main circadian system input, necessary for maintaining healthy circadian tuning. Correcting light-exposure patterns accordingly may help prevent or even reverse health problems associated with circadian disruption. (Author correspondence: angerol@um.es)     

INTERNAL TEMPORAL ORDER IN THE CIRCADIAN SYSTEM OF A DUAL-PHASING RODENT,THE OCTODON DEGUS

Daily rhythms in different biochemical and hematological variables have been widely described in either diurnal or nocturnal species, but so far no studies in the rhythms of these variables have been conducted in a dual-phasing species such as the degus. The Octodon degus is a rodent that has the ability to switch from diurnal to nocturnal activity under laboratory conditions in response to wheel-running availability. This species may help us discover whether a complete temporal order inversion occurs parallel to the inversion that has been observed in this rodent's activity pattern. The aim of the present study is to determine the phase relationships among 26 variables, including behavioral, physiological, biochemical, and hematological variables, during the day and at night, in diurnal and nocturnal degus chronotypes induced under controlled laboratory conditions through the availability of wheel running. A total of 39 male degus were individually housed under a 12:12 light-dark (LD) cycle, with free wheel-running access. Wheel-running activity (WRA) and body temperature (Tb) rhythms were recorded throughout the experiment. Melatonin, hematological, and biochemical variables were determined by means of blood samples obtained every 6?h (ZT1, ZT7, ZT13, and ZT19). In spite of great differences in WRA and Tb rhythms between nocturnal and diurnal degus, no such differences were observed in the temporal patterns of most of the biological variables analyzed for the two chronotypes. Variation was only found in plasma urea level and lymphocyte number. A slight delay in the phase of the melatonin rhythm was also observed. This study shows the internal temporal order of a dual-phasing mammal does not show a complete inversion in accordance with its activity and body temperature pattern; it would appear that the switching mechanism involved in the degu's nocturnalism is located downstream from the pacemaker. (Author correspondence: angerol@um.es).     

DISSOCIATION OF THE CIRCADIAN SYSTEM OF OCTODON DEGUS BY T28 AND T21 LIGHT-DARK CYCLES

Octodon degus is a primarily diurnal rodent that presents great variation in its circadian chronotypes due to the interaction between two phase angles of entrainment, diurnal and nocturnal, and the graded masking effects of environmental light and temperature. The aim of this study was to test whether the circadian system of this diurnal rodent can be internally dissociated by imposing cycles shorter and longer than 24?h, and to determine the influence of degus chronotypes and wheel-running availability on such dissociation. To this end, wheel-running activity and body temperature rhythms were studied in degus subjected to symmetrical light-dark (LD) cycles of T28h and T21h. The results show that both T-cycles dissociate the degus circadian system in two different components: one light-dependent component (LDC) that is influenced by the presence of light, and a second non–light-dependent component (NLDC) that free-runs with a period different from the external lighting cycle. The LDC was more evident in the nocturnal than diurnal chronotype, and also when wheel running was available. Our results show that, in addition to rats and mice, degus must be added to the list of species that show an internal dissociation in their circadian rhythms when exposed to forced desynchronization protocols. The existence of a multioscillatory circadian system having two groups of oscillators with low coupling strength may explain the flexibility of degus chronotypes. (Author correspondence: angerol@um.es)     

Duration Until Nighttime Blood Pressure Fall Indicates Excess Sodium Retention

Impaired renal sodium excretion causes sodium retention, which prevents the nocturnal dip in blood pressure (BP); thus, high BP persists until excess sodium is excreted. The authors defined “dipping time” (DT) as the duration until the nocturnal BP falls below 90% of the daytime average. Diuretic (e.g., hydrochlorothiazide [HCTZ]) and angiotensin receptor blocker (ARB) are able to eliminate sodium retention and restore the non-dipper BP rhythm. Reanalysis of two previous studies demonstrate that HCTZ and ARB shortened the DT. Shortening DT correlated directly with the increase in daytime urinary sodium excretion (Study 2). DT can be used as a preliminary indicator of sodium retention. (Author correspondence: m-fukuda@med.nagoya-cu.ac.jp)     

CIRCADIAN PATTERN OF AMBULATORY BLOOD PRESSURE IN UNTREATED HYPERTENSIVE PATIENTS WITH AND WITHOUT METABOLIC SYNDROME

There is a strong association between metabolic syndrome (MS) and increased risk of end-organ damage, cardiovascular disease, stroke, and cardiovascular mortality. Moreover, non-dipping (<?10% decline in the asleep relative to the awake blood pressure [BP] mean) and elevated ambulatory pulse pressure (PP), among other factors related to the circadian BP pattern, have also been associated with increased cardiovascular morbidity and mortality. This cross-sectional study investigated the circadian BP pattern in 2,045 non-diabetic untreated patients with uncomplicated essential hypertension (941 men/1,099 women), 48.7?±?11.9 yrs of age, classified by the presence or absence of MS. BP was measured by ambulatory monitoring for 48 consecutive hours to substantiate reproducibility of the dipping pattern. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately calculate mean BP when awake and asleep for each subject. MS was present in 40.7% of the patients. Patients with MS were characterized by a significantly higher 24?h mean of systolic BP and a lower diastolic BP compared to patients without MS. Accordingly, ambulatory PP was significantly elevated the entire 24?h in MS patients. The prevalence of an altered non-dipper BP profile was significantly higher in MS patients (48.4 vs. 36.1% in patients without MS, p?<?0.001). MS patients were characterized, among other risk factors, by significantly higher uric acid, fibrinogen, leukocyte count, hemoglobin and globular sedimentation velocity, plus lower estimated glomerular filtration rate. Apart from corroborating the significant increased prevalence of a blunted nocturnal BP decline in MS, this study documents ambulatory PP is higher in MS, without differences between groups in mean arterial pressure. This elevated PP might reflect increased arterial stiffness in MS. MS patients were also characterized by elevated values of relevant markers of cardiovascular risk, including fibrinogen and globular sedimentation velocity. These collective findings indicate that MS should be included among the clinical situations in which ambulatory BP monitoring is recommended. (Author correspondence: rhermida@uvigo.es)     

Seasonal Variation of Temporal Niche in Wild Owl Monkeys (Aotus azarai azarai) of the Argentinean Chaco: A Matter of Masking?

Among the more than 40 genera of anthropoid primates (monkeys, apes, and humans), only the South American owl monkeys, genus Aotus, are nocturnal. However, the southernmostly distributed species, Aotus azarai azarai, of the Gran Chaco may show considerable amounts of its 24-h activity during bright daylight. Due to seasonal changes in the duration of photophase and climatic parameters in their subtropical habitat, the timing and pattern of their daily activity are expected to show significant seasonal variation. By quantitative long-term activity recordings with Actiwatch AW4 accelerometer data logger devices of 10 wild owl monkeys inhabiting a gallery forest in Formosa, Argentina, the authors analyzed the seasonal variation in the temporal niche and activity pattern resulting from entrainment and masking of the circadian activity rhythm by seasonally and diurnally varying environmental factors. The owl monkeys always displayed a distinct bimodal activity pattern, with prominent activity bouts and peaks during dusk and dawn. Their activity rhythm showed distinct lunar and seasonal variations in the timing and daily pattern. During the summer, the monkeys showed predominantly crepuscular/nocturnal behavior, and a crepuscular/cathemeral activity pattern with similar diurnal and nocturnal activity levels during the cold winter months. The peak times of the evening and morning activity bouts were more closely related to the times of sunset and sunrise, respectively, than activity-onset and -offset. Obviously, they were better circadian markers for the phase position of the entrained activity rhythm than activity-onset and -offset, which were subject to more masking effects of environmental and/or internal factors. Total daily activity was lowest during the two coldest lunar months, and almost twice as high during the warmest months. Nighttime (21:00–06:00?h) and daytime (09:00–18:00?h) activity varied significantly across the year, but in an opposite manner. Highest nighttime activity occurred in summer and maximal daytime activity during the cold winter months. Dusk and dawn activity, which together accounted for 43% of the total daily activity, barely changed. The monkeys tended to terminate their nightly activity period earlier on warm and rainy days, whereas the daily amount of activity showed no significant correlation either with temperature or precipitation. These data are consistent with the dual-oscillator hypothesis of circadian regulation. They suggest the seasonal variations of the timing and pattern of daily activity in wild owl monkeys of the Argentinean Chaco result from a specific interplay of light entrainment of circadian rhythmicity and strong masking effects of various endogenous and environmental factors. Since the phase position of the monkeys' evening and morning activity peaks did not vary considerably over the year, the seasonal change from a crepuscular/nocturnal activity pattern in summer to a more crepuscular/cathemeral one in winter does not depend on a corresponding phase shift of the entrained circadian rhythm, but mainly on masking effects. Thermoregulatory and energetic demands and constraints seem to play a crucial role. (Author correspondence: hans.erkert@t-online.de)     

Administration-Time Differences in Effects of Hypertension Medications on Ambulatory Blood Pressure Regulation

Specific features of the 24-h blood pressure (BP) pattern are linked to progressive injury of target tissues and risk of cardiovascular disease (CVD) events. Several studies have consistently shown an association between blunted asleep BP decline and risk of fatal and nonfatal CVD events. Thus, there is growing focus on ways to properly control BP during nighttime sleep as well as during daytime activity. One strategy, termed chronotherapy, entails the timing of hypertension medications to endogenous circadian rhythm determinants of the 24-h BP pattern. Significant and clinically meaningful treatment-time differences in the beneficial and/or adverse effects of at least six different classes of hypertension medications, and their combinations, are now known. Generally, calcium channel blockers (CCBs) are more effective with bedtime than morning dosing, and for dihydropyridine derivatives bedtime dosing significantly reduces risk of peripheral edema. The renin-angiotensin-aldosterone system is highly circadian rhythmic and activates during nighttime sleep. Accordingly, evening/bedtime ingestion of the angiotensin-converting enzyme inhibitors (ACEIs) benazepril, captopril, enalapril, lisinopril, perindopril, quinapril, ramipril, spirapril, trandolapril, and zofenopril exerts more marked effect on the asleep than awake systolic (SBP) and diastolic (DBP) BP means. Likewise, the bedtime, in comparison with morning, ingestion schedule of the angiotensin-II receptor blockers (ARBs irbesartan, olmesartan, telmisartan, and valsartan exerts greater therapeutic effect on asleep BP, plus significant increase in the sleep-time relative BP decline, with the additional benefit, independent of drug terminal half-life, of converting the 24-h BP profile into a more normal dipping pattern. This is the case also for the bedtime versus upon-awakening regimen of combination ARB-CCB, ACEI-CCB, and ARB-diuretic medications. The chronotherapy of conventional hypertension medications constitutes a new and cost-effective strategy for enhancing the control of daytime and nighttime SBP and DBP levels, normalizing the dipping status of their 24-h patterning, and potentially reducing the risk of CVD events and end-organ injury, for example, of the blood vessels and tissues of the heart, brain, kidney, and retina. (Author correspondence: rhermida@uvigo.es)     

DO RESTLESS LEGS SYNDROME (RLS) AND PERIODIC LIMB MOVEMENTS OF SLEEP (PLMS) PLAY A ROLE IN NOCTURNAL HYPERTENSION AND INCREASED CARDIOVASCULAR RISK OF RENALLY IMPAIRED PATIENTS?

Hypertension can cause or promote renal failure and is related to cardiovascular mortality, the major cause of death in patients with renal impairment. Changes in the circadian BP pattern, particularly the blunting or reversal of the nocturnal decline in BP, are common in chronic renal failure. These changes in turn are among the major determinants of left ventricular hypertrophy. Using a chronobiological approach, it is possible to obtain better insight into the reciprocal relationship between hypertension, renal disease, and increased cardiovascular risk of renal patients. Disruption of the normal circadian rhythm of rest/activity may be hypothesized to underlie the high cardiovascular morbidity and mortality of such patients. Epidemiological studies reveal that hemodialysis patients experience poor subjective sleep quality and insomnia and, in comparison to healthy persons, are more likely to show shorter sleep duration and lower sleep efficiency. Sleep apnea may be present and is usually investigated in these patients; however, the prevalence of restless legs syndrome (RLS), which is high in dialysis patients and which has been associated with increased risk for cardiovascular disease in the general population, could also play a role in the pathogenesis of sleep-time hypertension in renal patients. Careful assessment of sleep quality, in particular, diagnostic screening for RLS and periodic limb movements (PLM) in renal patients, is highly recommended. In renal failure, attention to sleep quality and related perturbations of the sleep/wake cycle may help prevent the occurrence and progression of cardiovascular disease. (Author correspondence: prf@unife.it)     

Cardiovascular-Sleep Interaction in Drug-Naïve Patients With Essential Grade I Hypertension

Lack of nighttime blood pressure (BP) reduction by 10–20% from the mean daytime values (dipping) has been described as a distinguishing feature of essential hypertension and associated, also in normotensive subjects, with increased cardiovascular (CV) risk. Mechanisms involved in the loss of the nocturnal dip are still unclear, but involvement of autonomic nervous system (ANS) activity probably plays a crucial role. Sleep is fundamental in modulating ANS activity to maintain the physiological BP circadian rhythm, and for this reason its integrity has been widely investigated in hypertension. We investigated, under controlled conditions, the autonomic control of the CV system through an autonomic reflex screen in the awake condition and by assessment of circadian rhythm–, day-night-, time-, and state-dependent changes of BP and heart rate (HR) and associated sleep parameters in patients with a recent (≤1 yr) diagnosis of essential grade I hypertension naïve of therapy. Fourteen hypertensive patients (6 males, age: 43?±?11 yrs; body mass index [BMI]: 24?±?3?kg/m²) were compared with 28 healthy controls matched for sex, age, BMI (2 controls/patient) for cardiovascular reflex and to 8 different subjects from previous controls (6 males), comparable for age and BMI, for the day-night and nighttime CV profiles during two consecutive nights. The cardiovascular reflex screen data showed increased sympathetic effect in hypertensive patients, represented by higher overshoot of BP after Valsalva maneuver. Nighttime sleep architecture during the dark period in terms of duration, representation of sleep stages, sleep fragmentation, and incidence of arousals—periodic limb movements in sleep (PLMS) and PLMS arousals—was similar in patients and controls. Hypertensive patients displayed higher 24-h BP and HR values, but their sleep-related BP decrease was significantly reduced compared with controls. The circadian rhythms of BP and HR were intact and similar in patients and controls, coupling with the expected physiological peak time. BP and HR showed normal state-dependent modulation in hypertensive patients that, however, was higher in all sleep stages compared with controls. The lowering of systolic blood pressure (SBP) during non–rapid eye movement (NREM) sleep stages 1 and 2 and REM sleep, relative to daytime wake values, was significantly attenuated in the hypertensive group, whereas it was comparable to controls during slow-wave sleep. In hypertensive patients, analysis of sleep and CV parameters in the 90?min following sleep onset and preceding morning awakening showed normal depressor effect during the first part of the night after sleep onset and significantly higher BP rise in the hours preceding morning awakening. These findings were associated with comparable sleep architecture, sleep fragmentation, incidence of arousals, and PLMS and PLMS arousals in patients and controls. Our data suggest that drug-naïve essential grade I hypertension is associated with signs of increased vascular sympathetic response to standardized stress of the Valsalva maneuver during the awake condition, and during sleep with a non-dipping BP profile plus higher BP surge preceding morning awakening, assessable only by around-the-clock ambulatory BP monitoring, both representing additional CV risk already in early-stage hypertension and, therefore, requiring proper selection of pharmacological treatment. (Author correspondence: pietro.cortelli@unibo.it)     

PACEMAKER PHASE CONTROL VERSUS MASKING BY LIGHT: SETTING THE CIRCADIAN CHRONOTYPE IN DUAL OCTODON DEGUS

There are two main processes involved in the expression of circadian rhythmicity: entrainment and masking. Whereas the first operates via the central pacemaker to anticipate predictable environmental conditions, masking (mainly induced by light) functions as a direct modulator of the circadian output signal induced by nonpredictable events. The Chilean rodent Octodon degus presents both diurnal and nocturnal chronotypes when given free access to an exercise wheel. Two steady-entrainment phases and graded masking by light seem to generate the wide variability of chronotypes in this species. The aim of this study was to characterize the differential masking by light according to the individual chronotypes, their stability over time, and the influence of wheel running availability and ambient temperature upon the degus' nocturnality. To this end, diurnal and nocturnal degus were subjected to ultradian cycles (1:1-h light-dark [LD]), with and without wheel running availability, and under both normal and high diurnal ambient temperature cycles. The present results show that diurnal and nocturnal degus present a stable masking by light, each according to its respective chronotype. Thus, whereas diurnal animals increased their activity with light, in nocturnal degus light induced a sharp drop in wheel running activity. These two types of masking responses appeared not only when the animals were synchronized to the 12:12-h LD cycle, but also under ultradian cycles. Different masking effects persisted when wheel running was made unavailable and when the animals shifted their circadian activity patterns in response to ultradian cycles or to diurnal exposure to high temperatures. In conclusion, our results show that the positive and negative masking effects of light on diurnal and nocturnal degus, respectively, seem to occur independently of relative phase control by the central pacemaker or the negative masking induced by high environmental temperatures. (Author correspondence: angerol@um.es)     

Mice Show Circadian Rhythms of Blood Pressure During Each Wake-Sleep State

A daily rhythm of blood pressure (BP), with maximum values in the activity period, carries important prognostic information. The extent to which this rhythm depends on behavioral factors remains debated. Mice are the species of choice for functional genomics. In mice, episodes of wakefulness and sleep are not restricted to particular daily periods, allowing BP in each wake-sleep state to be measured at each time of day. The aim of this study was to investigate whether a circadian rhythm of BP is manifest in each wake-sleep state in mice. Mice with B6 genetic background (n?=?26) were implanted with a telemetric BP transducer and electrodes to discriminate wake-sleep states and recorded while housed under a 12:12?h light-dark period. For each mouse, 8 values of BP were obtained in each wake-sleep state (wakefulness, non-rapid-eye-movement sleep, and rapid-eye-movement sleep) by averaging over successive 3-h time bins. Analysis of variance evidenced a significant time effect in each wake-sleep state as well as a significant wake-sleep state?×?time interaction effect. In an additional group of mice (n?=?3) recorded in constant darkness, the Lomb-Scargle periodogram also revealed a significant circadian rhythm of BP in each wake-sleep state. These findings demonstrate that during each wake-sleep state, mice show daily and circadian rhythms of BP in conditions of entrainment to the light-dark cycle and in free-running conditions of constant darkness, respectively. (Author correspondence: giovanna.zoccoli@unibo.it)     

Evidence for a Plastic Dual Circadian Rhythm in the Oyster Crassostrea gigas

Although a significant body of literature has been devoted to the chronobiology of aquatic animals, how biological rhythms function in molluscan bivalves has been poorly studied. The first objective of this study was to determine whether an endogenous circadian rhythm does exist in the oyster, Crassostrea gigas. The second objective was to characterize it in terms of robustness. To answer these questions, the valve activity of 15 oysters was continuously recorded for 2 mo in the laboratory under different entrainment and free-running regimes using a high-frequency noninvasive valvometer. The present work demonstrates the presence of a circadian rhythm in the oyster Crassostrea gigas. First, oysters were entrained by 12?L:12 D conditions. Then, free-running conditions (D:D and L:L) indicated that the most frequently observed period ranged from 20 to 28?h, the circadian range. That endogenous circadian rhythm was characterized as weak. Indeed, the period (τ) of the individual animals exhibited high plasticity in D:D and L:L, and the animals immediately followed a 4-h phase advance or delay. Additionally, C. gigas appeared as a dual organism: all oysters were nocturnal at the beginning of the laboratory experiment (January), whereas they were diurnal at the end (March). That shift was progressive. Comparison with a full-year in situ record showed the same behavioral duality as observed in the laboratory: the animals were nocturnal in autumn–winter and diurnal in spring–summer. The significant advantage of a plastic and dual circadian rhythm in terms of adaptability in a highly changing environment is discussed. (Author correspondence: d.tran@epoc.u-bordeaux1.fr)     

The Effects of Thoracic and Cervical Spinal Cord Lesions on the Circadian Rhythm of Core Body Temperature

Individuals with a spinal cord injury (SCI) have compromised afferent and efferent information below the lesion. Intact afferent information regarding skin temperature and the ability to regulate skin blood flow lead to an altered heat balance, which may impact the circadian variation in core body temperature (Tcore) and sleep-wake cycle. The authors assessed the circadian variation of Tcore in SCI individuals and able-bodied controls matched for the timing of the sleep-wake cycle. The authors examined subjects who had a high (cervical) or a low (thoracic) lesion. Intestinal Tcore (telemetry system) and physical activity (ambulatory activity monitor) levels were measured continuously and simultaneously in 8 tetraplegics, 7 paraplegics, and 8 able-bodied controls during one 24-h period of “normal” living. The regression slope between activity and Tcore was also calculated for each 2-h bin. Circadian rhythm parameters were estimated with partial Fourier time-series analysis, and groups were compared with general linear models, adjusted for the influence of individual wake-time. The (mean?±?SD) dominant period length for controls, paraplegics, and tetraplegics were 24.4?±?5.4?h, 22.5?±?5.0?h, and 16.5?±?5.1?h, respectively (p?=?.02). A significantly more pronounced 8-h harmonic was found for the variation in Tcore of SCI individuals (p = .05). Tetraplegics showed the highest nocturnal mean Tcore (p = .005), a 5-h phase-advanced circadian trough time (p = .04), and more variable relationships between physical activity and Tcore (p = .03). Taken together, tetraplegics demonstrate a pronounced disturbance of the circadian variation of Tcore, whereas the variation of Tcore in paraplegics was comparable to able-bodied controls. (Author correspondence: D.Thijssen@fysiol.umcn.nl)     

Uncovering Different Masking Factors on Wrist Skin Temperature Rhythm in Free-Living Subjects

Most circadian rhythms are controlled by a major pacemaker located in the hypothalamic suprachiasmatic nucleus. Some of these rhythms, called marker rhythms, serve to characterize the timing of the internal temporal order. However, these variables are susceptible to masking effects as the result of activity, body position, light exposure, environmental temperature and sleep. Recently, wrist skin temperature (WT) has been proposed as a new index for evaluating circadian system status. In light of previous evidence suggesting the important relationship between WT and core body temperature regulation, the aim of this work was to purify the WT pattern in order to obtain its endogenous rhythm with the application of multiple demasking procedures. To this end, 103 subjects (18–24 years old) were recruited and their WT, activity, body position, light exposure, environmental temperature and sleep were recorded under free-living conditions for 1 week. WT demasking by categories or intercepts was applied to simulate a “constant routine” protocol (awakening, dim light, recumbent position, low activity and warm environmental temperature). Although the overall circadian pattern of WT was similar regardless of the masking effects, its amplitude was the rhythmic parameter most affected by environmental conditions. The acrophase and mesor were determined to be the most robust parameters for characterizing this rhythm. In addition, a circadian modulation of the masking effect was found for each masking variable. WT rhythm exhibits a strong endogenous component, despite the existence of multiple external influences. This was evidenced by simultaneously eliminating the influence of activity, body position, light exposure, environmental temperature and sleep. We therefore propose that it could be considered a valuable and minimally-invasive means of recording circadian physiology in ambulatory conditions.     

PLASMA LEVELS OF INTERFERON-γ CORRELATE WITH AGE-RELATED DISTURBANCES OF CIRCADIAN RHYTHMS AND SURVIVAL IN A NON-HUMAN PRIMATE

Aging can be associated with changes in circadian rhythms and reduction in adaptive immune responses accompanied by expansion of memory T cells and elevated levels of pro-inflammatory cytokines. Recent findings suggest the cytokine interferon-γ (IFN-γ) can affect the function of the hypothalamic suprachiasmatic nucleus (SCN), the master mammalian circadian pacemaker, both in vitro and in vivo. We studied the correlation of plasma levels of IFN-γ and changes in circadian rhythms in a non-human primate species, the nocturnal mouse lemur (Microcebus murinus). Plasma IFN-γ and dehydroepiandrosterone sulfate (DHEA-S), a known biomarker of aging, were determined in middle- to old-age animals by immunoenzymoassay. Daily rhythms of locomotor activity and body temperature as well as survival time of the lemurs were recorded. With aging, mean levels of DHEA-S decreased whereas IFN-γ increased. Aged animals showed biological rhythm alterations characterized by a high percentage of diurnal activity, anticipation of the activity onset relative to lights-off, short free-running period, and delayed occurrence of minimal body temperature. The magnitude of these disturbances was correlated with the plasma level of IFN-γ but not DHEA-S. Most remarkably, in contrast to DHEA-S, increased levels of IFN-γ correlated with duration of the lifetime of the lemurs. These results show the degree of circadian rhythm alterations in an individual is correlated with plasma IFN-γ level during aging, and that plasma IFN-γ level may predict survival, at least in this non-human primate. (Author correspondence: fabienne.aujard@wanadoo.fr)     

INFLUENCE OF CIRCADIAN TIME OF HYPERTENSION TREATMENT ON CARDIOVASCULAR RISK: RESULTS OF THE MAPEC STUDY

Clinical studies have documented morning-evening, administration-time differences of several different classes of hypertension medications in blood pressure (BP)-lowering efficacy, duration of action, safety profile, and/or effects on the circadian BP pattern. In spite of these published findings, most hypertensive subjects, including those under combination therapy, are instructed by their physicians and pharmacists to ingest all of their BP-lowering medications in the morning. The potential differential reduction of cardiovascular (CVD) morbidity and mortality risk by a bedtime versus upon-awakening treatment schedule has never been evaluated prospectively. The prospective MAPEC study was specifically designed to test the hypothesis that bedtime chronotherapy with ≥1 hypertension medications exerts better BP control and CVD risk reduction than conventional therapy, i.e., all medications ingested in the morning. A total of 2156 hypertensive subjects, 1044 men/1112 women, 55.6?±?13.6 (mean?±?SD) yrs of age, were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. At baseline, BP was measured at 20-min intervals from 07:00 to 23:00?h and at 30-min intervals at night for 48?h. Physical activity was simultaneously monitored every min by wrist actigraphy to accurately determine the beginning and end of daytime activity and nocturnal sleep. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Despite lack of differences in ambulatory BP between groups at baseline, subjects ingesting medication at bedtime showed at their last available evaluation significantly lower mean sleep-time BP, higher sleep-time relative BP decline, reduced prevalence of non-dipping (34% versus 62%; p?<?.001), and higher prevalence of controlled ambulatory BP (62% versus 53%; p?<?.001). After a median follow-up of 5.6 yrs, subjects ingesting ≥1 BP-lowering medications at bedtime exhibited a significantly lower relative risk of total CVD events than those ingesting all medications upon awakening (0.39 [0.29–0.51]; number of events 187 versus 68; p?<?.001). The difference between the treatment-time groups in the relative risk of major events (including CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also highly statistically significant (0.33 [0.19–0.55]; number of events: 55 versus 18; p?<?.001). The progressive decrease in asleep BP and increase in sleep-time relative BP decline towards a more normal dipping pattern, two novel therapeutic targets requiring proper patient evaluation by ambulatory BP, were best achieved with bedtime therapy, and they were the most significant predictors of event-free survival. Bedtime chronotherapy with ≥1 BP-lowering medications, compared to conventional upon-waking treatment with all medications, more effectively improved BP control, better decreased the prevalence of non-dipping, and, most importantly, significantly reduced CVD morbidity and mortality. (Author correspondence: rhermida@uvigo.es)     

PERSPECTIVES ON THE CHRONOTHERAPY OF HYPERTENSION BASED ON THE RESULTS OF THE MAPEC STUDY

Appreciation of chronotherapy in hypertension continues to lag, despite clear demonstrations by many studies of (i) clinically relevant dosing-time differences of the beneficial and adverse effects of most blood pressure (BP) medications and (ii) significant association between reduced sleep-time BP decline of non-dippers and their heightened risk of cardiovascular disease (CVD). The Syst-Eur and HOPE outcome trials showed evening administration of nitrendipine and ramipril in these respective studies impacts sleep-time BP, converting the 24-h BP pattern to a more dipper one and in the HOPE study decreasing CVD risk. The CONVINCE study intended to compare BP control and CVD protection afforded by conventional β-blocker and diuretic medications versus a special drug-delivery verapamil formulation as a bedtime hypertension chronotherapy; however, the trial was terminated prematurely, not based on inadequate performance of the chronotherapy but on a corporate business decision. The just completed MAPEC study is the first trial specifically designed to prospectively test the hypothesis that bedtime administration of ≥1 conventional medications exerts better BP control and CVD risk reduction than the traditional approach of scheduling all medications in the morning. The results of this 5.6-yr median follow-up study establish that bedtime chronotherapy more effectively improves BP control, better decreases prevalence of non-dipping, and, most importantly, best reduces CVD morbidity and mortality. This chronotherapeutic approach to hypertension is justified by the fact that BP is usually lowest at night as is sodium excretion, but when sodium intake is excessive or its daytime excretion hampered, nocturnal BP is adjusted higher, to a level required for compensation overnight, via the pressure/natriuresis mechanism, resulting in non-dipping 24-h BP patterning. In diurnally active persons, the entire circadian BP pattern may be reset to a lower mean level and to a “more normal” day-night variation, simply by enhancing natriuresis during the night—the time-of-day when it can be most effective. A modification as simple and inexpensive as switching ≥1 hypertension medications from morning to evening may be all that is needed to normalize nighttime BP, exerting an effect exactly like sodium restriction. Current clinical concepts such as “normotensive non-dipper” (with higher CVD risk than a hypertensive dipper), broad recommendation of pharmacotherapy with exclusively high “smoothness index” medications (without attention to individual patient needs defined by the features of the 24-h BP pattern), and reliance upon static daytime diagnostic BP thresholds based solely on single office cuff assessment necessitate urgent reconsideration. (Author correspondence: prf@unife.it)     

Differences in Daily Rhythms of Wrist Temperature Between Obese and Normal-Weight Women: Associations With Metabolic Syndrome Features

The circadian rhythm of core body temperature is associated with widespread physiological effects. However, studies with other more practical temperature measures, such as wrist (WT) and proximal temperatures, are still scarce. The aim of this study was to investigate whether obesity is associated with differences in mean WT values or in its daily rhythmicity patterns. Daily patterns of cortisol, melatonin, and different metabolic syndrome (MetS) features were also analyzed in an attempt to clarify the potential association between chronodisruption and MetS. The study was conducted on 20 normal-weight women (age: 38?±?11 yrs and BMI: 22?±?2.6?kg/m²) and 50 obese women (age: 42?±?10 yrs and BMI: 33.5?±?3.2?kg/m²) (mean?±?SEM). Skin temperature was measured over a 3-day period every 10?min with the “Thermochron iButton.” Rhythmic parameters were obtained using an integrated package for time-series analysis, “Circadianware.” Obese women displayed significantly lower mean WT (34.1°C?±?0.3°C) with a more flattened 24-h pattern, a lower-quality rhythm, and a higher intraday variability (IV). Particularly interesting were the marked differences between obese and normal-weight women in the secondary WT peak in the postprandial period (second-harmonic power [P2]), considered as a marker of chronodisruption and of metabolic alterations. WT rhythmicity characteristics were related to MetS features, obesity-related proteins, and circadian markers, such as melatonin. In summary, obese women displayed a lower-quality WT daily rhythm with a more flattened pattern (particularly in the postprandial period) and increased IV, which suggests a greater fragmentation of the rest/activity rhythm compared to normal-weight women. These 24-h changes were associated with higher MetS risk. (Author correspondence: garaulet@um.es)     

The benefits of four weeks of melatonin treatment on circadian patterns in resistance-trained athletes

Exercise can induce circadian phase shifts depending on the duration, intensity and frequency. These modifications are of special meaning in athletes during training and competition. Melatonin, which is produced by the pineal gland in a circadian manner, behaves as an endogenous rhythms synchronizer, and it is used as a supplement to promote resynchronization of altered circadian rhythms. In this study, we tested the effect of melatonin administration on the circadian system in athletes. Two groups of athletes were treated with 100?mg?day^?1 of melatonin or placebo 30?min before bed for four weeks. Daily rhythm of salivary melatonin was measured before and after melatonin administration. Moreover, circadian variables, including wrist temperature (WT), motor activity and body position rhythmicity, were recorded during seven days before and seven days after melatonin or placebo treatment with the aid of specific sensors placed in the wrist and arm of each athlete. Before treatment, the athletes showed a phase-shift delay of the melatonin circadian rhythm, with an acrophase at 05:00?h. Exercise induced a phase advance of the melatonin rhythm, restoring its acrophase accordingly to the chronotype of the athletes. Melatonin, but not placebo treatment, changed daily waveforms of WT, activity and position. These changes included a one-hour phase advance in the WT rhythm before bedtime, with a longer nocturnal steady state and a smaller reduction when arising at morning than the placebo group. Melatonin, but not placebo, also reduced the nocturnal activity and the activity and position during lunch/nap time. Together, these data reflect the beneficial effect of melatonin to modulate the circadian components of the sleep–wake cycle, improving sleep efficiency.