Possibilities of Interpreting the Night-to-Day Ratio Specified by 24-Hour Blood Pressure Monitoring.

Aim: Specify the risk rate of incorrect patient classification based on the night-to-day ratio specification from singular 24-h ABPM in comparison to the results of 7-day ABPM monitoring. Materials and Methods: 1197 24 h cycles were enrolled in 171 subjects in the study and divided into 4 groups: group 1 (40 healthy men and women without exercise), group 2 (40 healthy exercise-training men and women), group 3 (40 patients with ischemic coronary artery disease without exercise), and group 4 (51 patients with ischemic coronary artery disease following cardiovascular rehabilitation). The subject of the evaluation was the percentage rate of incorrect subject classification (dipper, nondipper, extreme dipper, and riser) based on the mean blood pressure values for 7 days and from seven independent 24-hour cycles (the mean value mode). Results: In the case of the individuals included in the monitored groups, the mean night-to-day ratio-based (mode for the 7 days versus the individual days of 24-hour monitoring) classification accordance ranged between 59% and 62%. Only in singular cases did the accordance reach 0% or 100%. The accordance size was not dependent on the health or cardiovascular disease (p < 0.594; 56% vs. 54%) or physical activity (p < 0.833; 55% vs. 54%) of the monitored individuals. Conclusion: The specification of the night-to-day ratio of each individual for each day of the 7-day ABPM monitoring would be the most convenient option. In many patients, diagnosing could thus be based on the most frequently occurring values (mode specification).

Pre-heart failure at 2D- and 3D-speckle tracking echocardiography: A comprehensive review.

Chronic heart failure (CHF) has different stages and includes pre-HF (PHF), a state of high risk of developing myocardial dysfunction and advanced CHF. Some major behavioral risk factors of PHF might predispose to biological risk factors such as obesity, diabetes mellitus, dyslipidemia, hypertension, myocardial infarction, and cardiomyopathy. These risk factors damage the myocytes leading to fibrosis, apoptosis, cardiac hypertrophy, along with alterations in cardiomyocyte' size and shape. A condition of physiological subcellular remodeling resulting into a pathological state might be developed, conducting to PHF. Both PHF and heart failure (HF) are associated with the activation of phospholipases and protease, mitochondrial dysfunction, oxidative stress and development of intra-cellular free Ca2+  [Ca2+ ]i overloading to an elevation in diastolic [Ca2+ ]i . Simultaneously, cardiac gene expression is activated leading to further molecular, structural and biochemical changes of the myocardium. The sub-cellular remodeling may be intimately involved in the transition of cardiac hypertrophy to heart failure. 2D- and 3D-speckle tracking echocardiography (STE) have been used to quantify regional alterations of longitudinal strain and area strain, through their polar projection, which permits a further assessment of both sites and degrees of myocardial damage. The examination of strain can identify sub-clinical cardiac dysfunction or cardiomyocyte remodeling. During remodeling of the myocardium cardiac strain is attenuated, therefore it is an indicator of disease assessment.

Melatonin mitigates disrupted circadian rhythms, lowers intraocular pressure, and improves retinal ganglion cells function in glaucoma.

Glaucoma is a progressive optic neuropathy associated with damage to retinal ganglion cells (RGCs) and disrupted circadian rhythms. Melatonin is a promising substance to ameliorate glaucoma-associated compromised circadian rhythms, sleep, mood, and retinal cells function. However, studies estimating melatonin effects in glaucoma are currently lacking. Therefore, In this study, we investigated the effect of long-term (daily at 10:30 pm for 90 days) oral melatonin administration on systemic (Tb) and local to the organ of vision (IOP) circadian rhythms, pattern electroretinogram (PERG), sleep, and mood, depending on glaucoma stage in patients diagnosed with stable or advanced primary open-angle glaucoma. In a laboratory study in 15 of them, 24-hour records of salivary melatonin were obtained and MTNR1B receptor gene polymorphism was assessed. Melatonin increased the stability of the Tb circadian rhythm by improving its phase alignment and alignment with IOP. Melatonin time-dependently decreased IOP and IOP standard deviation (SD). IOP 24-hour mean and IOP SD decreases were more pronounced in individuals with the higher initial 24-hour IOP mean. Melatonin improved RGCs function in advanced glaucoma; N95 amplitude increase correlated positively with RGCs loss. The beneficial effects of melatonin on sleep and mood were greater in advanced glaucoma. Finally, delayed salivary melatonin and Tb phases were observed in MTNR1B G-allele carriers with advanced glaucoma. Combined, these results provide evidence for melatonin efficiency in restoring disrupted circadian rhythms in glaucoma with different effects of melatonin on systemic vs. local circadian rhythms, indicating that a personalized strategy of melatonin administration may further refine its treatment benefits.

Applications of cosinor rhythmometry in pharmacology.

Study design and data analysis are two important aspects relevant to chronopharmacometrics. Blunders can be avoided by recognizing that most physiological variables are circadian periodic. Both ill health and treatment can affect the amplitude, phase, and/or period of circadian (and other) rhythms, in addition to their mean. The involvement of clock genes in molecular pathways related to important physiological systems underlies the bidirectional relationship often seen between circadian rhythm disruption and disease risk. Circadian rhythm characteristics of marker rhythms interpreted in the light of chronobiologic reference values represent important diagnostic tools. A set of cosinor-related programs is presented. They include the least squares fit of multiple-frequency cosine functions to model the time structure of individual records; a cosinor-based spectral analysis to detect periodic signals; the population-mean cosinor to generalize inferences; the chronobiologic serial section to follow the time course of changing rhythm parameters over time; and parameter tests to assess differences among populations. Relative merits of other available cosinor and non-parametric algorithms are reviewed. Parameter tests to compare individual records and a self-starting cumulative sum (CUSUM) make personalized chronotherapy possible, where the treatment of each patient relies on an N-of-1 design. Methods are illustrated in a few examples relevant to endocrinology, cancer and cardiology. New sensing technology yielding large personal data sets is likely to change the healthcare system. Chronobiologic concepts and methods should become an integral part of these evolving systems.

Disruption of 24-Hour Rhythm in Intraocular Pressure Correlates with Retinal Ganglion Cell Loss in Glaucoma.

Parameters of 24-h rhythm in intraocular pressure (IOP) were assessed in patients with stable or advanced primary open-angle glaucoma (S-POAG/A-POAG) and referenced to the phase of "marker" circadian temperature rhythm of each patient. Body temperature and IOP were measured over a 72-h span in 115 participants (65 S-POAG and 50 A-POAG). Retinal Ganglion Cell (RGC) damage was assessed by high-definition optical coherence tomography. The 24-h IOP rhythm in A-POAG patients peaked during the night, opposite to the daytime phase position in S-POAG patients (p < 0.0001). The 24-h IOP phase correlated with RGC loss (p < 0.0001). The internal phase shift between IOP and body temperature gradually increased with POAG progression (p < 0.001). Angiotensin converting enzyme Alu-repeat deletion/insertion (ACE I/D) emerged as a candidate gene polymorphism, which may play a role in the alteration of the circadian IOP variability in advanced glaucoma. To conclude, a reliable estimation of the 24-h rhythm in IOP requires the degree of RGC damage to be assessed. In advanced POAG, the 24-h phase of IOP tended to occur during the night and correlated with RGC loss, being progressively delayed relative to the phase of temperature.

Chronic heart failure: a disease of the brain.

The underlying mechanism for clinical and biochemical manifestations of chronic heart failure (HF) may be due in part to neurohumoral adaptations, such as activation of the renin-angiotensin-aldosterone and sympathetic nervous systems in the periphery and the brain. Internet search and discussion with colleagues are the methods for this study. Since chronic HF is associated with autonomic imbalance with increased sympathetic nerve activity and a withdrawal of parasympathetic activity, it may be considered a brain disease. This phenomenon may be the result of an increased systemic and cerebral angiotensin II signaling because plasma angiotensin II is increased in humans and animals with chronic HF. The increase in angiotensin II signaling enhances sympathetic nerve activity through actions on both central and peripheral sites during chronic HF. Activation of angiotensin II signaling in different brain sites such as the paraventricular nucleus (PVN), rostral ventrolateral medulla (RVLM), and area postrema (AP) may increase the release of norepinephrine, oxidative stress, and inflammation leading to increased cardiac contractility. It is possible that blocking angiotensin II type 1 receptors decreases sympathetic nerve activity and cardiac sympathetic afferent reflex when therapy is administered to the PVN. The administration of an angiotensin receptor blocker by injection into the AP activates the sympatho-inhibitory baroreflex indicating that receptor blockers act by increasing parasympathetic activity. In chronic HF, in peripheral regions, angiotensin II elevates both norepinephrine release and synthesis and inhibits norepinephrine uptake at nerve endings, which may contribute to the increase in sympathetic nerve activity. Increased circulating angiotensin II during chronic HF may enhance the sympatho-excitatory chemoreflex and inhibit the sympatho-inhibitory baroreflex resulting in worsening of HF. Increased circulating angiotensin II signaling can directly act on the central nervous system via the subfornical organ and the AP to increase sympathetic outflow resulting in to neurohumoral dysfunction, resulting in to heart failure.

Effect of Gender, Age, Diet and Smoking Status on the Circadian Rhythm of Serum Uric Acid of Healthy Indians of Different Age Groups.

The circadian rhythm of uric acid concentration was studied under near-normal tropical conditions in 162 healthy volunteers (103 males and 59 females; 7 to 75 year). They were mostly medical students, staff members and members of their families. They were classified into 4 age groups: A (7-20 y; N = 42), B (21-40 y; N = 60), C (41-60 y; N = 35) and D (61-75 y; N = 25). They followed a diurnal activity from about 06:00 to about 22:00 and nocturnal rest. Blood samples were collected from each subject every 6 for 24 h (4 samples). Serum uric acid was measured spectrophotometrically. Data from each subject were analyzed by cosinor rhythmometry. Effects of gender, age, diet (vegetarian vs. omnivore), and smoking status on the rhythm-adjusted mean (MESOR) and circadian amplitude were examined by multiple-analysis of variance. A marked circadian variation was found in uric acid concentration in healthy Indians of all age groups. Furthermore, both the MESOR and circadian amplitude underwent changes with advancing age. In addition to effects of gender and age, diet and smoking were also found to affect the MESOR of circulating uric acid concentration in healthy Indians residing in northern India. The present observations confirmed a definite rhythm in uric acid concentrations with significant effect of gender, age, diet, and smoking status on uric acid concentration in clinical health. Mapping the circadian rhythm of serum uric acid is needed to explore their role in different pathophysiological conditions.

Chronomics of Circulating Plasma Lipid Peroxides and Antioxidant Enzymes in Renal Stone Formers.

The chronome of lipid peroxidation and anti-oxidant defense mechanisms may relate to the efficacy and management of time qualified preventive therapeutic and dietary interventions. One hundred renal stone patients, 20-60 years of age, and 50 clinically healthy volunteers, 21-45 years, were synchronized for 1 week with diurnal activity from 06:00 to 22:00 and nocturnal rest. All subjects took their usual meals three times daily (breakfast around 08:30, lunch around 13:00, and dinner around 20:30) with usual fluid intake. Drugs known to affect free radical system were not taken. Blood samples were collected at 6-h intervals for 24-h under standardized, presumably 24-h synchronized conditions. Determinations included plasma lipid peroxides, in terms of malondialdehyde (MDA) and blood superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CAT) activities. A marked circadian variation was demonstrated for each studied variable by population-mean cosinor in renal stone patients and healthy participants (p < 0.001). By comparison to healthy subjects, parameter tests indicate that the stone formers had a higher MESOR of MDA, but a lower MESOR of SOD, GPx, GR and CAT. Furthermore, the patients also differed from the healthy controls in terms of their circadian amplitude and acrophase (tested jointly) of all variables (p < 0.001). Mapping the broader time structure with multifrequency circadian characteristics of oxidants and anti-oxidants is needed for exploring their role as marker in the treatment and management of urolithiasis.

Superposed epoch analysis of physiological fluctuations: possible space weather connections.

There is a strong connection between space weather and fluctuations in technological systems. Some studies also suggest a statistical connection between space weather and subsequent fluctuations in the physiology of living creatures. This connection, however, has remained controversial and difficult to demonstrate. Here we present support for a response of human physiology to forcing from the explosive onset of the largest of space weather events-space storms. We consider a case study with over 16 years of high temporal resolution measurements of human blood pressure (systolic, diastolic) and heart rate variability to search for associations with space weather. We find no statistically significant change in human blood pressure but a statistically significant drop in heart rate during the main phase of space storms. Our empirical findings shed light on how human physiology may respond to exogenous space weather forcing.

Chronobiology of Aging: A Mini-Review.

Aging is generally associated with weakening of the circadian system. The circadian amplitude is reduced and the circadian acrophase becomes more labile, tending to occur earlier with advancing age. As originally noted by Franz Halberg, similar features are observed in the experimental laboratory after bilateral lesioning of the suprachiasmatic nuclei, suggesting the involvement of clock genes in the aging process as they are in various disease conditions. Recent work has been shedding light on underlying pathways involved in the aging process, with the promise of interventions to extend healthy life spans. Caloric restriction, which is consistently and reproducibly associated with prolonging life in different animal models, is associated with an increased circadian amplitude. These results indicate the critical importance of chronobiology in dealing with problems of aging, from the circadian clock machinery orchestrating metabolism to the development of geroprotectors. The quantitative estimation of circadian rhythm characteristics interpreted in the light of time-specified reference values helps (1) to distinguish effects of natural healthy aging from those associated with disease and predisease; (2) to detect alterations in rhythm characteristics as markers of increased risk before there is overt disease; and (3) to individually optimize by timing prophylactic and/or therapeutic interventions aimed at restoring a disturbed circadian system and/or enhancing a healthy life span. Mapping changes in amplitude and/or acrophase that may overshadow any change in average value also avoids drawing spurious conclusions resulting from data collected at a fixed clock hour. Timely risk detection combined with treatment optimization by timing (chronotherapy) is the goal of several ongoing comprehensive community-based studies focusing on the well-being of the elderly, so that longevity is not achieved at the cost of a reduced quality of life.

Circadian Periodicity of Circulating Plasma Lipid Peroxides, Uric Acid and Ascorbic Acid in Renal Stone Formers.

Circadian periodicity of plasma lipid peroxides and serum ascorbic acid and uric acid levels were studied in one hundred renal stone formers (55 women and 45 men; age 20-60 years) and 50 clinically healthy volunteers (21 women and 29 men; age 21-45 years) with diurnal activity from 06:00 to 22:00 and nocturnal rest. A marked circadian variation was demonstrated by population-mean-cosinor for all studied variables in stone formers and healthy subjects. By comparison to the healthy controls, parameter tests indicate that the stone formers had a higher MESOR (±SE) of MDA (2.90 ± 0.03 vs. 2.28 ± 0.06; F = 94.929, p < 0.001), a lower MESOR of serum ascorbic acid (0.722 ± 0.010 vs. 0.839 ± 0.10; F = 32.083, p < 0.001), and a similar MESOR of serum uric acid. Furthermore, the patients also differed from the healthy subjects in terms of their circadian amplitude and acrophase (tested jointly) of all three variables (p < 0.001). The demonstration herein of a circadian rhythm in MDA, serum ascorbic and uric acid suggests that these variables could also serve as markers to optimize the timing of treatment and to assess the patient's response to treatment for further management.

Circadian Time Structure of Circulating Plasma Lipid Components in Healthy Indians of Different Age Groups.

The circadian rhythm of human circulating lipid components was studied under nearnormal tropical conditions in 162 healthy volunteers (103 males and 59 females; 7 to 75 years of age). They followed a diurnal activity from about 06:00 to about 22:00 and nocturnal rest. These volunteers were divided into four groups: Group A (7-20 years), Group B (21-40 years), Group C (41-60 years) and Group D (61-75 years), comprising 42, 60, 35 and 25 participants, respectively. A marked circadian rhythm was demonstrated for each studied variable in each group by population-mean cosinor analysis (almost invariably p < 0.001). Furthermore, circadian rhythm characteristics were compared among the 4 groups by parameter tests and regressed as a function of age, separately for males and females. A second-order polynomial characterized the MESOR of HDL cholesterol, phospholipids and total lipids, as well as the 24-h amplitude of total cholesterol and phospholipids. The 24-h amplitude of total lipids decreased linearly with age. The 24-h acrophase of the oldest age group (Group D) was advanced in the case of total cholesterol, HDL cholesterol, and total lipids, whereas that of phospholipids was delayed. Mapping the circadian rhythm (an important component of the broader time structure or chronome, which includes a. o., trends with age and extra-circadian components) of lipid components is needed to explore their role in the aging process in health.

Even mild depression is associated with among-day blood pressure variability, including masked non-dipping assessed by 7-d/24-h ambulatory blood pressure monitoring.

The effect of mild depression on blood pressure (BP) was assessed in 116 Japanese (32-79 years). As compared to non-depressive (Geriatric Depression Scale, GDS-15 score <5) subjects, mild depressives (GDS-15 score: 1-15) had shorter sleep duration (p = 0.021), lower subjective quality of life (health: p = 0.016; life satisfaction: p < 0.001; and happiness: p < 0.001), and higher 7-d systolic BP (p < 0.05). "Masked non-dipping" (dipping on day 1, but non-dipping on at least 1 of the following 6 d) was more frequent among depressive than non-depressive normotensives (p = 0.008). Among-day BP variability may underlie cardiovascular disease accompanying a key component of psychological depression.

Chronobiological changes in arterial blood pressure in participants of the 5th and 6th Czech Antarctic Scientific Expeditions.

OBJECTIVE: To evaluate potential changes in arterial blood pressure (ABP) and heart rate (HR) during a 2-month stay in Antarctica, using chronobiological analysis. METHODS: An observational study performed at Mendel research base, Antarctica, during 2011 and 2012. The studied group consisted of 24 participants of the 5th and 6th Czech Antarctic Scientific Expeditions. Three series of 24-hour ABP monitoring were performed, of these two in Antarctica and one in the Czech Republic. Chronobiological analyses of the data were performed (Halberg Chronobiology Center, Minnesota) using population-mean cosinor. The values of MESOR (Midline Estimating Statistic Of Rhythm), double amplitude and the acrophase were obtained for SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure) and HR. These rhythm characteristics were compared between the two locations by parameter tests and by the paired t-test. RESULTS: On the average, the MESORs of SBP, DBP and HR were significantly higher in Antarctica than in the Czech Republic, as were the double amplitudes of the 12-hour component of SBP and DBP. High prevalence of CHAT (Circadian Hyper-Amplitude-Tension) was detected in Antarctica (8/24 = 33%); only 2 persons had CHAT in the Czech Republic (χ²=3.945, p=0.047). CONCLUSIONS: A prolonged stay in Antarctica clearly affected certain chronobiological parameters of ABP and HR.

Cosinor-based rhythmometry.

A brief overview is provided of cosinor-based techniques for the analysis of time series in chronobiology. Conceived as a regression problem, the method is applicable to non-equidistant data, a major advantage. Another dividend is the feasibility of deriving confidence intervals for parameters of rhythmic components of known periods, readily drawn from the least squares procedure, stressing the importance of prior (external) information. Originally developed for the analysis of short and sparse data series, the extended cosinor has been further developed for the analysis of long time series, focusing both on rhythm detection and parameter estimation. Attention is given to the assumptions underlying the use of the cosinor and ways to determine whether they are satisfied. In particular, ways of dealing with non-stationary data are presented. Examples illustrate the use of the different cosinor-based methods, extending their application from the study of circadian rhythms to the mapping of broad time structures (chronomes).

[Vascular variability syndromes].

Analytical global and local methods applied to human blood pressure (BP) records of around-the-clock measurements. The chronobiological interpretation of ambulatory BP monitoring records in the light of time-specified reference values derived from healthy peers matched by sex and age identify vascular variability disorders (VVDs) for an assessment of cardio-, cerebro-, and renovascular disease risk. VVD includes circadian BP over-swinging (CHAT, short for circadian hyper-amplitude tension), deficient heart rate variability, MESOR (midline-estimating statistic of rhythm) hypertension, excessively elevated pulse pressure over 60 mmHg, BP ecphasia (an odd timing of the circadian rhythms in BP but not in that of heart rate) and frequency alteration. The term MESOR-hypertension indicates only one of several VVDs that can combine to for sets of 2, 3 and n-component vascular variability syndromes.

A primer on sampling rates of ambulatory assessments.

The use of ambulatory assessments (AAs) as an approach to gather self-reported questionnaires or self-collected biochemical data is constantly increasing to investigate the experiences, states, and behaviors of individuals and their interaction with external situational factors during everyday life. It is often implicitly assumed that data from different sampling protocols can be used interchangeably, despite them assessing processes over different timescales in different intervals and at different occasions, which depending on the variables under study may result in fundamentally different dynamics. There are multiple temporal parameters to consider and while there is an abundance of sampling protocols that are applied regularly, to date, there is only limited empirical background on the influence different approaches may have on the data and findings. In this review, we aim to give an overview of commonly used types of AA in psychology, psychiatry, and biobehavioral research with a breakdown by temporal design parameters. Additionally, we discuss potential advantages and pitfalls associated with the various approaches. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Chronobioethics: Symphony of biological clocks observed by 7-day/24-hour ambulatory blood pressure monitoring and cardiovascular health.

BACKGROUND: The high prevalence of desynchronized biological rhythms is becoming a primary public health concern. We assess complex and diverse inter-modulations among multi-frequency rhythms present in blood pressure (BP) and heart rate (HR). SUBJECTS: and Methods: We performed 7-day/24-hour Ambulatory BP Monitoring in 220 (133 women) residents (23 to 74 years) of a rural Japanese town in Kochi Prefecture under everyday life conditions. RESULTS: A symphony of biological clocks contributes to the preservation of a synchronized circadian system. (1) Citizens with an average 12.02-h period had fewer vascular variability disorders than those with shorter (11.37-h) or longer (12.88-h) periods (P<0.05), suggesting that the circasemidian rhythm is potentially important for human health. (2) An appropriate BP-HR coupling promoted healthier circadian profiles than a phase-advanced BP: lower 7-day nighttime SBP (106.8 vs. 112.9 mmHg, P=0.0469), deeper nocturnal SBP dip (20.5% vs. 16.8%, P=0.0101), and less frequent incidence of masked non-dipping (0.53 vs. 0.86, P=0.0378), identifying the night as an important time window. CONCLUSION: Adaptation to irregular schedules in everyday life occurs unconsciously at night, probably initiated from the brain default mode network, in coordination with the biological clock system, including a reinforced about 12-hour clock, as "a biological clock-guided core integration system".

Diagnosing vascular variability anomalies, not only MESOR-hypertension.

Chronobiology is the study of biological rhythms. Chronomics investigates interactions with environmental cycles in a genetically coded autoresonance of the biosphere with wrangling space and terrestrial weather. Analytical global and local methods applied to human blood pressure records of around-the-clock measurements covering decades detect physiological-physical interactions, a small yet measurable response to solar and terrestrial magnetism. The chronobiological and chronomic interpretation of ambulatory blood pressure monitoring (C-ABPM) records in the light of time-specified reference values derived from healthy peers matched by sex and age identify vascular variability anomalies (VVAs) for an assessment of cardio-, cerebro-, and renovascular disease risk. Even within the conventionally accepted normal range, VVAs have been associated with a statistically significant increase in risk. Long-term C-ABPM records help to "know ourselves," serving for relief of psychological and other strain once transient VVAs are linked to the source of a load, prompting adjustment of one's lifestyle for strain reduction. Persistent circadian VVAs can be treated, sometimes by no more than a change in timing of the daily administration of antihypertensive medication. Circadian VVA assessment is an emergency worldwide, prompted in the United States by 1,000 deaths per day every day from problems related to blood pressure. While some heads of state met under United Nation and World Health Organization sponsorship to declare that noncommunicable diseases are a slow-motion disaster, a resolution has been drafted to propose C-ABPM as an added tool complementing purely physical environmental monitoring to contribute also to the understanding of social and natural as well as personal cataclysms.

Toward a personalized chronotherapy of high blood pressure and a circadian overswing.

Timing can greatly affect the response to a stimulus, including antihypertensive medications. Herein, we assess the response of 30 patients to losartan/hydrochlorothiazide (L/H), administered for at least 1 month at a given circadian stage to each patient, this stage being changed during consecutive spans to cover six treatment times from awakening to bedtime at approximately 3-hour intervals. At the end of each stage, each patient underwent a 7-day around-the-clock ambulatory blood pressure (BP) profile, analyzed chronobiologically. A larger reduction of the midline estimating statistic of rhythm (MESOR; a rhythm-adjusted mean) of diastolic BP was achieved by L/H administration in the early morning for more patients (P < .05), while treatment upon awakening was the best choice for most patients to reduce the circadian amplitude of BP the most (P < .01). The optimal treatment time varied considerably among patients, however. Special attention should be given to the effect on the circadian amplitude since treatment can increase it above a threshold, beyond which there is a marked increase in cardiovascular disease risk. The results indicate the desirability to individualize the optimization of the antihypertensive effect of L/H by timing along the circadian scale.