Impaired modulation of circadian rhythms in patients with diabetes mellitus: a risk factor for cardiac thrombotic events?

Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from rupture of atherosclerotic plaques with superimposed thrombosis and exhibit a pronounced circadian rhythmicity, peaking in the morning hours. Two potentially synergistic mechanisms play a pathogenic role in the circadian variation of arterial thrombotic events. A morning surge in sympathetic activity alters hemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. Day-night variations of hemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting intraluminal thrombus formation at the same time when the risk for plaque rupture is highest. Diabetic patients have a very high cardiac event rate but fail to show normal circadian fluctuations in the occurrence of myocardial infarction. Alterations in the circadian variation autonomic tone, blood pressure, and the thrombotic-thrombolytic equilibrium have been documented in diabetic patients. These include reduced or absent 24-h periodicity in autonomic tone, fibrinolytic activity, and thrombotic tendency, and a blunted decline in nocturnal blood pressure. Disruption of these circadian rhythms explains the lack of significant circadian distribution of cardiac events in diabetic patients. Moreover, the loss of these normal biorhythms results in a continuous susceptibility to thrombotic events throughout the day and may contribute to the excess cardiovascular mortality and morbidity in these patients. (Chronobiology International, 18(1), 109-121, 2001)     

24-Hour Assessment of Performance on a Palmtop Computer: Validating a Self-Constructed Test Battery

Serious adverse cardiovascular events, including myocardial infarction, sudden cardiac death, and stroke, frequently result from rupture of atherosclerotic plaques with superimposed thrombosis and exhibit a pronounced circadian rhythmicity, peaking in the morning hours. Two potentially synergistic mechanisms play a pathogenic role in the circadian variation of arterial thrombotic events. A morning surge in sympathetic activity alters hemodynamic forces and predisposes vulnerable coronary atherosclerotic plaques to rupture. Day–night variations of hemostatic and fibrinolytic factors result in morning hypercoagulability and hypofibrinolysis, promoting intraluminal thrombus formation at the same time when the risk for plaque rupture is highest. Diabetic patients have a very high cardiac event rate but fail to show normal circadian fluctuations in the occurrence of myocardial infarction. Alterations in the circadian variation autonomic tone, blood pressure, and the thrombotic–thrombolytic equilibrium have been documented in diabetic patients. These include reduced or absent 24-h periodicity in autonomic tone, fibrinolytic activity, and thrombotic tendency, and a blunted decline in nocturnal blood pressure. Disruption of these circadian rhythms explains the lack of significant circadian distribution of cardiac events in diabetic patients. Moreover, the loss of these normal biorhythms results in a continuous susceptibility to thrombotic events throughout the day and may contribute to the excess cardiovascular mortality and morbidity in these patients. (Chronobiology International, 18(1), 109–121, 2001)     

Circadian Variations in Blood Coagulation Parameters, Alpha-Antitrypsin Antigen and Platelet Aggregation and Retention in Clinically Healthy Subjects

Ten clinically healthy subjects (5 men and 5 women), 31 11 yrs of age, were studied at six timepoints (0800, 1200, 1600, 2000, 0000, 0400) distributed over a 1-week span. Circadian rhythms in platelet aggregation in response to adenosine diphosphate (ADP) and adrenalin (A), platelet adhesiveness measured as retention in a glass bead column, prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, Factor VIII activity and alpha-1-antitrypsin antigen showed circadian rhythms. The plasma concentrations of plasminogen, alpha-2-macroglobulin, and antithrombin III (AT III) antigen, Factor V and fibrinogen degradation products showed no circadian rhythm by ANOVA or cosinor analysis. The phase relations of the rhythms of different coagulation parameters are of interest in the physiology and pathobiology of the coagulation-fibrinolytic system. The extent of the circadian rhythm (range of change) described is not of a magnitude to lead to diagnostic problems in the clinical laboratory. The timing of these rhythms, however, may determine transient risk states for thromboembolic phenomena, including myocardial infarction and stroke. Several but not all coagulation parameters suggest a transient state of hypercoagulability during the morning hours. The recognition of these rhythmic, and thus in the time of the occurrence predictable temporary risk states for thromboembolic phenomena, may lead to timed treatment and/or effective prevention.     

Circadian Variation of Myocardial Ischemia in Patients with Stable Coronary Artery Disease

The circadian variation of myocardial ischemia detected during 24-h ambulatory electrocardiographic monitoring (AEM) was analyzed in 123 patients with stable angina pectoris, positive exercise test, and angiographically proven coronary artery disease. A total of 437 ischemic episodes (ST-segment depression ≥ 1 mm and duration ≥ 1 min) were observed; 333 (76%) episodes remained asymptomatic, and only 104 (24%) episodes were accompanied by anginal pain. Ischemic episodes predominantly occurred during the morning hours, between 6 a.m. and noon, and another smaller peak was observed in the afternoon, between 4 and 5 p.m.; this diurnal pattern was influenced neither by the extent of coronary artery disease nor the degree of left ventricular dysfunction. The circadian variation was restricted to the 345 (78%) ischemic episodes preceded by increases in heart rate; the 92 (22%) episodes without prior heart rate changes occurred randomly throughout the day. The morning peak in ischemic episodes was not associated with less myocardial oxygen supply; in contrast, heart rate profile showed parallel increases during the morning and afternoon hours, indicating elevated myocardial demand during these periods. Ischemia-related ventricular arrhythmias were concentrated during the morning hours, but their overall prevalence was low-28 (6%) of 437 ischemic episodes. These findings may provide further insight into the pathomechanisms of acute clinical events in patients with coronary artery disease, since the circadian variation of myocardial ischemia is very similar to that observed for the onset of myocardial infarction and sudden cardiac death.     

Circadian Variation of Myocardial Ischemia in Patients with Stable Coronary Artery Disease

The circadian variation of myocardial ischemia detected during 24-h ambulatory electrocardiographic monitoring (AEM) was analyzed in 123 patients with stable angina pectoris, positive exercise test, and angiographically proven coronary artery disease. A total of 437 ischemic episodes (ST-segment depression ≥ 1 mm and duration ≥ 1 min) were observed; 333 (76%) episodes remained asymptomatic, and only 104 (24%) episodes were accompanied by anginal pain. Ischemic episodes predominantly occurred during the morning hours, between 6 a.m. and noon, and another smaller peak was observed in the afternoon, between 4 and 5 p.m.; this diurnal pattern was influenced neither by the extent of coronary artery disease nor the degree of left ventricular dysfunction. The circadian variation was restricted to the 345 (78%) ischemic episodes preceded by increases in heart rate; the 92 (22%) episodes without prior heart rate changes occurred randomly throughout the day. The morning peak in ischemic episodes was not associated with less myocardial oxygen supply; in contrast, heart rate profile showed parallel increases during the morning and afternoon hours, indicating elevated myocardial demand during these periods. Ischemia-related ventricular arrhythmias were concentrated during the morning hours, but their overall prevalence was low–28 (6%) of 437 ischemic episodes. These findings may provide further insight into the pathomechanisms of acute clinical events in patients with coronary artery disease, since the circadian variation of myocardial ischemia is very similar to that observed for the onset of myocardial infarction and sudden cardiac death.     

Circadian Rhythms of Early Afterdepolarizations and Ventricular Arrhythmias in a Cardiomyocyte Model

Sudden cardiac arrest is a malfunction of the heart’s electrical system, typically caused by ventricular arrhythmias, that can lead to sudden cardiac death (SCD) within minutes. Epidemiological studies have shown that SCD and ventricular arrhythmias are more likely to occur in the morning than in the evening, and laboratory studies indicate that these daily rhythms in adverse cardiovascular events are at least partially under the control of the endogenous circadian timekeeping system. However, the biophysical mechanisms linking molecular circadian clocks to cardiac arrhythmogenesis are not fully understood. Recent experiments have shown that L-type calcium channels exhibit circadian rhythms in both expression and function in guinea pig ventricular cardiomyocytes. We developed an electrophysiological model of these cells to simulate the effect of circadian variation in L-type calcium conductance. In our simulations, we found that there is a circadian pattern in the occurrence of early afterdepolarizations (EADs), which are abnormal depolarizations during the repolarization phase of a cardiac action potential that can trigger fatal ventricular arrhythmias. Specifically, the model produces EADs in the morning, but not at other times of day. We show that the model exhibits a codimension-2 Takens-Bogdanov bifurcation that serves as an organizing center for different types of EAD dynamics. We also simulated a two-dimensional spatial version of this model across a circadian cycle. We found that there is a circadian pattern in the breakup of spiral waves, which represents ventricular fibrillation in cardiac tissue. Specifically, the model produces spiral wave breakup in the morning, but not in the evening. Our computational study is the first, to our knowledge, to propose a link between circadian rhythms and EAD formation and suggests that the efficacy of drugs targeting EAD-mediated arrhythmias may depend on the time of day that they are administered.     

CLOCK is required for maintaining the circadian rhythms of Opsin mRNA expression in photoreceptor cells

In zebrafish, the expression of long-wavelength cone (LC) opsin mRNA fluctuated rhythmically between the day and night. In a 24-h period, expression was high in the afternoon and low in the early morning. This pattern of fluctuation persisted in zebrafish that were kept in constant darkness, suggesting an involvement of circadian clocks. Functional expression of Clock, a circadian clock gene that contributes to the central circadian pacemaker, was found to play an important role in maintaining the circadian rhythms of LC opsin mRNA expression. In zebrafish embryos, in which the translation of Clock was inhibited by anti-Clock morpholinos, the circadian rhythms of LC opsin mRNA expression diminished. CLOCK may regulate the circadian rhythms of LC opsin mRNA expression via cyclic adenosine monophosphate (cAMP)-dependent signaling pathways. In control retinas, the concentration of cAMP was high in the early morning and low in the remainder of the day and night. Inhibition of Clock translation abolished the fluctuation in the concentration of cAMP, thereby diminishing the circadian rhythms of opsin mRNA expression. Transient increase of cAMP concentrations in the early morning (i.e. by treating the embryos with 8-bromo-cAMP) restored the circadian rhythms of LC opsin mRNA expression in morpholino-treated embryos. Together, the data suggest that Clock plays important roles in regulating the circadian rhythms in photoreceptor cells.     

Circadian and seasonal variations of physiological and biochemical determinants of acute myocardial infarction

Almost all cardiovascular events occur according to a circadian rhythm with a greater frequency in the morning on waking and when resuming activity, the mechanism and precise triggering events for myocardial infarction (MI) are not yet fully known. Multiple biologic functions show a diurnal and/or seasonal variation that may contribute to adverse cardiac outomes. Exogenous factors may also modulates these variations. The MI peak usually occurs between 07:00 and 12:00 h. This timing corresponds to the concurrent increase in platelet aggregability, blood concentration of cortisol, catecholamines, angiotensin II, myocardial oxygen demand and coagulation activity, while fibrinolytic activity is decreased. In this review paper we will point out the biological rhythms of a number of functions involved in acute myocardial infarction e.g. blood pressure, hormonal determinants, cholesterol, among others.     

Circadian variation in stroke onset: identical temporal pattern in ischemic and hemorrhagic events

Stroke is the culmination of a heterogeneous group of cerebrovascular diseases that is manifested as ischemia or hemorrhage of one or more blood vessels of the brain. The occurrence of many acute cardiovascular events—such as myocardial infarction, sudden cardiac death, pulmonary embolism, critical limb ischemia, and aortic aneurysm rupture—exhibits prominent 24 h patterning, with a major morning peak and secondary early evening peak. The incidence of stroke exhibits the same 24 h pattern. Although ischemic and hemorrhagic strokes are different entities and are characterized by different pathophysiological mechanisms, they share an identical double-peak 24 h pattern. A constellation of endogenous circadian rhythms and exogenous cyclic factors are involved. The staging of the circadian rhythms in vascular tone, coagulative balance, and blood pressure plus temporal patterns in posture, physical activity, emotional stress, and medication effects play central and/or triggering roles. Features of the circadian rhythm of blood pressure, in terms of their chronic and acute effects on cerebral vessels, and of coagulation are especially important. Clinical medicine has been most concerned with the prevention of stroke in the morning, when population-based studies show it is of greatest risk during the 24 h; however, improved protection of at-risk patients against stroke in the early evening, the second most vulnerable time of cerebrovascular accidents, has received relatively little attention thus far.     

Effects of Pregnancy and Parturition on Free-Running Circadian Activity Rhythms in the Rat

Alterations in circadian rhythms have previously been associated with estrous and seasonal changes in reproductive state. In the present study we explored the effects of the reproductive events of pregnancy and parturition on free-running circadian activity rhythms in the rat. Free-running rhythms were monitored before mating, during pregnancy, and following parturition and removal of pups. Systematic and long-lasting alterations of the period of the free-running activity rhythm were seen following parturition. The effects of estrous, seasonal, and gestational reproductive states on circadian rhythms may be mediated by the endocrine events which accompany these states.     

Effects of Pregnancy and Parturition on Free-Running Circadian Activity Rhythms in the Rat

Alterations in circadian rhythms have previously been associated with estrous and seasonal changes in reproductive state. In the present study we explored the effects of the reproductive events of pregnancy and parturition on free-running circadian activity rhythms in the rat. Free-running rhythms were monitored before mating, during pregnancy, and following parturition and removal of pups. Systematic and long-lasting alterations of the period of the free-running activity rhythm were seen following parturition. The effects of estrous, seasonal, and gestational reproductive states on circadian rhythms may be mediated by the endocrine events which accompany these states.     

Circadian Variations of Heart Rate and Premature Beats in Healthy Subjects and in Patients with Previous Myocardial Infarction

Chronobiological analysis of the circadian variations of heart rate, ventricular and atrial ectopies, was carried out on 11 patients with previous myocardial infarction matched with 11 controls. Individual circadian rhythms in heart rate were seen in all the control subjects but only in 6 patients with previous myocardial infarction. The behaviour of the individual circadian rhythms of premature beats was not significantly different between the two groups. A significant group rhythm in ectopies was not demonstrated, nevertheless a trend to higher frequency of arrhythmias during the activity span was detected. These results do not allow to postulate a circadian pattern of arrhythmias common to all the subjects examined. Therefore, the individual circadian behaviour of premature atrial and ventricular beats should be recognized for monitoring antiarrhythmic therapy. A significant group rhythm in heart rate was demonstrated for the two populations studied and linear discriminant analysis showed that the amplitude of this rhythm was significantly lower in patients than in controls. Possibly, myocardial infarction may affect the sinus node function producing a “flattened” range of heart rates during the 24 hours.     

RETINAL CIRCADIAN RHYTHMS IN HUMANS *

Circadian rhythms in the retina may reflect intrinsic rhythms in the eye. Previous reports on circadian variability in electrophysiological human retinal measures have been scanty, and the results have been somewhat inconsistent. We studied the circadian variation of the electrooculography (EOG), electroretinography (ERG), and visual threshold (VTH) in subjects undergoing a 36h testing period. We used an ultrashort sleep-wake cycle to balance effects of sleep and light-dark across circadian cycles. Twelve healthy volunteers (10 males, 2 females; mean age 26.3 years, standard deviation [SD] 8.0 years, range 19-40 years) participated in the study. The retinal functions and oral temperature were measured every 90 min. The EOG was measured in the light, whereas the ERG and the VTH were measured in the dark. Sleep was inferred from activity detected by an Actillume monitor. The EOG peak-to-peak responses followed a circadian rhythm, with the peak occurring late in the morning (acrophase 12:22). The ERG b-wave implicit time peaked in the early morning (acrophase 06:46). No statistically significant circadian rhythms could be demonstrated in the ERG a-wave implicit time or peak-to-peak amplitude. The VTH rhythm peaked in the early morning (acrophases 07:59 for blue and 07:32 for red stimuli). All retinal rhythms showed less-consistent acrophases than the temperature and sleep rhythms. This study demonstrated several different circadian rhythms in retinal electrophysiological and psychophysical measures of healthy subjects. As the retinal rhythms had much poorer signal-to-noise ratios than the temperature rhythm, these measures cannot be recommended as circadian markers. (Chronobiology International, 18(6), 957-971, 2001)     

The human endogenous circadian system causes greatest platelet activation during the biological morning independent of behaviors

Background

Platelets are involved in the thromboses that are central to myocardial infarctions and ischemic strokes. Such adverse cardiovascular events have day/night patterns with peaks in the morning (∼9AM), potentially related to endogenous circadian clock control of platelet activation. The objective was to test if the human endogenous circadian system influences (1) platelet function and (2) platelet response to standardized behavioral stressors. We also aimed to compare the magnitude of any effects on platelet function caused by the circadian system with that caused by varied standardized behavioral stressors, including mental arithmetic, passive postural tilt and mild cycling exercise.

Methodology/Principal Findings

We studied 12 healthy adults (6 female) who lived in individual laboratory suites in dim light for 240 h, with all behaviors scheduled on a 20-h recurring cycle to permit assessment of endogenous circadian function independent from environmental and behavioral effects including the sleep/wake cycle. Circadian phase was assessed from core body temperature. There were highly significant endogenous circadian rhythms in platelet surface activated glycoprotein (GP) IIb-IIIa, GPIb and P-selectin (6–17% peak-trough amplitudes; p≤0.01). These circadian peaks occurred at a circadian phase corresponding to 8–9AM. Platelet count, ATP release, aggregability, and plasma epinephrine also had significant circadian rhythms but with later peaks (corresponding to 3–8PM). The circadian effects on the platelet activation markers were always larger than that of any of the three behavioral stressors.

Conclusions/Significance

These data demonstrate robust effects of the endogenous circadian system on platelet activation in humans—independent of the sleep/wake cycle, other behavioral influences and the environment. The ∼9AM timing of the circadian peaks of the three platelet surface markers, including platelet surface activated GPIIb-IIIa, the final common pathway of platelet aggregation, suggests that endogenous circadian influences on platelet function could contribute to the morning peak in adverse cardiovascular events as seen in many epidemiological studies.     

Circadian rhythm of activity and sleep‐wakefulness in elderly institutionalized persons

Abstract

The circadian rhythms of blood pressure (BP) and heart rate (HR) were documented in 30 patients for a 24‐hour period before and during the 24 hours that included unilateral surgery for senile cataract or retinal detachment. The patients were premedicated with diazepam. Anaesthesia was induced at a fixed time (09.00) in all patients with thiopentone, and muscle relaxation was with pancuronium. Maintenance was with enflurane in 15 patients and with fentanyl and droperidol in the rest. Though the intraoperative changes in haemodynamic parameters were dissimilar with the two types of maintenance agents, but both types had a similar effect on the circadian rhythms of blood pressure and heart rate. Whereas preoperatively the BP and HR circadian rhythms were nearly in phase, with their peaks in the late morning to early afternoon, the postoperative rhythms underwent a dissociation to a phase shift in the BP 24‐h pattern. The phase effect may be hypothetically attributed to direct pharmacological actions or to masking effects.     

RETINAL CIRCADIAN RHYTHMS IN HUMANS*

Circadian rhythms in the retina may reflect intrinsic rhythms in the eye. Previous reports on circadian variability in electrophysiological human retinal measures have been scanty, and the results have been somewhat inconsistent. We studied the circadian variation of the electrooculography (EOG), electroretinography (ERG), and visual threshold (VTH) in subjects undergoing a 36h testing period. We used an ultrashort sleep-wake cycle to balance effects of sleep and light-dark across circadian cycles. Twelve healthy volunteers (10 males, 2 females; mean age 26.3 years, standard deviation [SD] 8.0 years, range 19–40 years) participated in the study. The retinal functions and oral temperature were measured every 90 min. The EOG was measured in the light, whereas the ERG and the VTH were measured in the dark. Sleep was inferred from activity detected by an Actillume monitor. The EOG peak-to-peak responses followed a circadian rhythm, with the peak occurring late in the morning (acrophase 12:22). The ERG b-wave implicit time peaked in the early morning (acrophase 06:46). No statistically significant circadian rhythms could be demonstrated in the ERG a-wave implicit time or peak-to-peak amplitude. The VTH rhythm peaked in the early morning (acrophases 07:59 for blue and 07:32 for red stimuli). All retinal rhythms showed less-consistent acrophases than the temperature and sleep rhythms. This study demonstrated several different circadian rhythms in retinal electrophysiological and psychophysical measures of healthy subjects. As the retinal rhythms had much poorer signal-to-noise ratios than the temperature rhythm, these measures cannot be recommended as circadian markers. (Chronobiology International, 18(6), 957–971, 2001)     

Role of photoperiodicity and circadian rhythm of glucocorticoids in synchronizing the fluctuations in free-radical oxidation of lipids in rats

A biphasic circadian rhythm in the content of liver lipid peroxidation products has been demonstrated in male Wistar rats housed under the conditions of 12L: 12D, with 3 hours of morning and evening twilight. Maxima of the concentration of the products were observed in the morning and early at night. The rhythm of lipid anti-oxidative activity was found in an anti-phase. Inversion of both the L: D cycle and glucocorticoid circadian rhythms (cortisol injections) led after 14-16 days to the same shifts in the rhythm of anti-oxidative activity. The data indicate that glucocorticoids modulate the diurnal rhythms of lipid anti-oxidative activity and may be responsible for the shifts in the rhythms of free radical oxidation, induced by inversion of the L: D cycle.     

Orcadian, Weekly, and Seasonal Variations in Cardiac Mortality, Blood Pressure, and Catecholamine Excretion

Time of occurrence of cardiac death due to arrhythmia, heart failure, or acute myocardial infarction was recorded in 86 elderly subjects, belonging to a group in whom circadian and circannual rhythms in blood pressure and urinary catecholamine excretion had been studied previously. All patients were retired, with no work responsibilities, and lived-closely-supervised in a home for the aged-on a routine that provided little differences between weekdays and weekends. Cardiac mortality showed a circadian variation, with a peak in the early morning hours, coinciding with the circadian peak in systolic and diastolic blood pressures. A weekly (circaseptan) variation in cardiac mortality was found, with the greatest number of patients dying on Mondays and the least on Thursdays. There were seasonal differences in cardiac mortality, with a peak in July and a broader peak during the cold season (December to February). The former coincides with the circannual peak in diastolic blood pressure, but is unrelated to the seasonal variation in norepinephrine excretion. Circadian, circaseptan, and circannual variations in cardiac mortality appear to be the expression of time-dependent, transient risk states for catastrophic cardiac events, which may lend themselves to preventive treatment.     

Rev-erb alpha gives a time cue to metabolism

Normal physiological processes are under control of circadian rhythms. Moreover, certain pathological events, such as cardiovascular accidents (myocardial infarction, stroke) occur more frequently at specific times of the day. Recent observations demonstrate a causal relationship between alterations in circadian rhythmicity and metabolic disorders. Disruption of clock genes results in dyslipidemia, insulin resistance and obesity, all predisposing to atherosclerosis. The nuclear receptor Rev-erb alpha is part of the clock circuitry and plays an important role in keeping proper timing of the clock. Rev-erb alpha also regulates lipid metabolism, adipogenesis and vascular inflammation. Interestingly, Rev-erb alpha also cross-talks with several other nuclear receptors involved in energy homeostasis. Therefore Rev-erb alpha may serve to couple metabolic and circadian signals.     

Twenty-four-hour pattern of angina pectoris, acute myocardial infarction and sudden cardiac death: Role of blood pressure, heart rate and rate-pressure product circadian rhythms

Population-based epidemiology and clinical case studies document a prominent 24-hour pattern in the occurrence of silent and non-silent angina pectoris (AP), acute myocardial infarction (AMI), and sudden cardiac death (SCD). When the data are summarized per 3 - 6 hour intervals of the 24 hours, the temporal pattern of these ischemic heart disease (IHD) events shows a single morning peak between 06:00 and 12:00 h in incidence. However, when the occurrence of such events is examined according to the hour of their occurrence, several studies reveal a second late-afternoon/early-evening minor peak. The true day - night pattern in AP, AMI, and SCD is unknown because the data represent nothing more than the recorded “time of day” of the events. It has been postulated that the day - night pattern in IHD events is at least in part dependent on endogenous circadian rhythms, which are synchronized by the daily routine of sleep in darkness/activity in light. Approximately 20% of the working population is involved in night and rotating shift employment; thus, “time of day” studies are not likely to accurately represent the actual “chronorisk” of vulnerable individuals to IHD events. Moreover, it is likely that the events in the persons comprising the population and clinical case studies were influenced by ongoing treatment with antihypertensive, anticoagulant, and antianginal medications. Details regarding the class, dose, and schedule of such medications are rarely if ever reported in accounts of IHD events. Many of the investigations were conducted decades ago, when short-acting antihypertensive and cardiovascular medications required twice or thrice-a-day dosing, and thus the observed day - night variations could be significantly affected by such multiple treatment timings each day. Thus, the magnitude and nature (single versus multiple peaks) of the reported day - night patterns in AP, AMI, and SCD are suspect, as are their geneses. Presently, it is hypothesized that multiple cyclic exogenous triggers (e.g. posture, physical exertion, emotional stress, and medication scheduling) superimposed upon an endogenous 24-hour susceptibility-resistance pattern that arises from circadian rhythms in heart rate, blood pressure, rate-pressure product, and haemostasis, are major contributory factors.