Dipper and Non-Dipper Blood Pressure 24-Hour Patterns: Circadian Rhythm–Dependent Physiologic and Pathophysiologic Mechanisms

Neuroendocrine mechanisms are major determinants of the normal 24-h blood pressure (BP) pattern. At the central level, integration of the major driving factors of this temporal variability is mediated by circadian rhythms of monoaminergic systems in conjunction with those of the hypothalamic-pituitary-adrenal, hypothalamic-pituitary-thyroid, opioid, renin-angiotensin-aldosterone, plus endothelial systems and specific vasoactive peptides. Humoral secretions are typically episodic, coupled either to sleep and/or the circadian endogenous (suprachiasmatic nucleus) central pacemaker clock, but exhibiting also weekly, monthly, seasonal, and annual periodicities. Sleep induction and arousal are influenced also by many hormones and chemical substances that exhibit 24-h variation, e.g., arginine vasopressin, vasoactive intestinal peptide, melatonin, somatotropin, insulin, steroids, serotonin, corticotropin-releasing factor, adrenocorticotropic hormone, thyrotropin-releasing hormone, endogenous opioids, and prostaglandin E2, all with established effects on the cardiovascular system. As a consequence, physical, mental, and pathologic stimuli that activate or inhibit neuroendocrine effectors of biological rhythmicity may also interfere with, or modify, the temporal BP structure. Moreover, immediate adjustment to exogenous components/environment demands by BP rhythms is modulated by the circadian-time-dependent responsiveness of biological oscillators and their neuroendocrine effectors. This knowledge contributes to a better understanding of the pathophysiology of abnormalities of the 24-h BP pattern and level and their correction through circadian rhythm-based chronotherapeutic strategies. (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)     

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)     

Cardiovascular Risk of Resistant Hypertension: Dependence on Treatment-Time Regimen of Blood Pressure–Lowering Medications

In resistant hypertension, ingesting one or more blood pressure (BP)-lowering medications at bedtime is associated with significant reduction of sleep-time BP, a sensitive prognostic marker of cardiovascular disease (CVD) risk. This randomized trial investigated if bedtime therapy with at least one hypertension medication exerts better BP control and CVD risk reduction than conventional, morning-time therapy with all medications. We conducted a prospective, open-label, blinded-endpoint trial on 776 patients (387 men/389 women) with resistant hypertension, 61.6?±?11.2 (mean?±?SD) yrs of age. Patients were randomized to ingest all their prescribed hypertension medications upon awakening or ≥1 of them at bedtime. BP was measured by ambulatory monitoring for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required. After a median follow-up of 5.4 yrs (range, .5–8.5 yrs), participants ingesting ≥1 hypertension medications at bedtime showed a significantly lower hazard ratio (HR) of total CVD events (adjusted by age, sex, and diabetes) than those ingesting all medications upon awakening (.38 [95% CI: .27–.55]; number of events 102 vs. 41; p?<?.001). The difference between groups in the adjusted HR of major CVD events (a composite of CVD death, myocardial infarction, ischemic stroke, and hemorrhagic stroke) was also statistically significant (.35 [95% CI: .18–.68]; number of events 32 vs. 12; p?=?.002). At the last evaluation, patients treated with the bedtime versus awakening-time-treatment regimen showed significantly lower sleep-time systolic/diastolic BP mean values (121.6/65.4 vs. 113.0/61.1?mm Hg; p?<?.001) and higher prevalence of controlled ambulatory BP (61% vs. 46%; p?<?.001). The progressive decrease in the sleep-time systolic BP mean during follow-up was the most significant predictor of event-free survival (15% risk reduction per 5?mm Hg decreased asleep systolic BP mean). Among patients with resistant hypertension, ingestion of at least one hypertension medication at bedtime, compared with all medications upon waking, resulted in improved ambulatory BP control and fewer hard and soft CVD events. (Author correspondence: rhermida@uvigo.es)     

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)     

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 Risk of Essential Hypertension: Influence of Class,Number, and Treatment-Time Regimen of Hypertension Medications

A number of observational studies have found that treated hypertensive patients, even those with controlled clinic blood pressure (BP), might have poorer prognosis than untreated hypertensives. Different trials have also shown that relatively low cardiovascular disease (CVD) risk cannot be achieved in high-risk hypertensive patients, leading to the belief they have a “residual CVD risk” that cannot be attenuated by conventional treatment. All these conclusions disregard the facts that the correlation between BP level and CVD risk is stronger for ambulatory than clinic BP and that the BP-lowering efficacy and effects on the 24-h BP pattern of different classes of hypertension medications exhibit statistically and clinically significant treatment-time (morning versus evening) differences. Accordingly, we evaluated the potential differential administration-time-dependent effects on CVD risk of the various classes of hypertension medications and the number of them used for therapy in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study, a prospective, open-label, blinded-endpoint trial on 2156 hypertensive patients (1044 men/1112 women), 55.6?±?13.6 (mean?±?SD) yrs of age, randomized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. Ambulatory BP was measured for 48?h at baseline, and again annually or more frequently (quarterly) when adjustment of treatment was necessary to achieve ambulatory, i.e., awake and asleep, BP control. CVD risk according to the number and classes of medications used at the final evaluation was calculated by comparison with that of 734 normotensive subjects who were identically followed and remained untreated. After a median follow-up of 5.6 yrs, CVD risk of hypertensive patients randomized to ingest all medications upon awakening was progressively higher with increase in the number of medications (adjusted hazard ratio [HR]: 1.75, 2.26, 3.02, and 4.18 in patients treated with 1, 2, 3, and ≥4 medications daily, respectively; p?<?.001 compared with normotensive subjects). CVD risk was markedly lower in patients ingesting ≥1 medications at bedtime (HR: .35, 1.45, .94, and 2.28 with 1, 2, 3, and ≥4 medications daily, respectively), and even lower in patients ingesting all medications at bedtime (HR: .35, .39, .87, and .79 with 1, 2, 3, and ≥4 medications daily, respectively). Patients ingesting ≥1 medications at bedtime evidenced significantly lower CVD risk than those ingesting all medications upon awakening, independent of class. Greater benefits were observed for bedtime compared with awakening treatment with angiotensin-II receptor blockers (ARBs) (HR: .29 [95% confidence interval, CI .17–.51]; p?<?.001) and calcium channel blockers (HR: .46 [95% CI: .31–.69]; p?<?.001). CVD risk was similar for all six classes of tested hypertension medications in patients randomized to ingest all of them upon awakening. Among patients randomized to ingest ≥1 medications at bedtime, however, ARBs were associated with significantly lower HR of CVD events than ingestion of any other class of medication also at bedtime (p?<?.017). We document significantly reduced CVD risk among hypertensive patients ingesting medications at bedtime, independent of the number of hypertension medications required to achieve proper ambulatory BP control. These findings challenge the current belief of “residual CVD risk,” as a bedtime-treatment regimen of current hypertension medications, even in risk-high patients, can reduce such risk. (Author correspondence: rhermida@uvigo.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)     

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)     

Blunted Sleep-Time Relative Blood Pressure Decline Increases Cardiovascular Risk Independent of Blood Pressure Level—The “Normotensive Non-dipper” Paradox

Numerous studies have consistently shown an association between blunted sleep-time relative blood pressure (BP) decline (non-dipping) and increased cardiovascular disease (CVD) risk in hypertension. Normotensive persons with a non-dipper BP profile also have increased target organ damage, namely, increased left ventricular mass and relative wall thickness, reduced myocardial diastolic function, increased urinary albumin excretion, increased prevalence of diabetic retinopathy, and impaired glucose tolerance. It remains a point of contention, however, whether the non-dipper BP pattern or just elevated BP, alone, is the most important predictor of advanced target organ damage and future CVD events. Accordingly, we investigated the role of dipping status and ambulatory BP level as contributing factors for CVD morbidity and mortality in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study. We prospectively studied 3344 individuals (1718 men/1626 women), 52.6?±?14.5 (mean?±?SD) yrs of age, during a median follow-up of 5.6 yrs. BP was measured by ambulatory monitoring (ABPM) for 48?h at baseline, and again annually or more frequently (quarterly) if treatment adjustment was required in treated hypertensive patients. At baseline, those with ABPM-substantiated hypertension were randomized to one of two treatment-time regimen groups: (i) ingestion of all prescribed hypertension medications upon awakening or (ii) ingestion of the entire dose of ≥1 of them at bedtime. Those found to be normotensive at baseline were untreated but followed and evaluated by repeated ABPM like the hypertensive patients. Participants were divided into four investigated categories on the basis of dipping status and ambulatory BP: (i) dipper vs. non-dipper, and (ii) normal ambulatory BP if the awake systolic (SBP)/diastolic (DBP) BP means were <135/85?mm Hg and the asleep SBP/DBP means were <120/70?mm Hg, and elevated ambulatory BP otherwise. Cox survival analyses, adjusted for significant confounding variables, documented that non-dippers had significantly higher CVD risk than dippers, whether they had normal (p?=?.017) or elevated ambulatory BP (p?<?.001). Non-dippers with normal awake and asleep SBP and DBP means, who accounted for 21% of the studied population, had similar hazard ratio (HR) of CVD events (1.61 [95% confidence interval, CI: 1.09–2.37]) as dippers with elevated ambulatory BP (HR: 1.54 [95% CI: 1.01–2.36]; p?=?.912 between groups). These results remained mainly unchanged for treated and untreated patients analyzed separately. Our findings document that the risk of CVD events is influenced not only by ambulatory BP elevation, but also by blunted nighttime BP decline, even within the normotensive range, thus supporting ABPM as a requirement for proper CVD risk assessment in the general population. The elevated CVD risk in “normotensive” individuals with a non-dipper BP profile represents a clear paradox, as those persons do not have “normal BP” or low CVD risk. Our findings also indicate the need to redefine the concepts of normotension/hypertension, so far established on the unique basis of BP level, mainly if not exclusively measured at the clinic, independently of circadian BP pattern. (Author correspondence: rhermida@uvigo.es)     

Role of Time-of-Day of Hypertension Treatment on the J-Shaped Relationship Between Blood Pressure and Cardiovascular Risk

Several previous studies found that too great a reduction of clinic blood pressure (BP) by treatment increased cardiovascular disease (CVD) risk, whereas moderate reduction decreased it. Thus, it has been suggested that the relationship between BP and CVD events is J-shaped, with CVD risk decreasing as BP is lowered, and then rising as BP is further decreased. Correlation between BP level and CVD risk, however, is stronger for ambulatory BP monitoring (ABPM) than clinical BP measurements. We previously established that the hypertension treatment-time regimen, upon awakening versus at bedtime, exerts differential effect on BP control during the day and nighttime, which translates into a differential degree of CVD risk prevention. We, therefore, investigated the role of hypertension treatment-time scheme on the nature of the relationship between achieved clinic and ambulatory BP and CVD risk in the MAPEC (Monitorización Ambulatoria para Predicción de Eventos Cardiovasculares, i.e., Ambulatory Blood Pressure Monitoring for Prediction of Cardiovascular Events) study, a prospective, open-label, blinded-endpoint trial on 2156 hypertensive patients (1044 men/1112 women), 55.6?±?13.6 (mean?±?SD) yrs of age, randomized to ingest all prescribed once-a-day hypertension medications upon awakening or the entire daily dose of ≥1 of them at bedtime. Ambulatory BP was measured for 48-h at baseline and annually thereafter, and more frequently (quarterly) when adjustment of treatment was necessary. After a median follow-up of 5.6 yrs, a J-shaped relationship was detected between total CVD events and clinic as well as awake BP mean, but only for the group of patients ingesting all medications upon awakening. The relationship was different in the group of patients who ingested ≥1 medications at bedtime; the risk of CVD events progressively diminished in a linear, rather than J-shaped, manner with treatment-induced decrease in awake BP mean. The adjusted hazard ratio of CVD events was significantly lower with the progressive reduction in the asleep BP mean, independent of the hypertension treatment-time regimen. There was no single major event, i.e., CVD death, myocardial infarction, or stroke, in patients who achieved an asleep systolic BP mean <103?mm Hg. Our findings indicate that bedtime hypertension treatment is not associated with a J-shaped relationship between achieved BP and CVD risk. The decreased CVD risk associated with the progressive reduction in asleep BP, more feasible by bedtime than morning hypertension treatment, has clinical implications, in particular, the need to consider the proper timing of hypertension medications, in conjunction with ABPM for proper assessment of BP control, as an improved and potentially safer means of reducing CVD risk of hypertensive patients. (Author correspondence: rhermida@uvigo.es)     

CIRCADIAN MODULATION OF CRUSTACEAN HYPERGLYCEMIC HORMONE IN CRAYFISH EYESTALK AND RETINA

Previous studies suggested the retina could be a putative locus of daily crustacean hyperglycemic hormone (CHH) secretion, as it possesses its own metabolic machinery and is independent of the well-known CHH eyestalk locus responsible for the circadian secretion of this peptide. However, it has been proposed that hemolymph glucose and lactate concentrations play a dual role in the regulation of CHH in crayfish. To elucidate the temporal relationship between these two different CHH production loci and to examine their relationship with glucose regulation, we investigated the expression of CHH daily and circadian rhythms in the eyestalk and retina of crayfish using biochemical methods and time series analysis. We wanted to determine whether (1) putative retina and eyestalk CHH rhythmic expressions are correlated and if the oscillations of the two metabolic products of lactate and glucose in the blood due to CHH action on the target tissue correlate, and (2) retina CHH (RCHH) and the possible retinal substrate glycogen and its product glucose are temporally correlated. We found a negative correlation between daily and circadian changes of relative CHH abundance in the retina and eyestalk. This correlation and the cross-correlation values found between eyestalk CHH and hemolymph and glucose confirm that CHH produced by the X-organ sinus gland complex is under the previously proposed dual feedback control system over the 24?h time period. However, the presence of both glycogen and glucose in the retina, the cross-correlation values found between these parameters and hemolymph lactate and glucose, as well as RCHH and hemolymph and retina metabolic markers suggest RCHH is not under the same temporal metabolic control as eyestalk CHH. Nonetheless, their expression may be linked to common rhythms-generating processes. (Author correspondence: mlfm@hp.fciencias.unam.mx; mfajul@gmail.com)     

Effects of Time-of-Day of Hypertension Treatment on Ambulatory Blood Pressure and Clinical Characteristics of Patients With Type 2 Diabetes

Generally, hypertensive patients ingest all their blood pressure (BP)-lowering agents in the morning. However, many published prospective trials have reported clinically meaningful morning-evening, treatment-time differences in BP-lowering efficacy, duration of action, and safety of most classes of hypertension medications, and it was recently documented that routine ingestion of ≥1 hypertension medications at bedtime, compared with ingestion of all of them upon awakening, significantly reduces cardiovascular disease (CVD) events. Non-dipping (<10% decline in asleep relative to awake BP mean), as determined by ambulatory BP monitoring (ABPM), is frequent in diabetes and is associated with increased CVD risk. Here, we investigated the influence of hypertension treatment-time regimen on the circadian BP pattern, degree of BP control, and relevant clinical and analytical parameters of hypertensive patients with type 2 diabetes evaluated by 48-h ABPM. This cross-sectional study involved 2429 such patients (1465 men/964 women), 65.9?±?10.6 (mean?±?SD) yrs of age, enrolled in the Hygia Project, involving primary care centers of northwest Spain and designed to evaluate prospectively CVD risk by ABPM. Among the participants, 1176 were ingesting all BP-lowering medications upon awakening, whereas 1253 patients were ingesting ≥1 medications at bedtime. Among the latter, 336 patients were ingesting all BP-lowering medications at bedtime, whereas 917 were ingesting the full daily dose of some hypertension medications upon awakening and the full dose of others at bedtime. Those ingesting ≥1 medications at bedtime versus those ingesting all medications upon awakening had lower likelihood of metabolic syndrome and chronic kidney disease (CKD); had significantly lower albumin/creatinine ratio, glucose, total cholesterol, and low-density lipoprotein (LDL) cholesterol; and had higher estimated glomerular filtration rate and high-density lipoprotein (HDL) cholesterol. Moreover, patients ingesting all medications at bedtime had lowest fasting glucose, serum creatinine, uric acid, and prevalence of proteinuria and CKD. Ingestion of ≥1 medications at bedtime was also significantly associated with lower asleep systolic (SBP) and diastolic BP (DBP) means than treatment with all medications upon awakening. Sleep-time relative SBP and DBP decline was significantly attenuated in patients ingesting all medications upon awakening (p?<?.001). Thus, the prevalence of non-dipping was significantly higher when all hypertension medications were ingested upon awakening (68.6%) than when ≥1 of them was ingested at bedtime (55.8%; p?<?.001 between groups), and even further attenuated (49.7%) when all of them were ingested at bedtime (p?<?.001). Additionally, prevalence of the riser BP pattern, associated with highest CVD risk, was much greater (23.6%) among patients ingesting all medications upon awakening, compared with those ingesting some (20.0%) or all medications at bedtime (12.2%; p?<?.001 between groups). The latter group also showed significantly higher prevalence of properly controlled ambulatory BP (p <?.001) that was achieved by a significantly lower number of hypertension medications (p?<?.001) compared with patients treated upon awakening. Our findings demonstrate significantly lower asleep SBP mean and attenuated prevalence of a blunted nighttime BP decline, i.e., lower prevalence of markers of CVD risk, and improved metabolic profile in patients with type 2 diabetes ingesting hypertension medications at bedtime than in those ingesting all of them upon awakening. These collective findings indicate that bedtime hypertension treatment, in conjunction with proper patient evaluation by ABPM to corroborate the diagnosis of hypertension and avoid treatment-induced nocturnal hypotension, should be the preferred therapeutic scheme for type 2 diabetes. (Author correspondence: rhermida@uvigo.es)     

Relationship Between Metabolic Syndrome,Circadian Treatment Time,and Blood Pressure Non-Dipping Profile in Essential Hypertension

There is a strong association between metabolic syndrome (MS) and increased cardiovascular risk. Moreover, elevated nighttime blood pressure (BP) and non-dipping (subjects with <10% decline in the asleep relative to the awake BP mean) have been also linked to increased cardiovascular morbidity and mortality. We investigated the relation between MS, circadian time of hypertension treatment, and impaired nighttime BP decline in a cross-sectional study on 3352 (1576 men/1776 women) non-diabetic hypertensive subjects, 53.7?±?13.1 (mean?±?SD) yrs of age. Among them, 2056 were ingesting all their prescribed hypertension medication upon awakening, and 1296 were ingesting at least one of their BP medications at bedtime. BP was measured by ambulatory monitoring for 48 consecutive hours to substantiate reproducibility of the dipping pattern. Physical activity was simultaneously monitored every minute by wrist actigraphy to accurately calculate mean BP when awake and asleep for each subject. MS was present in 52.6% of the subjects. The prevalence of an altered non-dipper BP profile was significantly higher among subjects with MS (52.0% vs. 39.5% in subjects without MS, p < .001). Non-dipping was significantly more prevalent among subjects ingesting all BP-lowering medications upon awakening (56.8%) than among those ingesting at least one of their BP medications at bedtime (29.1%; p < .001). Subjects with MS had significantly higher values of uric acid (6.0 vs. 5.3?mg/dL, p < .001), plasma fibrinogen (331 vs. 315?mg/dL, p < .001), and erythrocyte sedimentation rate (14.8 vs. 12.4?mm, p < .001). Non-dipping was significantly associated with the presence of MS and treatment upon awakening in a multiple logistic regression model adjusted by significant confounding factors, including age, creatinine, erythrocyte sedimentation rate, and cigarette smoking. This cross-sectional study documents a significant increase of a blunted sleep-time BP decline in treated hypertensive subjects with MS. Even in the presence of MS, treatment at bedtime is significantly associated with lower prevalence of a high-risk non-dipper BP profile. (Author correspondence: rhermida@uvigo.es)     

Daily Changes in Ultraviolet Light Levels Can Synchronize the Circadian Clock of Bumblebees (Bombus terrestris)

Endogenous circadian clocks are synchronized to the 24-h day by external zeitgebers such as daily light and temperature cycles. Bumblebee foragers show diurnal rhythms under daily light:dark cycles and short-period free-running circadian rhythms in constant light conditions in the laboratory. In contrast, during the continuous light conditions of the arctic summer, they show robust 24-h rhythms in their foraging patterns, meaning that some external zeitgeber must entrain their circadian clocks in the presence of constant light. Although the sun stays above the horizon for weeks during the arctic summer, the light quality, especially in the ultraviolet (UV) range, exhibits pronounced daily changes. Since the photoreceptors and photopigments that synchronize the circadian system of bees are not known, we tested if the circadian clocks of bumblebees (Bombus terrestris) can be entrained by daily cycles in UV light levels. Bumblebee colonies were set up in the laboratory and exposed to 12?h:12?h UV?+?:UV? cycles in otherwise continuous lighting conditions by placing UV filters on their foraging arenas for 12?h each day. The activity patterns of individual bees were recorded using fully automatic radiofrequency identification (RFID). We found that colonies manipulated in such a way showed synchronized 24-h rhythms, whereas simultaneously tested control colonies with no variation in UV light levels showed free-running rhythms instead. The results of our study show that bumblebee circadian rhythms can indeed be synchronized by daily cycles in ambient light spectral composition. (Author correspondence: r.stanewsky@qmul.ac.uk)     

THE EFFECT OF 40 HOURS OF CONSTANT WAKEFULNESS ON NUMBER COMPARISON PERFORMANCE

We investigated the effects of sleep loss and circadian rhythm on number comparison performance. Magnitude comparison of single-digits is robustly characterized by a distance effect: Close numbers (e.g., 5 versus 6) produce longer reaction times than numbers further apart (e.g., 2 versus 8). This distance effect is assumed to reflect the difficulty of a comparison process based on an analogous representation of general magnitude. Twelve male participants were required to stay awake for 40?h in a quasi-constant-routine protocol. Response speed and accuracy deteriorated between 00:00 and 06:00?h but recovered afterwards during the next day, indicating a circadian rhythm of elementary cognitive function (i.e., attention and speed of mental processing). The symbolic distance effect, however, did not increase during the nighttime, indicating that neither cumulative sleep loss nor the circadian clock prolongs numerical comparison processes. The present findings provide first evidence for a relative insensitivity of symbolic magnitude processing against the temporal variation in energy state. (Author correspondence: michael.steinborn@uni-tuebingen.de)     

CIRCADIAN STUDY OF DECOMPRESSION SICKNESS SYMPTOMS AND RESPONSE-ASSOCIATED VARIABLES IN RATS

In order to study circadian rhythms and decompression sickness (DCS), we determined: 1) the baseline circadian time structure in noncompressed rats of potential response variables to compression/decompression (C/D), and 2) whether rats subjected to C/D display a circadian time-dependent difference in inflammatory response intensity and biological tolerance. Subgroups of male rats, standardized to a 12?h light/12?h dark schedule, were evaluated every 4?h over 24?h after they were either compressed to 683?kPa (group E) or remained at sea level (group C). During 60?min recovery, evaluation included gross DCS symptoms and pulmonary edema in all E rats, and cell counts, nitric oxide, protein, thromboxane B_2, and leukotriene E₄ levels in survivors. Chi-square, ANOVA, and 24?h cosinor analyses were used to test for time-of-day effects. C/D exposures near the end of dark/activity or during light/resting were generally better tolerated, with lowest signs of DCS symptoms and lowest responses by most of the variables monitored. More deaths were observed in the first half of the dark/activity span. Of the 16 subsets of inflammatory-associated variables, overall increases were observed in 13 and decreases in 2. Significant or borderline significant circadian time effects were found in 14 variables in group C, 12 variables in group E, and 13 variables in response (E%C). Thus, nearly all baseline indices of DCS demonstrated circadian time-dependencies in the sea-level exposed control rats (group C), and nearly all were modified by the circadian time of C/D. Such time-of-day effects of DCS are potentially relevant to the operational concerns of occupations involving decompression exposures and the investigation of prevention and treatment intervention strategies of DCS. (Author correspondence: Bruce.D.Butler@uth.tmc.edu).     

Differences Between Men and Women in Ambulatory Blood Pressure Thresholds for Diagnosis of Hypertension Based on Cardiovascular Outcomes

Previous studies have reported sex differences in the pathophysiology of hypertension and responses to blood pressure (BP)-lowering medications. Moreover, men exhibit typically higher BP than women, the differences being greater for systolic (SBP) than diastolic (DBP) BP. These differences become apparent during adolescence and remain significant at least until 55–60 yrs of age. Despite such significant sex-related differences in BP regulation, the current recommended ambulatory BP monitoring (ABPM) thresholds for diagnosis of hypertension do not differentiate between men and women. We aimed to derive separate male and female diagnostic thresholds for the awake and asleep SBP and DBP means based upon cardiovascular disease (CVD) outcome. We prospectively studied 3344 subjects (1718 men/1626 women), 52.6?±?14.5 yrs of age, during a median follow-up of 5.6 yrs. Those with hypertension at baseline were randomized to ingest all their prescribed hypertension medications upon awakening or the entire daily dose of ≥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, and physical activity was simultaneously monitored every minute by wrist actigraphy to accurately derive the awake and asleep BP means. Identical assessment was scheduled annually and more frequently (quarterly) if treatment adjustment was required. Cox regression analysis was used to derive outcome-based reference thresholds for ABPM in men and women. Men exhibited greater event rates than women of CVD death, myocardial infarction, angina pectoris, coronary revascularization, and heart failure; however, event rates of non-CVD death and cerebrovascular events were comparable. The relationship between progressively higher ambulatory BP and CVD risk increased more rapidly in women than men for awake SBP/DBP means ≥125/75?mm Hg and asleep means ≥110/70?mm Hg. The derived outcome-based reference thresholds for men were 135/85?mm Hg for the awake and 120/70?mm Hg for the asleep SBP/DBP means. In terms of CVD outcome, the equivalent cutoff threshold values for women were 125/80?mm Hg for the awake and 110/65?mm Hg for the asleep SBP/DBP means. Outcome-based reference thresholds for the diagnosis of hypertension were 10/5?mm Hg lower for ambulatory SBP/DBP in women than men. This marked sex difference indicates the need for revision of current guidelines that propose diagnostic thresholds for ambulatory BP without differentiation between men and women. (Author correspondence: rhermida@uvigo.es)