Chronophysiology of the cardiovascular system

The development of ambulatory blood pressure monitoring devices and the beat-by-beat measurement of heart rate have enabled it to be established that there are circadian rhythms in heart rate and blood pressure in subjects living normally. Investigations of these variables have led to quantification of their fall at night, and rapid rise on awakening and becoming active in the morning. These changes are of particular interest insofar as abnormalities in them are associated with cardiovascular problems and morbidity in patients and also act as risk factors in otherwise healthy individuals. It has also been shown that there are many other variables of the cardiovascular system. The causes of the circadian rhythms in heart rate and blood pressure are outlined, with particular stress upon the role of the autonomic nervous system, as assessed from low- and high-frequency components of the variation in heart rate measured beat-by-beat. Activity increases blood pressure, but there is evidence that this “reactivity” varies with time of day, and this also might be related to cardiovascular morbidity. Based upon data from several sources, including night work, resting subjects and bed-ridden patients, it is concluded that the contribution of the “body clock” to producing the circadian rhythm in heart rate and blood pressure is relatively small. A bias towards an exogenous cause applies also to most other circadian rhythms in the cardiovascular system. Knowledge of circadian rhythmicity in cardiovascular system, together with an understanding of its causes, provides a rationale for advice to reduce cardiovascular risk and to assess the efficacy of therapies.     

Chronopharmacology of cardiovascular medications

The cardiovascular system is well organized in time. Mechanisms of regulation and pathophysiological events are not evenly distributed over the 24-h scale. Moreover, certain diseases may even alter the physiological circadian pattern in the cardiovascular system. This observation bares implications for drug treatment, e.g. regarding drug formulations and dosing time intervals. Pitfalls may arise from neglecting circadian phase-dependency in pharmacokinetics and in the concentration-dependent effect relationship. Moreover, different types of drugs may be superior to others when circadian time-related symptoms are concerned. There is sound evidence that “time-of-day” has to be included in our diagnostic and therapeutic strategies.     

Correcting rhythms in urinary excretion for masking effects: Some preliminary considerations

Abstract

This study deals with the non‐invasive ambulatory monitoring of blood pressure (BP) in obese patients. The individual data were analyzed by means of chronobiometric procedures which allow us to estimate the BP values in their within‐day discrete variability, circadian rhythmicity and daily pressure load (Daily Baric Impact). The estimates of time‐qualified values documented that both male and female obese patients show an elevation of BP values all over the 24‐h span. The cosine function revealed that the BP circadian rhythm in obese males and females is preserved but shows a higher level of oscillation. The measure of the area under this oscillation (aesor) provided evidence that the Daily Baric Impact is higher in obese patients as compared to non‐obese subjects. The spectral analysis, in turn, revealed that the BP 24‐h variability in obese patients is sustained by oscillatory components which are not detectable in the physiologic spectrum of resolution in harmonics, suggesting an abnormal tone in regulatory mechanisms. The relation of the Daily Baric Impact to the body surface (Baric Index) demonstrated that the increase in BP values in obesity is a phenomenon which is secondary to the overweight.     

Blood pressure and heart rate variability are linked with hyperphosphatemia in chronic kidney disease patients

ABSTRACT

Hyperphosphatemia is a common complication of chronic kidney disease (CKD) and is associated with cardiovascular disease (CVD), which has contributed to an increase in mortality of CKD patients. The onset of CVD often varies by time-of-day. Acute myocardial infarction or ventricular arrhythmia occurs most frequently during early morning. Blood pressure (BP) and heart rate circadian rhythms account for the diurnal variations in CVD. Preservation of normal circadian time structure from the cardiomyocyte level to the whole organ system is essential for cardiovascular health and CVD prevention. Independent risk factors, such as reduced heart rate variability (HRV) and increased BP variability (BPV), are particularly prevalent in patients with CKD. Analysis of HRV is an important clinical tool for characterizing cardiac autonomic status, and reduced HRV has prognostic significance for various types of CVD. Circadian BP rhythms are classified as extreme dipper, dipper, non-dipper or riser. It has been reported that nocturnal riser BP pattern contributes to cardiovascular threats. Previous studies have indicated that the circadian rhythm of serum phosphate in CKD patients is consistent with the general population, with the highest diurnal value observed in the early morning hours, followed by a progressive decrease to the lowest value of the day, which occurs around 11:00 am. Rhythm abnormalities have become the main therapeutic target for treating CVD in CKD patients. It has been reported that high levels of serum phosphate are associated with reduced HRV and increased BPV in CKD patients. However, the mechanisms related to interactions between hyperphosphatemia, HRV and BPV have not been fully elucidated. This review focuses on the evidence and discusses the potential mechanisms related to the effects of hyperphosphatemia on HRV and BPV.     

Pyrolytic Yields of 2-Amino-9H-pyrido[2,3-b]indole and 3-Amino-1-methyl-5H-pyrido[4,3-b]indole as Matagens from Proteins

An extracellular exo-maltohexaohydrolase [EC 3.2.1.98] from a Klebsiella pneumoniae (Aerobacter aerogenes) mutant produced about 40% maltohexaose (G₆) from short-chain amylose ( =23). Mostly G₆ was produced from maltooligosaccharides larger than G₆ by an exo-mechanism action. It also hydrolyzed G₆ and shorter maltooligosaccharides to give smaller maltooligosaccharides. Its position specificity of action on G₃ through G₈ was studied with maltodextrins specifically labeled at the reducing-end glucose unit with ¹⁴C. The highest frequency of cleavage was at the second bond from the reducing end in G₃ through G₆. For G₇ and G₈, the sixth bond from the nonreducing end of the substrate was cleaved with absolute specificity by the exo-mechanism action.

Kinetic parameters of the exo-maltohexaohydrolase on various substrates were also studied. The Michaelis constant (Km) for short-chain amylose was the smallest among the various substrates examined.

G₆ was also formed from G₄ by a transfer action of the enzyme, with an action pattern dependent on the substrate concentration.     

Behavioral and Neurochemical Effects of Fencamfamine on Rats: A Chronobiologic Approach

Fencamfamine (FCF) is a psychostimulant classified as an indirect dopaminergic agonist. Circadian rhythms of some behavioral and neurochemical parameters were investigated in control rats and in rats which had been treated with a single dose of FCF across the 24-hr span. Rats were entrained to light/dark (LD) 12:12, lights on from 0700 to 1900. In behavioral experiments (performed in March) the rats were injected intraperitoneally with saline or FCF (3.5 mg/kg) at one of six times: 0900, 1300, 1700, 2100, 0100 or 0500. Fifteen minutes after treatment the duration of sniffing, rearing and locomotion was recorded during 120 min. Controls showed circadian rhythms for sniffing and rearing with acrophases at 2255 and 0118, respectively. In animals treated with FCF, only locomotion displayed significant circadian variation with acrophase at 1912. Two-way analysis of variance (ANOVA) showed a statistically significant circadian time-dependent effect of FCF on all behavioral parameters studied; the increase of sniffing, rearing and locomotion induced by FCF was higher in rats treated during the rest phase. In the biochemical studies (performed between March-June), rats were treated (i.p.) with saline or FCF (10 mg/kg) at one of four times: 0900, 1700, 2100 or 0100. The levels of homovanillic acid (HVA) in the striatum and tuberculum olfactorium, 5-hydroxyindolacetic acid (5-HIAA) in the cerebellum and 3-methoxy-4-hydroxypheniglycol (MHPG) in the frontal cortex were determined. Controls showed circadian rhythms for HVA (striatum), MHPG (frontal cortex) and 5-HIAA (cerebellum) with acrophases at 2233, 1955 and 1029, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Behavioral and Neurochemical Effects of Fencamfamine on Rats: A Chronobiologic Approach

Biological Rhythms in Clinical and Laboratory Medicine. Edited by Y. Touitou and E. Haus. Berlin, Heidelberg, New York Springer-Verlag, 1992, 730 pp. (347 figures and 54 tables), $210.     

Allatostatin-C/AstC-R2 Is a Novel Pathway to Modulate the Circadian Activity Pattern in Drosophila

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Hemodynamic Changes During Long Meditation

Changes in heart rate (HR) and blood pressure (BP) in advanced male meditators during 1 hr of meditation were compared with matched control participants resting for 1 hr. Also, changes in HR and BP during 3-hr meditation were analyzed. HR was recorded continuously during meditation (n = 38) and the control rest (n = 21). BP was measured before and after the meditation (n = 44) and the rest (n = 30). During the first hour, HR declined more in the meditators than the controls (p < .01). Within participant variability of HR was significantly lower during meditation than rest (p < .05). In the second hour of meditation, HR declined further (p = .01). BP was unaffected by either meditation or rest. In conclusion, meditation reduced the level of HR and within participant variability of HR more than rest. HR continued to decline during the second hour of meditation.     

XIIIth INTERNATIONAL COURSE ON CHRONOPHARMACOLOGY Ruprecht-Karls-Universität Heidelberg Summer School 2012: 30 July – 4 August

Daily rhythmicity in the locomotor activity of laboratory animals has been studied in great detail for many decades, but the daily pattern of locomotor activity has not received as much attention in humans. We collected waist-worn accelerometer data from more than 2000 individuals from five countries differing in socioeconomic development and conducted a detailed analysis of human locomotor activity. Body mass index (BMI) was computed from height and weight. Individual activity records lasting 7 days were subjected to cosinor analysis to determine the parameters of the daily activity rhythm: mesor (mean level), amplitude (half the range of excursion), acrophase (time of the peak) and robustness (rhythm strength). The activity records of all individual participants exhibited statistically significant 24-h rhythmicity, with activity increasing noticeably a few hours after sunrise and dropping off around the time of sunset, with a peak at 1:42?pm on average. The acrophase of the daily rhythm was comparable in men and women in each country but varied by as much as 3?h from country to country. Quantification of the socioeconomic stages of the five countries yielded suggestive evidence that more developed countries have more obese residents, who are less active, and who are active later in the day than residents from less developed countries. These results provide a detailed characterization of the daily activity pattern of individual human beings and reveal similarities and differences among people from five countries differing in socioeconomic development.     

Hypothermia after chronic mild stress exposure in rats with a history of postnatal maternal separations

The circadian system develops and changes in a gradual and programmed process over the lifespan. Early in life, maternal care represents an important zeitgeber and thus contributes to the development of circadian rhythmicity. Exposure to early life stress may affect circadian processes and induce a latent circadian disturbance evident after exposure to later life stress. Disturbance of the normal regulation of circadian rhythmicity is surmised to be an etiological factor in depression. We used postnatal maternal separation in rats to investigate how the early life environment might modify the circadian response to later life unpredictable and chronic stress. During postnatal days 2–14, male Wistar rats (n?=?8 per group) were daily separated from their mothers for a period of either 180?min (long maternal separation; LMS) or 10?min (brief maternal separation; BMS). In adulthood, rats were exposed to chronic mild stress (CMS) for 4 weeks. Body temperature, locomotor activity and heart rate were measured and compared before and after CMS exposure. LMS offspring showed a delayed body temperature acrophase compared to BMS offspring. Otherwise, adult LMS and BMS offspring demonstrated similar diurnal rhythms of body temperature, locomotor activity and heart rate. Exposure to CMS provoked a stronger and longer lasting hypothermia in LMS rats than in BMS rats. The thermoregulatory response appears to be moderated by maternal care following reunion, an observation made in the LMS group only. The results show that early life stress (LMS) in an early developmental stage induced a thermoregulatory disturbance evident upon exposure to unpredictable adult life stressors.     

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

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

Activity Monitoring of the Inhabitants in Tauwema,a Traditional Melanesian Village: Rest/Activity Behaviour of Trobriand Islanders (Papua New Guinea)

The inhabitants of Tauwema village represent a traditionally living society. Altogether, 39 inhabitants belonging to seven families were included in this study. Families or people living in one household were preferentially chosen for monitoring particularly the effects of social zeitgebers and synchronization within families. They were observed continuously for 7 consecutive days using microelectronic actometers that register locomotor activity with a sampling period of 2 minutes and a resolution of 7 bit. The activity data obtained showed that in young infants circadian patterns develop out of ultradian components dominating in the first months of life. The rhythmicity of the adults was well-related to the natural light-dark cycle, combined with a strong social component which is reflected in a comparatively small intra- and inter-individual variability in the time of the end of the main sleep span in the morning, while the variability in the beginning of the main sleep period in the evening is much greater. The mean sleep duration of the younger infants (up to 11 months; n =4) varied between 9 and 12 h per day and that of the adults (n = 23) between 7 and 10 h. Gender-specific differences occurred in married couples with wives having a longer sleep duration in 7 out of 9 cases.     

Depression-like behavior is associated with lower Per2 mRNA expression in the lateral habenula of rats

Circadian rhythm dysfunction is primary symptom of depression and is closely related to depression onset. The role of the lateral habenula (LHb) of the thalamus in the pathogenesis of depression has been a research topic of great interest. The neuronal activity of this structure has circadian characteristics, which are related to the regulation of circadian rhythms. However, in depression model of rats, the role of clock genes in the LHb has not been assessed. To address this gap, we used a clomipramine (CLI) injection-induced depression model in rats to assess the daily expression of rhythmic genes in the LHb and depression-like behavior in rats at multiple time points. In determining the role of the Per2 gene in the development of depression-like behavior in the LHb, we found that the expression of this clock gene differed in a circadian manner. Per2 expression was also significantly decreased in CLI-treated rats in late afternoon (17:00) and in the middle of the night (1:00). Furthermore, silencing Per2 in the LHb of normal rats induced depression-like behavior at night, suggesting that Per2 may play an important role in the pathogenesis of depression. Collectively, these results indicate that decreased Per2 expression in the LHb may be related to increased depression-like behavior at night in depression model of rats.     

General health of elderly institutionalised and community-dwelling Brazilians

Objective: To evaluate the heart rate, blood pressure, blood glucose and other important indicators of the general health of an elderly population of São José dos Campos, Brazil. Materials and methods: A cross‐sectional study was conducted among 150 institutionalised and 150 community‐dwelling individuals aged 60 years or more. The parameters evaluated were heart rate, blood pressure and blood glucose. The elderly also answered a questionnaire about osteoporosis, falls, physical exercising, participation in social events, type of foods ingested, Alzheimer and Parkinson’s diseases and medication. Results: The institutionalised elderly showed an average heart rate of 75.1, while that of the community‐dwelling elderly was 76.7. The percentage of systolic hypertension in the institutionalised and community‐dwelling groups was 36% and 30% respectively, while diastolic hypertension showed a percentage of 40% and 57%, and diabetes was 32% and 30%. Among the institutionalised and community‐dwelling groups, 13.3% and 21.3% respectively, reported osteoporosis, 31.3% and 42.7% falls, 7.3% and 24% exercised regularly, 4% and 69.3% participated regularly in social events, 58.7% and 51.3% reported eating solid foods, and 13.3% and 2%, respectively, suffered from Alzheimer’s disease. Parkinson’s disease was reported by 2% in both groups. The institutionalised elderly reported taking an average of 3.2 medications, while among community‐dwelling elderly this number was 1.8. Conclusion: The entire sample presented a high prevalence of hypertension, diabetes and osteoporosis. No significant differences were found in the systemic health of the elderly institutionalised and community‐dwelling groups. However, the latter group reported more frequent falls, participation in social events and exercised regularly.