[Enzymatic activity of paraoxonase depending on polymorphism Q192R of the PON1 gene in patients with primary open-angle glaucoma]. / Fermentativnaya aktivnost' paraoksonazy v zavisimosti ot polimorfizma Q192R gena PON1 u patsientov s pervichnoi otkrytougol'noi glaukomoi.

It is believed that one of the main blood enzymes that hydrolyzes oxidized lipids incorporated in lipoproteins is the calcium-dependent hydrolase of paraoxonase 1, which has a significant antioxidant effect depending on the polymorphism of the PON1 gene. PURPOSE: To genotype patients with primary open-angle glaucoma (POAG) by the Q192R polymorphism of the PON1 gene in order to identify their genetic predisposition to dyslipidemia and atherosclerosis, as well as to determe the possibility of correcting the reduced activity of the PON1 enzyme in the examined individuals by the complex drug Cytoflavin. MATERIAL AND METHODS: The study included 25 men with advanced POAG, IOP compensated by hypotonic agents, and 20 volunteers without POAG (mean age 63.0±5.4 years). All subjects underwent genotyping by the Q192R polymorphism of the PON1 gene using an analyzer. PON1 activity was assessed by the rate of nitrophenol formation when paraoxone diluted in acetone was added to the blood plasma. At the second stage, patients (of different phenotypes) were prescribed the complex drug Cytoflavin. RESULTS: Homozygous carriers of the 192R allele were found to have significantly lower levels of PON1 activity than homozygous carriers of the Q192 allele. Carriage of the 192R allele may determine an increased risk of atherosclerotic injury in patients with POAG, especially in cases with high levels of atherogenic blood lipoproteins, low levels of high-density lipoproteins, or high levels of peroxidized lipids in the blood. The drug Cytoflavin showed a positive therapeutic effect on oxidative stress and hypercholesterinemia in POAG patients. CONCLUSION: These findings can be used to determine the atherogenicity of lipoproteins and the progression of glaucomatous optic neuropathy and to optimize the therapy of PAHO.

Progressive retinal ganglion cell loss in primary open-angle glaucoma is associated with temperature circadian rhythm phase delay and compromised sleep.

Advanced primary open-angle glaucoma (POAG) is characterized by progressive retinal ganglion cell complex (RGCC) damage that may cause subsequent disruption of the circadian rhythms. Therefore, we evaluated circadian body temperature (BT) rhythm and sleep characteristics of 115 individuals (38 men and 77 women) diagnosed with POAG. GLV (global loss volume; %), a measure of RGCC damage, was estimated by high-definition optical coherence tomography, and RGC functional ability was assessed by pattern electroretinogram amplitude (PERGA). Depending on dynamics of POAG progression criteria, two groups were formed that were distinctively different in GLV: Stable POAG group (S-POAG; GLV = 5.95 ± 1.84, n = 65) and Progressive POAG group (P-POAG; GLV = 24.27 ± 5.09, n = 50). S-POAG and P-POAG groups were not different in mean age (67.61 ± 7.56 versus 69.98 ± 8.15) or body mass index (24.66 ± 3.03 versus 24.77 ± 2.90). All subjects performed 21 around-the-clock BT self-measurements during a 72-h period and kept activity/sleep diaries. Results showed pronounced disruption of circadian physiology in POAG and its progression with increasing severity of the disease. The daily mean of BT was unusually low, compared to age-matched controls. Moreover, our results revealed distinctive features of BT circadian rhythm alterations in POAG development and POAG progression. S-POAG is associated with lowered BT circadian rhythm robustness and inter-daily phase stability compared to controls. In the P-POAG group, the mean phase of the circadian BT rhythm was delayed by about 5 h and phases were highly scattered among individual patients, which led to reduced group mean amplitude. Circadian amplitudes of individuals were not different between the groups. Altogether, these results suggest that the body clock still works in POAG patients, but its entrainment to the 24-h environment is compromised. Probably because of the internal desynchronization, bedtime is delayed, and sleep duration is accordingly shortened by about 55 min in P-POAG compared to S-POAG patients. In the entire POAG cohort (both groups), later sleep phase and shorter mean sleep duration correlate with the delayed BT phase (r = 0.215; p = 0.021 and r = 0.322; p = 0.0004, respectively). An RGCC GLV of 15% apparently constitutes a threshold above which a delay of the circadian BT rhythm and a shortening of sleep duration occur.

Disrupted circadian rhythms of body temperature, heart rate and fasting blood glucose in prediabetes and type 2 diabetes mellitus.

We report a progressive disruption of 24-h rhythms in fasting blood glucose (FBG), body temperature (BT) and heart rate (HR) associated with metabolic dysfunction and the development of prediabetes (PD) and type 2 diabetes mellitus (T2DM) in overweight middle-aged (40-69 years old) humans. Increasing BT and HR mean values and declining 24-h BT and HR amplitudes accompany adverse changes in metabolic state. Increased nocturnal BT and a phase delay of the 24-h BT rhythm, deviant 24-h HR profile and a phase advance of the 24-h HR and FBG rhythms are early signs of the PD metabolic state. In T2DM, the 24-h FBG rhythm is no longer detectable, and the 24-h amplitudes of BT and HR are greatly diminished. In addition, lepton and creatinine values were lowered in T2DM. Moreover, positive correlations between FBG and body mass index, BMI, and negative correlations between the 24-h amplitude of FBG and BMI indicate that overweight is an additional factor causing disruption of the circadian rhythms. Further studies on circadian disruption as a consequence of metabolic dysfunction are necessary. The quantitative analysis of changing circadian BT and HR rhythms may provide prognostic markers of T2DM and therapeutic targets for its prevention and correction.

Activity, sleep and ambient light have a different impact on circadian blood pressure, heart rate and body temperature rhythms.

The aim of the present study was to investigate the impact of endogenous and exogenous factors for the expression of the daily rhythms of body temperature (BT), blood pressure (BP) and heart rate (HR). One hundred and seventy-three young adults (YA), 17-24 years old (y.o.), of both genders were studied under a modified constant-routine (CR) protocol for 26 h. Participants were assigned randomly to groups with different lighting regimens: CR-LD, n = 77, lights (>400 l×) on from 09:00 to 17:00 h and off (<10 l×) from 17:00 to 09:00 next morning; CR-LL, n = 81, lights on (>400 l×) during the whole experimental session; CR-DD, n = 15, constant dim light (<10 l×) during the whole experiment. Systolic (SBP) and diastolic (DBP) BP, HR and BT were measured every 2 h. For comparison, the results of the former studies performed under conditions of regular life with an activity period from 07:00 to 23:00 h and sleep from 23:00 till 07:00 h (Control) were reanalyzed. Seven-day Ambulatory Blood Pressure Monitoring (ABPM) records from 27 YA (16-38 y.o.) and BT self-measurement data from 70 YA (17-30 y.o.) taken on ≥ 3 successive days at 08:00, 11:00, 14:00, 17:00, 20:00, 23:00 and 03:00 were available. The obtained daily patterns were different between Control and CR-DD groups, due to effects of activity, sleep and light. The comparison of Control and CR-LD groups allowed the effects of sleep and activity to be estimated since the lighting conditions were similar. The activity level substantially elevated SBP, but not DBP. Sleep, on the other hand, lowered the nighttime DBP, but has no effect on SBP. HR was affected both by activity and sleep. In accordance with previous studies, these results confirm that the steep BP increase in the morning is not driven by the circadian clock, but rather by sympathoadrenal factors related to awakening and corresponding anticipatory mechanisms. The effect on BT was not significant. To investigate the impact of light during the former dark time and darkness during the former light time, the CR-LL and CR-DD groups were each compared with the CR-LD group. Light delayed the evening decrease of BT, most likely via a suppression of the melatonin rise. Besides, it had a prominent arousal effect on SBP both in the former light and dark phases, a moderate effect on DBP and no effect on HR. Darkness induced decline in BT. BP values were decreased during the former light time. No effects on HR were found. Altogether, the results of the present paper show that BT, BP and HR are affected by exogenous factors differently. Moreover, the effect was gender-specific. Especially, the response of BT and BP to ambient light was evident only in females. We suppose that the distinct, gender-specific responses of SBP, DBP and HR to activity, sleep and ambient light do reflect fundamental differences in the circadian control of various cardiovascular functions. Furthermore, the presented data are important for the elaboration of updated reference standards, the interpretation of rhythm disorders and for personalized chronotherapeutic approaches to prevent adverse cardiovascular events more effectively.

[Temporal order deterioration and circadian disruption with age. 2. Systemic mechanisms and correction].

Part 2 of the present review highlights the impact of aging on mechanisms involved in response of the circadian system to different photic and non-photic factors, especially zeitgebers. Promising strategies to prevent age-dependent circadian disruption using internal and external factors that may entrain circadian rhythms are presented. In particular, benefits of bright light, melatonin and other chronobiotics, the circadian body temperature rhythm, physical activity and regular feeding schedules to preserve the temporal order of aged organisms are discussed, emphasizing especially a personalized approach based on the assessment of individual overt rhythms parameters.

[TEMPORAL ORDER DETERIORATION AND CIRCADIAN DISRUPTION WITH AGE].

The present review summarizes the current knowledge of gradual deterioration of temporal order in aging humans and other mammals. An obvious consequence of age-dependent circadian disruption in complex mechanisms is extra-circadian dissemination (ECD) that can be observed in overt rhythmic functions. ECD is a variance transposition from circadian to ultradian and infradian frequencies accompanied by a loss of interdaily phase stability. Moreover, heterochronic changes in central and peripheral tissue-specific cellular mechanisms are involved in circadian desychronization. A multitude of internal factors accounts for cumulative clockwork misalignment. Age-related circadian disruption is a consequence of weaker rhythm generation and the loss of proper orchestration on molecular, tissue and systemic levels, disabling their circadian synchrony and resonance.

[Molecular basis of circadian rhythms and principles of circadian disruption].

Current knowledge of core molecular mechanisms of circadian system is reviewed with intent look at consequences of pleiotropic effects of phase and amplitude disturbances in rhythmic expression of genome-transcriptome-proteome elements in development of desynchronized phenotypic functions. Multiple adverse implications of compromised circadian synchronization for health and longevity are discussed. Concept of extracircadian dissemination of output physiological functions as a general feature of phenotypic circadian disorder is PRESENTED.

[Proliferativeactivity biorhythms of museum and hospital strains of microorganisms].

In series of experiments intraday dynamics of proliferative activity of museum and hospital strains of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa was revealed. Statistically significant circadian and ultradian biorhythms in these strains were detected. Chronoinfrastructure of hospital strains differed from museum ones. This finding allows to detect hospital strains of these bacteria.

The circadian body temperature rhythm in the elderly: effect of single daily melatonin dosing.

The present study is part of a more extensive investigation dedicated to the study and treatment of age-dependent changes/disturbances in the circadian system in humans. It was performed in the Tyumen Elderly Veteran House and included 97 subjects of both genders, ranging from 63 to 91 yrs of age. They lived a self-chosen sleep-wake regimen to suit their personal convenience. The experiment lasted 3 wks. After 1 control week, part of the group (n=63) received 1.5 mg melatonin (Melaxen) daily at 22:30 h for 2 wks. The other 34 subjects were given placebo. Axillary temperature was measured using calibrated mercury thermometers at 03:00, 08:00, 11:00, 14:00, 17:00, and 23:00 h each of the first and third week. Specially trained personnel took the measurements, avoiding disturbing the sleep of the subjects. To evaluate age-dependent changes, data obtained under similar conditions on 58 young adults (both genders, 17 to 39 yrs of age) were used. Rhythm characteristics were estimated by means of cosinor analyses, and intra- and inter-individual variability by analysis of variance (ANOVA). In both age groups, the body temperature underwent daily changes. The MESOR (36.38+/-0.19 degrees C vs. 36.17+/-0.21 degrees C) and circadian amplitude (0.33+/-0.01 degrees C vs. 0.26+/-0.01 degrees C) were slightly decreased in the elderly compared to the young adult subjects (p<0.001). The mean circadian acrophase was similar in both age groups (17.19+/-1.66 vs. 16.93+/-3.08 h). However, the inter-individual differences were higher in the older group, with individual values varying between 10:00 and 23:00 h. It was mainly this phase variability that caused a decrease in the inter-daily rhythm stability and lower group amplitude. With melatonin treatment, the MESOR was lower by 0.1 degrees C and the amplitude increased to 0.34+/-0.01 degrees C, a similar value to that found in young adults. This was probably due to the increase of the inter-daily rhythm stability. The mean acrophase did not change (16.93 vs. 16.75 h), although the inter-individual variability decreased considerably. The corresponding standard deviations (SD) of the group acrophases were 3.08 and 1.51 h (p<0.01). A highly significant correlation between the acrophase before treatment and the phase change under melatonin treatment indicates that this is due to a synchronizing effect of melatonin. Apart from the difference in MESOR, the body temperature rhythm in the elderly subjects undergoing melatonin treatment was not significantly different from that of young adults. The data clearly show that age-dependent changes mainly concern rhythm stability and synchronization with the 24 h day. A single daily melatonin dose stabilizes/synchronizes the body temperature rhythm, most probably via hypothermic and sleep-improving effects.

[The rhythms of arterial pressure and heart rate in individuals with arterial hypertension under the conditions of Far North].

The circadian and ultradian rhythms of blood pressure (BP) and heart rate (HR) were studied by means of 24-hour BP monitoring in patients with arterial hypertension (AH) and practically healthy people working in Far North shifts. The subjects were 418 men. The main group consisted of 177 men aged 18 to 59 working in trans-polar shifts in Yamburg, Tyumen region, latitude 57 North. The comparison group included 158 residents of a moderate climatic zone (Tyumen, latitude 57 North). The control group consisted of 83 practically healthy men, of whom 43 worked in Far North shifts, and 40 were residents of Tyumen. The groups were comparable by age, AH duration, and office systolic and diastolic BP (SBP; DBP). The study demonstrates that even healthy people working in Far North shifts display high BP variability and the decrease of the stability and power of SBP, DBP and HR circadian rhythms due to the reduction of the amplitude, contribution of the rhythm to the total variability, and the increase of the amplitude of high-frequency harmonics of the spectrum (a manifestation of extracircadian dissemination), which may be a sign of accelerated ageing and biological age increase, and may facilitate AH development. Development of AH under the extreme conditions of Far North shifts, unlike the conditions of moderate climatic zones, is accompanied by progressive BH variability increase, the worsening of the chronological structure of SBP and DBP, the increase of extracircadian dissemination, which can be of both clinical and prognostic significance.

[Desynchronization: mechanisms of development from molecular to systemic levels]. / Desinkhronoz: mekhanizmy razvitiia ot molekuliarno-geneticheskogo do organizmennogo urovnia.

Striking progress in the field of molecular chronobiology has been made during the last years. It renders us to reconsider some traditional viewpoints concerning circadian system functioning. Not only we are able now to explain basic concept of how clock genes pass through transcriptional and post-transcriptional pathways and how circadian system eventually "comes to life" at the cellular level, but we are also in position to speculate on how the whole organism constitutes its space-temporal order and how certain ultradians and infradians could be generated. Herein we propose a concept of multifuctorial genesis of chronomes and suggest terms such as "input rhythm" (or influencing rhythm) and "output rhythm" (or modulated rhythm). We stress on a viewpoint that the majority of investigated variables are multifuctorial by its nature because of vast net of regulatory mechanisms lied down in between the molecular basis of the clock and the output rhythms which are actually measurable by investigators. An attempt to follow down mechanisms of loss in the circadian temporal order (desynchronization) from the molecular level to that of a whole organism has been provided.

[Circadian rhythms and seasonally dependent variability of arterial pressure in patients with arterial hypertension in the Khanty-Mansiysky region]. / Sutochnye ritmy i variabel'nost' arterial'nogo davleniia v zavisimosti ot sezonov goda u bol'nykh arterial'noi gipertoniei v Khanty-Mansiiskom okruge.

Key parameters of 24-h blood pressure monitoring (BPM) in 46 18-50-year-old patients (men and women) with arterial hypertension (AH) stage I, II and 33 healthy persons living in the Tyumen North (Khanty-Mansiysky Region, the town of Nyagan) were investigated. The comparison group consisted of 55 patients with AH stage I, II and 33 healthy persons living in moderate climate (Tyumen) matched by sex, age, duration of AH, office systolic and diastolic arterial pressure (SAP, DAP). General patterns of 24-h and seasonal rhythms of AP fluctuations in healthy northerners and citizens of moderate climatic zone and mismatch of these rhythms in AH patients more evident in the northerners are shown. Paired correlations were obtained which indirectly confirm the priority role of daily AP rhythm in development of visceral lesions irrespective of the season of the year and climatic load. In the North, when winter meets spring, a surge of SAP, DAP and mean AP occurs as well as an increase in heart rate, number of patients with disturbed circadian profile of AP. In moderate climate these changes are more typical for summer period. The results of the study necessitate design of programs of additional pharmacological and preventive measures for hypertensive northerners with consideration of AP seasonal rhythms and climatic load.

[Development and course of arterial hypertension based on 24-hour monitoring of arterial pressure in a population of the Tyumen region]. / Razvitie i techenie arterial'noi gipertonii po dannym sutochnogo monitorirovaniia arterial'nogo davleniia v usloviiakh Tiumenskogo priob'ia.

Arterial pressure (AP) was monitored in 46 patients with arterial hypertension (AH) aged 18-50 years and in 33 healthy subjects living in Russian North (Tyumen Ob area, Nyagan). The comparison group consisted of 55 patients with AH and 33 healthy subjects living in a moderate climatic zone (Tyumen). The groups were comparable by gender, age, duration of AH, office systolic and diastolic AP (SAP and DAP). Healthy subjects of Tyumen North compared to those living in the moderate climate had more pronounced vegetative imbalance which may transform into AH. The North AH is characterized by high meteorability, impaired circadian AH profile with reduction of the SAP fall day-night and an increase of the DAP fall, greater variability of AP, elevated AP day load, low night DAP. This classifies AH in the northerners as isolated systolic. While AH development in the North takes place due to marked AP fluctuations, in moderate climate it follows a classic variant--due to a DAP rise. The above changes may help prognosis of emergence of cardiovascular complications in hypertensive patients living in the North.

[Characteristics of circadian rhythms of arterial pressure and heart rate in hypertensive subjects living in the North of the Tiumen' region]. / Osobennosti tsirkadiannykh ritmov arterial'nogo davleniia i chastoty serdechnykh sokrashchenii u bol'nykh arterial'noi gipertoniei, postoianno prozhivaiushchikh v usloviiakh Tiumenskogo Pripoliar'ia.

Chronostructure of arterial pressure (AP) and heart rate (HR) was studied in 62 residents of Tumen Region North with arterial hypertension (AH) aged 18-50 years and 56 AH controls living in the temperate zone. The groups were matched by age, sex, AH duration, office systolic and diastolic arterial pressure (SAP and DAP, respectively). Circadian AP profile with night hypertension was registered in 76.6 and 28.3% patients of the test and control groups, respectively. Test group patients had more pronounced defects in DAP and HR chronostructures. Thus, AH patients living in the Tumen North demonstrate abnormal circadian AP profile and AP and HR chronostructure. This may be prognostically important for development of cardiovascular complications.

[Chronological structure of arterial pressure in hypertensive patients on enalapril]. / Khronostruktura arterial'nogo davleniia u bol'nykh gipertonicheskoi bolezn'iu na fone terapii énalaprilom.

34 male patients with hypertension stage I and II aged 29-52 years (mean age 40.9 +/- 6.00) having mean 24-h arterial pressure (AP) above 135/85 mm Hg in mean daytime AP above 140/90 mm Hg and heart rate maximum 80 b/m entered the study of AP chronostructure in conditions of pure background and on enalapril treatment week 4, 8 and 12. The initial dose of the drug was 5 mg. Dose selection was controlled by 24-h AP monitoring. Enalapril was shown to significantly reduce mean daytime and 24-h AP as well as hyperbaric index, chronobiological time index, variability of systolic AP. The above dose selection brought more balanced AP lowering at daytime and at night. After 11 weeks of treatment no night-peakers were registered, the number of over-dippers decreased. Circadian rhythm of some hemodynamic parameters was characterized by a significant fall of rhythm average in unchanged acrophase and circadian AP amplitude indicating physiological action of enalapril.

The cosmos and CHAT, prompting blood pressure and heart rate monitoring for Dérer's week.

BACKGROUND: The effects of natural environmental factors upon health, documented in Minnesota, support the proposition of Bratislava's champions of the cosmos and of the biological week, gauged via circaseptan rhythms by the late Ladislav Dérer, whose "macro-rhythm" lasted "most frequently about 6 days". MAIN PURPOSE: To introduce 7-day monitoring of blood pressure and heart rate into routine practice. STARTING POINTS AND METHODS: Cosinor analysis on 7-day series determines (conventionally ignored) consistent blood pressure overswinging, i.e., circadian hyper-amplitude-tension (CHAT), a disease risk syndrome, whether it is associated with a normal average blood pressure or a high blood pressure. RESULTS: Summary of information understandable by the general population on the dynamics of blood pressure. CONCLUSIONS AND MEANING FOR PRACTICE AND THEORY: Space weather reports may prompt preventive measures. Caution dictates in any event monitoring blood pressure and heart rate for 7 days to attempt to prevent strokes, rather than to ignore the greatest yet detectable risk of catastrophic vascular disease, CHAT, a risk greater than old age or high blood pressure. (Tab. 1, Fig. 3, Ref. 31.)

Spin-offs from blood pressure and heart rate studies for health care and space research.

Evidence here cited underlies resolutions at international meetings to initiate a chronobiology project for health improvement. This project demonstrates expeditiously the feasibility and the health benefits of incorporating chronomedical considerations in the diagnosis, treatment, and prevention of one (or a few closely related) vascular (and oncological) diseases, that have high awareness and importance in the public perspective. Thereby, chronomedicine should become a mainstream basic and applied speciality leading to continual improvement in national/international health status. Reference data obtained for health care can also serve to give a better understanding of the relationship between the terrestrial biosphere and cosmoi near and far.

Chronomedical aspects of oncology and geriatrics.

Extensive laboratory evidence on the merits of cancer chronotherapy is validated by the doubling of 2-year disease-free survival rate obtained by the chronoradiotherapy of patients with very advanced perioral cancers and by the quadrupling of the 5-year survival achieved by the chronochemotherapy of patients with advanced ovarian and bladder cancer. Miniaturized monitors for marker rhythmometry of tumor and core temperature recorded over long spans should facilitate the optimization of treatment by timing, while also serving the purpose of earliest intervention. The likelihood of a cure should be increased by focusing upon the now extensively documented tumor marker rhythms that may show time structure (chronome) alterations before exceeding the physiological range (that is otherwise neglected as one of random variation), and before overt symptoms appear.

Multivariant analysis of men from infertile couples with and without antisperm antibodies.

PROBLEM: Research studies in animal and human systems have demonstrated conclusively that antisperm antibodies can interfere with fertilization. In the male, autoantibodies to sperm can be detected both in the sera and seminal plasma. METHOD OF STUDY: Ninety-seven men who were tested for antisperm antibodies as a part of an infertility evaluation were identified. Complete medical history was obtained, including information related to events suspected of being associated with antisperm antibodies. History of surgery (varicocele repair, hernia repair, and vas reversal) and infection (epididymitis, sexually transmitted disease, and orchitis) were compared with semen parameters (motility less than 60%, concentration less than 20 x 10(6), and volume less than 2 cc). These were compared to antisperm antibody results of mixed agglutination reaction (MAR) and direct immunobead binding test (IBT) for immunoglobulin G (IgG). Statistical analysis was performed using Fishers exact two-tailed test. RESULTS: As expected, prior vas reversal was significantly associated with the presence of antisperm antibodies (P = 0.0002) by MAR or IBT with a fivefold increased relative risk (95% confidence interval, 1.97-12.38). Other surgeries manipulating the cord structures independent of vas reversal were not associated with antisperm antibodies (P = 0.09). Prior infections, independent of vas reversal, were significantly associated with antisperm antibodies by MAR (P = 0.04) with a 3.8-fold increased relative risk (95% confidence interval, 1.06-13.87) but not by IBT. Sperm concentration less than 20 x 10(6), motility less than 60%, and a volume less than 2 cc were not associated with antisperm antibodies by MAR or IBT. CONCLUSION: These findings suggest that manipulation of the cord structures excluding the vas were not associated with antisperm antibodies; however, vas reversal and prior infection are significant risk factors for the development of antisperm antibodies.

Rewards in practice from chrono-meta-analyses 'recycling' heart rate, ectopy, ischemia and blood pressure information.

Previously published average curves of heart rate and duration of ischemia in patients with coronary artery disease, studied while on placebo or on treatment with either atenolol or diltiazem, are re-analysed for the assessment of about-daily (circadian) and about-weekly (circaseptan) changes in these variables and of any treatment effect on rhythm characteristics. In addition to circadians, a circaseptan pattern characterizes the duration of ischemia in all three aforementioned study stages. Both drugs decrease the duration of ischemia, atenolol, but not diltiazem, also affects the circadian amplitude and acrophase of this variable. A circaseptan pattern is also found for heart rate on placebo and on treatment with atenolol, but not with diltiazem. Both drugs lower heart rate and the circadian amplitude and 24-h standard deviation of heart rate, atenolol much more markedly than diltiazem. Circadian and circaseptan rhythm characteristics and their alterations with treatment serve to optimize treatment by timing its administration. Chronobiologic surveillance of variables that are being readily monitored as-one-goes by modern implantable devices can also serve for the validation of the effectiveness of drug and electrical therapy. Rhythm alterations, in turn, can provide the earliest warnings of an elevated disease risk and lead to an improved diagnosis.