Circadian Influence in Cardiovascular Disease (part 2)

Gabriel A. Valle, M.D., Louis Lemberg, M.D., F.C.C.P.

This department will offer stylized clinical presentations of current cardiovascular issues. Questions raised as a case history evolves highlight key elements that are elaborated upon in the discussions which follow.

The circadian effects on major cardiovascular and cerebrovascular diseases result in increased vulnerability to myocardial ischemia, cerebral ischemia, and myocardial dysfunction during the early hours of the morning after awakening and rising.

A comprehensive approach to treatment in patients with cardiovascular disorders must take into consideration the chronobiology of the cardiovascular system and its relevance to the underlying disease process that affects the cardiovascular system. The interaction between endogenous and exogenous daily rhythms can moderate cardiovascular morbidity and mortality. The capacity to adapt to temporal changes in the environment may well be a factor in the survival of the species.

This is the second of a two-part series, in which a third case is presented to permit elaboration on additional aspects of circadian influence in cardiovascular disease.

Case Reports
Cask 3

A 53-year-old hanker was brought to the emergency room after experiencing a syncopal episode during an early morning meeting at his office. At the scene fire rescue personnel found the patient alert and lying on the floor. He complained of light-headedness and a burning sensation in the epigastrium. Vital signs by paramedics revealed a regular heart rate of 40 beats/minute, blood pressure of 85/65 mm Hg, and respirations of 16/minute. His skin was clammy, the lung fields were clear. Examination of the heart revealed an S1 variable in intensity and no heart murmurs.

An electrocardiographic rhythm strip revealed third-degree atrioventricular block with narrow QRS complexes. Following 1 mg of intravenous atropine sulfate the heart rate increased to 60 beats/minute and the blood pressure rose to 110/70 mm Hg. He was warm and dry and no longer lightheaded.

The patient was a heavy smoker who had been seeing his physician regularly because of recurrent upper gastrointestinal symptoms occurring predominantly in the morning hours. A gallbladder ultrasound examination disclosed no abnormalities and upper gastrointestinal tract series revealed a small sliding hiatal hernia without reflux. Therapy with an H2-antagonist yielded inconsistent results and the patient had been scheduled to undergo an exercise stress test. Earlier that day, he was awakened at 6:30 am by an insidious feeling of indigestion and nausea that improved partially after taking liquid antacids.

On arrival at the hospital an electrocardiogram revealed sinus bradycardia and ST segment elevation in the inferior leads consistent with an early pattern of acute myocardial infarction. A low-dose aspirin tablet was given and intravenous nitroglycerin and tissue-type plasminogen activator infusion were begun two hours after the syncopal episode. Hours later the electrocardiogram had normalized and the patient was asymptomatic. He was discharged on the sixth hospital day on a regimen of low-dose aspirin, propranolol, and oral nitrates.

One month later cardiac catheterization revealed subtotal occlusion of the right coronary artery and 50 percent stenosis of the left anterior descending and circumflex arteries. He underwent successful single-vessel percutaneous transluminal angioplasty and was discharged from the hospital three days later on a regimen of low-dose aspirin, long-acting nitrates, and propranolol.

1. Concerning the clinical implications of time-related changes in cardiovascular integration:

aa circadian variability on the incidence of major cardiovascular events (myocardial ischemia, infarction, sudden cardiac death, strokes, and certain arrhythmias) has been demonstrated in recent years (T,F)
btransient myocardial ischemia, whether silent or symptomatic, is more likely to occur within the first four waking hours (T,F)
cthe circadian variation in the frequency of onset of acute myocardial infarction demonstrates a significant morning peak (between 6 am and 12 noon) for each day of the week (T,F)
dsudden cardiac death occurs more frequently in the early hours of the morning (7 am to 11 am) and is less likely to occur during the evening hours (11 pm to 6 pm) (T,F)
ecerebrovascular accidents (subarachnoid and intraparenchymal hemorrhages and thromboembolic cerebral infarction) have a peak incidence between 10 am and 12 noon (T,F)
fin-hospital cardiovascular mortality displays a significant circadian variation. (T,F)
2. Concerning the chronobiology of human cardiovascular function:

amany rhythmic variations in cardiovascular integration follow a circadian periodicity (T,F)
bchanges in the “autonomic tone” of the body are the major determinants of the variability of several cardiovascular parameters (T,F)
cdaily changes in hemodynamic measurements (ie, blood pressure, heart rate) are closely related to the astronomic cycle of day and night (T,F)
dthe arousal phenomena (awakening/rising) is characterized by a sympathetic predominance affecting the cardiovascular system (T,F)
eone of the earliest pathophysiologic changes observed in hypertensive individuals is the absence of a circadian cardiovascular rhythm (T,F)
fthe exogenous daily rhythms that begin after waking (ie, increased physical and mental activity, components of the rest-activity cycle) can modulate the extent and quality of the cardiovascular circadian response. (T,F)
gunder normal circumstances the morning hours (6 am to 12 noon) constitute the period of maximal spontaneous (unprovoked) cardiovascular stress. (T,F)

1. a. T; b. T; c. F; d. T; e. T; f F.

In recent years, a number of authors have clearly documented a circadian rhythm in the timing of cardiovascular morbidity and mortality. Several studies have shown that the major acute cardiovascular disorders, transient myocardial ischemia, acute myocardial infarction, sudden cardiac death, and stroke, occur more frequently within the interval from 6 am to 12 noon and reach their lowest incidence during the night (midnight to 6 am).1, 2, 3, 4

Various reports on ambulatory ischemia monitoring have demonstrated a predominance of ischemic activity in the mornings.2, 3, 4, 5 Using 24-hour Holter monitoring to detect transient myocardial ischemia in 32 patients with chronic stable angina, Rocco and associates2 established a significant circadian variation in the incidence of transient ischemic events: 39 percent of such episodes occurred between 6 am and 12 noon. Furthermore, an even stronger relationship was found when the occurrence of ischemic ST segment depressions (with or without symptoms) was corrected for the time of awakening and arising. The maximal incidence of transient myocardial ischemia was observed during the first four hours after waking and peak ischemic activity occurred one to two hours after rising.

The same authors found no difference in the incidence of painful ischemic attacks (15 percent overall), activity level, threshold heart rate, ischemic threshold, or the duration of attacks at different times of the day. They found, however, that heart rates within the “ischemic range” were more common in the morning, and that the likelihood of developing ischemic ST depression once these rates were exceeded was significantly higher in the morning. The ratio of total ischemic time to the total threshold time was 26 percent in the morning and only 15 percent in the evening.2
Similar studies have also shown that the episodes of ischemic ST changes are often prolonged, asymptomatic, and frequently associated with nonexertional, nonstressful, routine activities.5, 6, 7 These findings taken collectively offer support to the concept of an enhanced vasomotor coronary tone associated with awakening/rising.

Two major studies on the cyclic variation of the incidence of acute myocardial infarction and sudden cardiac death have demonstrated a remarkably similar circadian periodicity.3,4 The incidence of both cardiac disorders was maximal during the morning hours, ie, 6 am to 12 noon. Although data concerning time of awakening in the populations studied were not available, it was suggested that recalculation of the hourly frequencies of such morbid events related to waking time would likely yield a more prominent circadian rhythm.1
In the acute myocardial infarction study group, (a byproduct of the original multicenter investigation of limitation of infarct size [MILIS] study), this salient circadian variation was consistently observed in various population subgroups and showed no difference related to age, history of coronary artery disease, cigarette smoking, or coffee ingestion.3 After further analysis of their database the investigators made two important collateral observations: the 24-hour periodicity was not present in patients whose myocardial infarction began on Saturday or Sunday, nor was it present when they were taking β-blockers in the 24 hours before the onset of myocardial infarction.3 Due to sample size and lack of correction for waking time, no definite conclusions could be reached from those observations. A suggestion was made, however, that one of the mechanisms by which adrenergic blocking agents may protect from ischemic cardiac events is by suppressing or blunting the effects of the catecholamine surge associated with the arousal phenomenon. The absence of a circadian rhythm on weekends may reflect differences in the collective habits of a population and the importance of exogenous daily rhythms in modulating the hemodynamic response associated with waking.

The circadian variability in the incidence of sudden cardiac death is virtually identical to the periodicity seen in transient myocardial ischemia and acute myocardial infarction. On the other hand, in accordance with several previous reports that indicate a low incidence of sudden cardiac death during sleep (average 12 percent), Muller and associates4also established a trough in the incidence of sudden cardiac death from 11 pm to 6 am.

Assuming that ischemia is the common pathophysiologic denominator linking these cardiovascular disorders, it is clear that the physiologic events that constitute the arousal phenomenon (waldng/arising) increase the risk of ischemiainduced myocardial damage. The lack of differences related to age, gender, and known risk factors in the different populations involved in these three major studies2, 3, 4 indicates that the multiple cardiovascular changes occurring during the transition from sleep to an aroused, active state constitute a universal physiologic adaptation to the return to mental and physical activity.

In addition to these major cardiovascular manifestations of coronary insufficiency, certain arrhythmias (atrioventricular junctional and idioventricular rhythms, ventricular premature beats, nonsustained ventricular tachycardia, and the ventricular rates in atrial fibrillation to mention a few) exhibit characteristic circadian variations. Establishing a direct cause-effect relationship between arrhythmic events and myocardial ischemia/necrosis is not always possible, and although many rhythm abnormalities are manifestations of impaired coronary blood supply, the incidence of primary arrhythmias could be modulated by the increased adrenergic tone that characterizes the awakening/rising period.

Additionally, two recent studies using computed tomographic scanning of the brain have demonstrated a circadian pattern of stroke onset similar to that of acute myocardial infarction and sudden cardiac death.8,9 These multiple observations underscore the clinical relevance of the complex cardiovascular and hemodynamic changes that take place on awakening/rising that are conducive to a state of increased cardiovascular vulnerability; the hourly incidence of in-hospital cardiac death is virtually identical for each hour of the day.

2. a. T; b. T; c. F; d. T; e. F; f T; g. T.

The presence of an internal biologic clock has been long recognized by physiologists. Multiple hemodynamic and neurohumoral changes occur with predictable and consistent periodicity in the human. The repetitive, cyclic nature of these biorhythms and its relationship with the environment is the subject of study of human chronobiology.

In practical terms, the functional timing unit for the human appears to be approximately one day: the 24-hour cycle of alternating light and darkness. Many biorhythms exhibit a periodicity that approximates 24 hours. The term circadian encompasses the chronologic variability of such biologic phenomena during a given time interval. Circadian (circa: about, dies: a day), pertaining to a period of about 24 hours, is applied especially to the rhythmic repetition of certain phenomena about the same time each day. The phasic secretion of cortisol and growth hormone and the cyclic variation of body temperature are classic examples of circadian biorhythms.

At first hand, intuitive reasoning tends to correlate the day and night or more appropriately the sleep-wake cycle with the structure of the circadian variations of certain biologic rhythms. Despite the relative simplicity of this assumption, the time course of many physiologic phenomena nevertheless occurs with a predictable periodicity which is tightly linked to these external (environmental) cycles. However, organization of the human circadian timing system and its relationship with the environment appears to be more complex. Inherent to the circadian concept is the need for an accurate perception of a reliable indicator of environmental time. This precise dynamic interaction between external and internal rhythms implies the ability to recognize and quantitate time.

The term “Zeitgeber” (a German neologism translated as “time giver”) encompasses the concept of this nature’s clock capable of being perceived by the human body.10 The timing and organization of many internal phenomena are guided by this environmental “pacemaker,” resulting in the predictable periodicity of many biorhythms. Of the many potential atmospheric Zeitgeber, the most reliable indicator of environmental time is the regular diurnal alternation of light and darkness.

The endogenous nature of circadian rhythms has been long established. Studies in humans and other mammalian species involving complete isolation from environmental time cues (periodic variations of light, temperature, and humidity) demonstrated the presence of an internal “biological clock” localized in the brain. Under these circumstances all mammalians had a persistent rhythmicity in the rest-activity, body temperature, and other cycles. It is therefore the interaction between these markers of environmental time and the internal pacemaker(s) (capable of being reset) that determines the structure and rhythmicity of many physiologic biorhythms. Under most circumstances, however, this time-dependent interaction between the organism and its surroundings is bidirectional: changes in patterns of activity (ie, inversion of the sleep-wake pattern; sleep deprivation) or in the environment (ie, resulting from travel to another time zone or significant variations in daylight time) may result in the temporary disruption and/or resetting of endogenous biorhythms.

Adding to the complexity of the circadian timing system, increasing evidence supports the existence of two independent internal pacemakers. Under normal circumstances physiologic systems are influenced by signals from both sources. The circadian rhythms observed in each variable are the results of this dual interaction. Theoretic mathematical models of the human circadian system considering two interacting oscillators have been remarkably successful in reproducing and predicting experimental findings.11
In recent years, extensive research in the field of cardiovascular diseases supports the contention that this interaction between endogenous and exogenous daily rhythms is of significant clinical relevance and could potentially modulate cardiovascular morbidity and mortality (vide infra).

The circadian variability of certain hemodynamic measurements has been long recognized. In normal individuals blood pressure levels and heart rate decline during sleep and increase during waking/rising time. Millan-Craig and associates12 studied normotensive and hypertensive volunteers using continuous ambulatory intra-arterial blood pressure monitoring during a 48-hour period. These authors showed similar rhythmic variations in blood pressure/heart rate in both groups of subjects, with a circadian periodicity.

In all individuals the rate of increase in blood pressure (dP/dT) is maximal during the waking period. Moreover, the increases in blood pressure begin approximately 1 h before waking and peak 2 h after waking. Changes in heart rate were also maximal during the first 2 h following awakening rising, but no increase in heart rate preceded waking time.12As mentioned previously, despite a consistently elevated mean arterial pressure, this rhythmic pattern was maintained in hypertensive volunteers.

The controlling mechanism for this circadian blood pressure/heart rate variation is primarily neurohumoral. In contrast to a predominantly vagotonic state during sleep, the arousal phenomenon is associated with sympathetic stimulation.1,13,14 Wertheimer and associates14 studied ten normotensive subjects and reported a 24-hour rhythmic variation of blood pressure/heart rate and systolic time intervals that correlated with endogenous catecholamine secretion. Thus, these periodic hemodynamic changes are the consequence of a precise integration between an endogenous biologic clock in the human brain which determines the autonomic tone of the body and the peripheral effects of a timed catecholamine release, both of which are independent of the astronomical cycle of day and night. This synchronized cardiovascular response may be disrupted by abnormalities involving the neural pacemaker, the efferent pathways, target organs, or by the presence of other modulators of cardiovascular function. Attenuated and/or absent circadian related changes in sinus node function are seen in patients with diabetic autonomic neuropathy, transplanted hearts, severe congestive heart failure, hyperthyroidism,15and treatment with certain cardiotropic agents. Moreover, in some of these clinical entities a dissociation between the circadian variations of blood pressure/heart rate is also present.

The remarkable influence of external stimuli in modulating this cardiovascular response during the transition from sleep to an active state is underscored by the observation that individuals who arouse from sleep but remain in bed (nonambulatory) exhibit a blunted hemodynamic response. The change to an erect position and possibly the mental stress associated with initiating the daily activities is an important component of this arousal phenomenon. In addition to enhancing catecholamine secretion, other hormonal systems with vasoactive properties are activated on standing (renin-angiotensin-aldosterone, antidiuretic hormone) and may contribute to this cardiovascular integration.

Some of the consequences of circadian rhythmicity in physiology are exemplified by the differences in integration of a given response in certain phases of the circadian cycle that may render the individual more vulnerable to challenge. Likewise, time-dependent variations in compensatory mechanisms activated to counteract ongoing disease processes may create abnormal rhythms of susceptibility to additional stimuli. For instance, the physiologic increase in many cardiovascular variables (ie, blood pressure, heart rate, left ventricular contractility, conduction system dromotropic states, etc) which occurs in early morning as a consequence of the return to physical activity after sleep and the resulting increase in cardiovascular work and stress substantiate the early morning hours as a potentially vulnerable period for individuals with underlying cardiovascular disorders. Moreover, added to the paramount clinical relevance of circadian variability in the integration of bodily function in health and disease, several pharmacologic agents have circadian rhythms of drug effectiveness or toxicity. Like rhythms of disease susceptibility, these variations in the profiles of safety or effectiveness of many drugs appear to be a function of multiple component physiologic rhythms.16

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