(Circulation. 1995;92:1507-1516.)
© 1995 American Heart Association, Inc.
Articles |
Circadian Variation in Human Ventricular Refractoriness
From the Division of Cardiology, Department of Internal Medicine, and the Feinberg Cardiovascular Research Center, Northwestern University Medical School, Chicago, Ill.
Correspondence to Alan H. Kadish, MD, Northwestern Memorial Hospital, 250 E Superior St, Suite 524, Chicago, IL 60611.
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Abstract |
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Background The incidence of sudden cardiac death is highest in the morning hours. Although a circadian variation in myocardial ischemia may be responsible in part for this observation, other factors also may be contributory. It is not known whether a circadian variation in ventricular refractoriness exists that may be related to the increased morning incidence of sudden cardiac death.
Methods and Results Nine subjects with primary conduction system disease, no evidence of structural heart disease, and permanent pacemakers were studied. Autonomic nervous system function as assessed by tilt table and baroreflex sensitivity testing was normal in all subjects. Using noninvasive programmed stimulation, ventricular effective refractory periods were measured hourly for 24 hours. Potassium, epinephrine, and norepinephrine levels also were measured hourly. In a subset of five subjects, ventricular refractory periods were again measured hourly over 24 hours during ß-blockade. A significant circadian variation in ventricular refractoriness was noted, with a mean difference between the shortest and longest refractory periods in individual subjects of 23 ms and 21 ms at drive cycle lengths of 600 ms and 400 ms, respectively. In eight subjects, the shortest refractory periods observed over 24 hours occurred within 2 hours of waking (random probability <10-8). Adjustment of refractory period data according to the hour of waking resulted in a better correlation between ventricular refractory periods and time. Although a significant circadian variation was observed in potassium and catecholamine levels, neither was an independent predictor of refractory periods after adjustment for the hour of waking. The adjusted time of day was the only significant (P<.0001) independent predictor of refractory periods. ß-Blockade abolished the circadian variation in ventricular refractory periods.
Conclusions A significant circadian variation in ventricular refractory periods exists. Maximal shortening between hourly refractory periods as well as the shortest refractory periods occur in the early morning hours when the incidence of sudden cardiac death is greatest. Fluctuations in ß-adrenergic tone appear to be largely responsible for this phenomenon.
Key Words: circadian rhythm • refractoriness • death, sudden • electrophysiology
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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A circadian variation in the occurrence of acute cardiac events has been noted since 1960.1 Several studies have demonstrated that the incidence of sudden cardiac death is highest during the morning hours.2 3 The circadian variation in biochemical measures of thrombogenicity,4 5 anginal attacks,6 7 and the occurrence of acute myocardial infarction8 9 is similar to that of sudden cardiac death. These observations have led to the hypothesis that a circadian variation in the occurrence of myocardial ischemia is responsible for the observed increased morning incidence of sudden death.
However, the mechanisms underlying sudden cardiac death probably are multifactorial, and in some patients, primarily electrical factors or an interaction between electrical abnormalities and myocardial ischemia may be responsible for sudden cardiac death. Ambulatory recordings at the moment of sudden death have shown that ventricular tachycardia degenerating into ventricular fibrillation is a common terminal rhythm and often occurs in the absence of antecedent ischemic ST segment shifts.10 11 In addition, the frequency of complex ventricular ectopy12 13 and the occurrence of sustained monomorphic ventricular tachycardia14 15 also are greatest in the early morning hours when the incidence of sudden death is greatest. Thus, a circadian variation in cardiac electrophysiological parameters may be an alternate mechanism contributing to the circadian variation in sudden death.
ß-Adrenergic blocking drugs have been shown to reduce the incidence of sudden cardiac death,16 17 18 in some studies by as much as 30%. However, the mechanisms by which ß-blockers protect against sudden death are not entirely clear; antiplatelet, anti-ischemic, and antiarrhythmic effects have been proposed.19 20 To investigate whether a circadian variation in ventricular refractoriness exists that might contribute to the observed morning increase in the incidence of sudden cardiac death, hourly measurements of ventricular refractory periods over 24 hours were performed in subjects with permanent pacemakers and structurally normal hearts. Furthermore, to determine the effect of ß-blockade on ventricular refractory periods over 24 hours, refractory periods were remeasured hourly during a continuous infusion of propranolol.
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Methods |
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Subject Selection and Study Design
Men and women with permanent pacemakers that had been in place for at least 6 months were included in the present study. All were free of detectable coronary artery disease by history and previous stress testing, were in sinus rhythm, and had normal right and left ventricular function by two-dimensional echocardiography. No subject was receiving medications, had any conditions associated with autonomic nervous system dysfunction (such as diabetes mellitus), had a sleep disorder, or had a history of ventricular arrhythmias. All subjects had normal baseline complete blood counts and serum chemistry profiles, including calcium and magnesium levels. Written informed consent was provided by all participants, and the protocol was approved by the Institutional Review Board at Northwestern University Medical School.
Subjects were studied on three separate occasions. At the first visit, autonomic nervous system function was evaluated. At the second visit, subjects were admitted to the Clinical Research Center, and hourly determinations of ventricular refractory periods were performed over a 24-hour period in the drug-free state. A subset of subjects returned for a third visit, during which refractory periods were again determined hourly over a 24-hour period during ß-adrenergic blockade.
Autonomic Nervous System Testing
Head-up tilt table testing
was used to assess the integrity of
sympathetic cardiovascular reflexes. Pacemakers were
programmed to the lowest demand rates (usually 45 beats per minute) in
the DDD mode. Intravenous access and continuous ECG
monitoring were established. After supine vital signs had been stable
for 5 minutes, subjects were tilted to 70° for 40 minutes. An
abnormal response was defined as a drop in systolic blood pressure >30
mm Hg, a drop in diastolic blood pressure >15 mm Hg, or
failure of the heart rate to increase 
11 beats per
minute.21
Baroreflex sensitivity testing was used to
assess parasympathetic
cardiovascular reflexes. After heart rate and blood
pressure had returned to baseline, testing was performed with the
subject in the supine position. Phenylephrine was injected
as a bolus at an initial dose of 2.0 µg/kg; subsequent boluses were
given at least 10 minutes apart, increasing by 25 µg per bolus, to
achieve a rise in systolic blood pressure of 25 mm Hg. The
baroreflex sensitivity index was defined as the change in mean RR
interval divided by the change in systolic blood pressure compared with
baseline values. A baroreflex sensitivity index 9.0 ms/mm Hg was
considered normal.22 Although some subjects had had
pacemakers implanted for suspected sinus node dysfunction, this would
have resulted in lower baroreflex sensitivity indices, and all subjects
in the present study had normal values.
Circadian Protocol
Subjects were admitted to the Clinical
Research Center in the
morning in the nonfasting state. All rooms had windows facing open
environments. During the waking hours, subjects had no activity
restrictions but were required to rest supine for at least 10 minutes
before hourly measurements. Before sleep, the ECG leads and pacemaker
programming head were secured in place with an elastic bandage. Blood
samples were collected during sleep through extended
intravenous tubing. Thus, we were able to obtain blood
samples, reprogram pacemakers, and perform noninvasive programmed
stimulation from outside the room so that subjects were not awakened by
these maneuvers.
Assessment of Circadian Variation in Ventricular
Effective Refractory Periods
Baseline
Ventricular
effective refractory periods were
measured using noninvasive programmed electrical stimulation
techniques, as described previously.23 The right
ventricular effective refractory period was defined as the
longest S2 coupling interval at which capture failed to
occur. Ventricular refractory periods were measured using
eight-beat drive trains at drive cycle lengths of 600 ms and 400 ms
with 4-second intertrain pauses. A 1-minute ventricular
conditioning period was used at both drive cycle lengths before all
refractory period determinations,24 and refractory periods
were determined using the incremental method at 2-ms
steps.25 Bipolar distal cathodal stimulation was performed
at a pulse width of 0.6 ms and at a stimulus intensity of twice late
diastolic capture threshold as determined immediately
before each set of hourly measurements.
At the beginning of the protocol, ventricular stimulation was performed in each subject to exclude inducible ventricular arrhythmias. Two extrastimuli were introduced at basic drive cycle lengths of 600 ms and 400 ms, and coupling intervals were progressively shortened to 200 ms or until refractoriness occurred. No subject had inducible ventricular arrhythmias. Next, 10 sequential determinations of ventricular effective refractory periods were performed at both drive cycle lengths to determine the immediate reproducibility of refractory period measurements. Ventricular refractory periods then were determined in duplicate each hour at both drive cycle lengths over a 24-hour period. Refractory period measurements after waking were performed before subjects arose from bed. The mean of the two refractory periods at a given drive cycle length was taken as the hourly value. If the two refractory period measurements at a given hour and drive cycle length varied by more than 2 ms, a third measurement then was made, and the mean of the three refractory period measurements was taken as the hourly value. Pacemakers were reprogrammed to the DDD mode at 45 beats per minute between measurements.
ß-Blockade
A
subset of the original subjects underwent the identical
circadian protocol during a continuous infusion of
propranolol. Based on previously published data on
propranolol pharmacokinetics,26 a series of
propranolol infusions was designed to achieve sustained
serum levels of approximately 150 ng/dL because levels in this range
correlate with near-maximal ß-blockade.27 An initial
bolus of 0.25 mg/kg was given, followed by a high-dose infusion at a
rate of 0.002 mg/kg per minute for 1 hour; propranolol then
was infused at a maintenance rate of 6 mg/h over the next 24
hours. The first ventricular refractory period measurements
were performed at the beginning of the maintenance infusion and
were determined hourly for the next 24 hours by using the techniques
described above. Similarly, hourly blood samples for
epinephrine, norepinephrine, and potassium levels
were obtained.
As a physiological measure of the degree of
ß-blockade achieved during the propranolol infusion,
subjects were challenged with isoproterenol immediately after the 24th
refractory period measurements. Isoproterenol infusion was begun at 2
µg/min and was increased by 2 µg/min every 5 minutes to a maximum
rate of 6 µg/min. End points were defined as a rise in heart rate
20% from baseline, a drop in systolic blood pressure of 20 mm Hg,
or a drop in diastolic blood pressure of 10 mm Hg.
No arrhythmias were induced during the stimulation protocols. When using chest wall stimulation techniques to perform ventricular pacing, stimuli were not perceptible by subjects. Subjects were not awakened by ventricular pacing.
Blood Sampling
Blood samples for plasma epinephrine and
norepinephrine levels and serum potassium levels were
obtained immediately before all hourly refractory period measurements.
Samples were collected through intravenous catheters
without the use of tourniquets. Samples for catecholamine
levels were immediately transferred into chilled glass tubes containing
lithium heparin, and the plasma was immediately separated by
centrifugation at 3000 rpm for 15 minutes and stored at
-70°C until assayed. Catecholamine levels were
determined by high-performance liquid
chromatography with electrochemical
detection.28 In subjects who underwent testing during
propranolol infusion, blood samples for
propranolol levels were obtained immediately before the
1st, 6th, 12th, 18th, and 24th refractory period measurements. Blood
samples for propranolol levels were collected and processed
using an all-glass system29 in the absence of
heparin,30 and propranolol levels were
determined by fluorometric assay.
Statistical Analyses
The reproducibility of ventricular
refractory period
measurements was determined by calculating the coefficient of variation
of the 10 successive refractory period measurements performed at the
beginning of testing for each subject.
Two methods were used to analyze trends in study variables over 24 hours: harmonic regression analysis was used to demonstrate a significant circadian periodicity, and ANOVA with repeated measures was used to detect significant differences in a given variable at different times of day. A similar dual method of analysis has been used recently.14
The circadian variation in refractory period measurements was assessed using harmonic least-squares regression analysis.14 Results were fit to an equation of the form
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where
=2
/24, and ai,
bi, and ci are constants. The
highest-order harmonic equation with a significant (P<.05)
b or c coefficient was used to fit the data. A circadian variation in a
given variable was considered to be absent if neither coefficient
was significant.
After demonstrating by harmonic regression analysis that a significant circadian periodicity existed in ventricular refractory periods, ANOVA with repeated measures was performed to identify the times of day during which refractory periods differed significantly. All 24-hourly refractory period measurements were used at the repeated measure, with time of day being the factor. The Tukey method of adjustment for multiple comparisons was used to test for hourly differences in ventricular refractory periods. The relation between ventricular refractory periods and serum potassium or plasma catecholamine levels was examined by linear regression analysis in individual subjects. To identify independent predictors of ventricular refractory periods, ANCOVA with repeated measures was performed to assess the effects of time of day, serum potassium levels, and plasma epinephrine and norepinephrine levels.31 Time of day was treated as a categorical variable, and separate analyses of covariance were performed for each of the continuous variables.
An analysis was then performed to determine whether the circadian variation in ventricular refractory periods was more closely linked to the sleep-wake cycle than to the absolute time of day. To accomplish this, data for all subjects were realigned on a relative time scale, with time 0 representing the hour of waking or the hour of sleep onset for each subject.32 The temporal sequence in which the data were collected for each subject remained unchanged. The hours of waking and sleep onset were reported by subjects and referenced to the nearest hourly refractory period measurements. ANOVA was performed after the data were adjusted first according to the hour of waking and then according to the hour of sleep onset. To determine if adjustment for the sleep-wake cycle was an important factor in the circadian variability in refractoriness, the mean square error in the ANOVA models for the circadian variation in ventricular refractory periods was compared before and after adjustment. If adjustment for the hour of waking or the hour of sleep onset reduced the mean square error in the model by more than 25%, the fit of the model then was considered to be superior. Similarly, ANCOVA was performed after adjustment of all data for the hour of waking and the hour of sleep onset. Continuous variables are expressed as the mean±SD. A probability value of <.05 was considered statistically significant.
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Results |
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Subject Characteristics and Results of Autonomic Nervous System Testing
Characteristics of the study population are shown in Table 1
. Three women and six men with permanent pacemakers
were enrolled. The mean age was 54±10 years (range, 21 to 72 years).
Six subjects had received pacemakers for complete heart block. In three
subjects, the heart block was idiopathic and acquired; in two subjects,
it occurred after radiofrequency ablation for
supraventricular tachycardia; and in one
subject, it was congenital. The remaining subjects had received
pacemakers for apparent symptomatic sinus node dysfunction.
All subjects were in sinus rhythm at the time of study.
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The results of
sympathetic and parasympathetic nervous system
testing are shown in Table 1
. In all nine subjects, there was
an
appropriate blood pressure and heart rate response during the initial
10 minutes of upright tilt, indicating intact sympathetic
cardiovascular reflexes. The mean baroreflex
sensitivity index was 11.0 ms/mm Hg (range, 9.0 to 23.5 ms/mm Hg).
All subjects had baroreflex sensitivity indices 9.0
ms/mm Hg,22 indicating intact parasympathetic
cardiovascular reflexes.
Circadian Variation in Ventricular Effective
Refractory Periods
Baseline
Ten sequential
determinations of ventricular
refractory periods at both drive cycle lengths were performed in all
subjects at the beginning of each 24-hour protocol to determine the
reproducibility of refractory period measurements. The greatest
difference in any subject among these 10 refractory period
determinations at either drive cycle length was 6 ms. The mean
coefficient of variation was 0.39±0.20% at a drive cycle length of
600 ms and 0.55±0.26% at a drive cycle length of 400 ms. Thus,
determinations of refractory periods were highly reproducible. The mean
capture threshold during the waking hours was 1.2±0.4 V.
Hourly
ventricular refractory periods demonstrated a
significant circadian variation at both drive cycle lengths (Fig
1). The mean ventricular refractory period
for the group was 262±18 ms at drive cycle length 400 ms and
297±17
ms at drive cycle length 600 ms. At both drive cycle lengths, a single
harmonic model best fit the circadian variation in
ventricular refractory periods over 24 hours. Fig 1 shows
actual and estimated refractory periods at both drive cycle lengths.
The fitted equation at drive cycle length 600 ms was
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and the fitted equation at drive cycle length 400 ms was
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Ninety-five
percent confidence intervals for the coefficients
indicating statistical significance are shown in Table 2.
Extension of the expression to second-order harmonic
analysis did not yield any significant coefficients at either
drive cycle length. By ANOVA with repeated measures,
ventricular refractory periods between 9:00 AM
and 8:00 PM were significantly shorter (P<.05)
than those between 11:00 PM and 4:00 AM at both
drive cycle lengths. The mean difference between the longest and
shortest refractory periods was 22.6±2.5 ms at drive cycle length 600
ms and 21.1±2.2 ms at drive cycle length 400 ms.
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To determine whether the circadian variation in ventricular refractory periods was more closely linked to the absolute time of day or to the sleep-wake cycle, refractory period data were reanalyzed after adjustment according to the hour of waking and the hour of sleep onset (see "Statistical Analyses"). Adjustment of refractory periods according to the hour of waking significantly improved the fit of the ANOVA model for the circadian variation in refractory periods in that the mean square error decreased from 26.5 to 15.6 at drive cycle length 600 ms and from 18.4 to 11.8 at drive cycle length 400 ms. In contrast, adjustment of refractory periods according to the hour of sleep onset resulted in only a modest reduction in the mean square error and thus did not appear to significantly improve the fit of the ANOVA model for the circadian variation in refractory periods.
Mean ventricular refractory periods
adjusted according to
the hour of waking at drive cycle length 400 ms are shown in Fig
2. Refractory periods for each subject were normalized
to that subject's 24-hour mean value to correct for intersubject
variability in the absolute magnitudes of refractory periods. A similar
curve resulted using refractory period data obtained at drive cycle
length 600 ms. The shortest ventricular refractory periods
in six of nine subjects were observed within 1 hour of waking and, in
eight of nine subjects, were observed within 2 hours of waking. If it
were assumed that the minimum ventricular refractory period
occurred randomly throughout the day, then the probability that the
minimum refractory period over 24 hours would occur within 2 hours of
waking would be 1:12, or .083, and the probability that the
minimum refractory periods would occur during this period in eight of
nine subjects would be <10-8. The greatest differences
between hourly ventricular refractory periods were also
noted during the transition from sleeping to waking. In eight of nine
subjects, maximal shortening between hourly ventricular
refractory periods was seen in the early morning around the hour of
waking (10.7±1.5 ms/h and 9.9±1.2 ms/h at drive cycle lengths
600 ms
and 400 ms, respectively).
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ß-Blockade
In
subjects 1 through 5 (see Table 1), the protocol was repeated
during a continuous infusion of propranolol over 24 hours.
The mean dose of propranolol over 24 hours was 194±66 mg.
The mean propranolol level during maintenance
infusion was 120±63 ng/dL, with a mean range in
propranolol levels over 24 hours of 67±34 ng/dL. One
subject who received 169 mg of propranolol over 24 hours
had levels all 
31 ng/dL, but because of insufficient remaining serum
samples, propranolol levels in this subject could not be
verified by repeated assay.
Ten sequential determinations of ventricular refractory periods at both cycle lengths were also performed at the beginning of the maintenance propranolol infusion to determine the reproducibility of refractory period measurements during ß-blockade. The mean coefficient of variation was 0.53±0.1% at drive cycle length 600 ms and 0.69±0.3% at drive cycle length 400 ms. Thus, ventricular refractory period measurements were as highly reproducible during the propranolol infusions as at baseline. Capture thresholds in three of the five subjects during ß-blockade were higher than during baseline testing. Thus, the mean capture threshold during ß-blockade (1.7±0.4 V) was higher than the mean capture threshold at baseline (1.3±0.4 V); therefore, the mean stimulus intensity during ß-blockade (3.4±0.6 V) was higher than during baseline testing (2.6±0.9 V), although these differences were of borderline statistical significance (P=.09).
The
mean ventricular refractory period over 24 hours during
propranolol infusion was 272±12 ms at drive cycle length
600 ms and 245±9 ms at drive cycle length 400 ms. Mean
ventricular refractory periods during ß-blockade were
significantly shorter than at baseline. Fig 3 shows
refractory periods at drive cycle length 400 ms at baseline and during
ß-blockade in the subgroup of five subjects who were studied under
both conditions. As before, hourly refractory periods for each subject
were normalized to that subject's 24-hour mean value to correct for
intersubject variability in the absolute magnitudes of refractory
periods. In these five subjects, harmonic regression analysis
demonstrated a significant circadian variation in
ventricular refractory periods at baseline. This circadian
variation was abolished by ß-blockade, as none of the coefficients in
the harmonic regression model was significant during ß-blockade
(Table 2). In addition, compared with baseline, the presence of
ß-blockade was consistently and independently associated with
the elimination of the circadian variation in ventricular
refractory periods (P<.0001 by two-way ANOVA with repeated
measures). No significant circadian variation was present even
after adjustment of refractory periods according to the hour of waking
or the hour of sleep onset. Nearly identical results were obtained when
the same analyses as above were performed on refractory period
data at drive cycle length 600 ms (Table 2).
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All subjects received the maximum infusion rate of isoproterenol (6 µg/min). The greatest observed rise in heart rate was 6 beats per minute (from 50 to 56 beats per minute). No subject demonstrated a drop in systolic or diastolic blood pressure. These results suggest that near-maximal ß-blockade had been achieved in all subjects during this phase of testing.
Circadian Variation in Serum Potassium and Plasma
Catecholamine Levels
Mean serum potassium levels demonstrated a
significant circadian
variation (Fig 4), with the highest levels observed
during the waking hours and the lowest levels during sleep. In eight of
nine subjects, the minimum potassium levels were observed between the
hours of 1:00 AM and 4:00 AM; the ninth subject
had a minimum level at 2:00 PM. The lowest observed
potassium level in any subject was 2.8 mEq/L. The mean maximum
difference in potassium levels over the 24-period was 1.0 mEq/L (range,
0.5 to 1.8 mEq/L). A double harmonic model provided the best fit for
the circadian variation in potassium levels. In this model, peaks were
observed at 10:00 AM and 9:00 PM, with a nadir
at 3:00 AM. Adjustment of potassium levels according to the
hour of waking or the hour of sleep onset did not result in a
substantial reduction in the mean square error in the ANOVA model for
the circadian variation in potassium levels; thus, the circadian
variation in potassium levels appeared to be as closely related to the
absolute time of day as to the sleep-wake cycle.
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A significant
circadian variation was also observed in mean levels of
plasma epinephrine and norepinephrine (Fig 5). Mean levels of
each were highest during the day and
lowest during sleep. A single harmonic model with a peak at 3:00
PM provided the best fit for epinephrine levels,
and a double harmonic model with peaks at 9:00 AM and 9:00
PM provided the best fit for norepinephrine
levels. Although a circadian variation in epinephrine and
norepinephrine levels was noted, there was considerable
variability between consecutive hourly measurements in individual
subjects. Adjustment of epinephrine and
norepinephrine levels according to the hour of waking or
the hour of sleep onset did not result in a substantial reduction in
the mean square error in the ANOVA models for the circadian variation
in either epinephrine or norepinephrine levels.
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Correlates of Ventricular Refractory
Periods
During baseline testing, epinephrine and
norepinephrine levels were significantly inversely related
to ventricular refractory periods by univariate
analysis in five of nine subjects each. However, the
intersubject variability in these relations was great. The mean
correlation coefficient between epinephrine levels and
ventricular refractory periods at drive cycle length 400 ms
was -.43, with a range of -.80 to -.11 (Fig
6). A
similar correlation existed between epinephrine levels and
ventricular refractory periods at drive cycle length 600
ms. The range in correlation coefficients between plasma
norepinephrine levels and ventricular
refractory periods at drive cycle length 400 ms in individual subjects
was also quite broad (mean, r=-.34; range, -.58 to
.08;
Fig 7), with a similar correlation at drive cycle length
600 ms. In five of nine subjects, serum potassium levels were
negatively correlated with ventricular refractory periods
at drive cycle length 400 ms (mean, r=-.30; range,
-.75 to
.44). Once again, however, the correlation was highly variable and
was similar at drive cycle length 600 ms.
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Table 3 shows
the results of the analyses of
covariance to determine independent predictors of
ventricular refractory periods at drive cycle length 400
ms. Similar results were obtained using data at drive cycle length 600
ms. In all covariate analyses, time of day was
consistently a highly significant independent predictor of
ventricular refractory periods. Epinephrine levels
were independently predictive of ventricular refractory
periods at both drive cycle lengths before adjustment according to the
sleep-wake cycle; however, after adjustment, epinephrine levels
no longer demonstrated an independent influence. Neither
norepinephrine nor potassium levels were independent
predictors of ventricular refractory periods, either before
or after adjustment for the hour of waking or sleep onset. Thus, in a
multivariate model, adjusted time of day was the sole
independent predictor of ventricular refractory
periods.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The major findings of this study are that a substantial circadian variation exists in ventricular effective refractory periods and that this circadian variation is abolished by ß-blockade. The circadian pattern was highly consistent, with the shortest refractory periods observed around the hour of waking and the longest refractory periods observed during sleep. Maximal shortening between hourly refractory periods also was observed around the hour of waking. Time of day was the only independent predictor of ventricular refractory periods, and neither plasma catecholamine levels nor serum potassium levels appeared to be additional determinants of the circadian variation in ventricular refractory periods. However, the fact that ß-blockade eliminated the circadian variation in ventricular refractory periods strongly suggests that the circadian variation in ventricular refractoriness is largely modulated by ß-adrenergic influences.
Circadian Variation in Cardiac Events
Some of the circadian
variability in the incidence of sudden death
may be due to a morning increase in myocardial
ischemia.4 5 8 9 33
However, ischemic
events do not account for all instances of sudden cardiac death, as
autopsy studies of sudden death victims have failed to demonstrate
acute coronary lesions in up to 42% of
cases.34 35 Furthermore, the occurrence of sustained
monomorphic ventricular tachycardia, which is not
generally a consequence of acute ischemia,36 also
demonstrates a substantial variation.14 15 Therefore,
a
circadian variation in cardiac
electrophysiological parameters
could potentially contribute to the increased morning incidence of
sudden cardiac death.
Prior studies also have shown that acute cardiac events are temporally linked to waking.32 37 In the Physicians' Health Study,37 25% of myocardial infarctions occurred within 3 hours of waking, and the relative risk of infarction during this time interval was almost twice that during any other 3-hour period during the day. In the present study, the most pronounced changes in ventricular refractoriness were also more closely linked to the hour of waking than to the absolute time of day. Our results therefore extend previous findings and suggest that the time around waking is characterized by marked electrophysiological changes and possibly an increased vulnerability to arrhythmias.
Circadian Variation in Refractoriness, Repolarization, and
Ventricular Fibrillation
The QT interval as measured on the surface
ECG reflects global
ventricular myocardial repolarization. A circadian
variation in the QT interval has been described
previously38 39 40 and has been
attributed to a circadian
variation in ventricular repolarization. The QT interval
has been found to be longest during sleep and shortest during the
waking hours. However, the relevance of these observations to a
potential circadian variation in ventricular refractoriness
is not completely clear because the refractory period and action
potential duration (as reflected globally by the QT interval) may be
dissociated in some situations.41 In addition, evaluation
of the QT interval at different times of the day requires a correction
for heart rate, which could limit the accuracy of the analysis
of circadian changes in the QT interval. Finally, unlike refractory
periods that were generally reproducible to within 4 ms with the
methodology used in the present study, estimation of the QT
interval may be somewhat less reproducible. Despite these potential
differences, the results of the present study suggest that the
circadian variation in ventricular refractoriness
qualitatively parallels the previously described circadian variation in
the QT interval.
The circadian variation in the incidence of sudden cardiac death mainly appears to be due to variability in the time of onset of ventricular fibrillation.42 Recent evidence has provided confirmation of the traditional hypothesis that ventricular fibrillation is due to multiple functional reentrant circuits, which change over time.43 44 Shorter refractory periods promote reentry by allowing reentrant circuits to be maintained in a smaller mass of tissue and by decreasing the length of lines of block, leading to the variability in reentry observed during ventricular fibrillation. Experimental studies also have demonstrated that shortening of refractory periods under a variety of conditions may be proarrhythmic.45 In the present study, maximal shortening between hourly refractory periods as well as the shortest absolute refractory periods were observed around the hour of waking, raising the possibility of a close relation between these findings and the increased morning incidence of arrhythmic sudden death. Although not measured in this study, an increased dispersion of refractoriness, which has been shown to promote ventricular arrhythmias,46 47 might be expected when overall ventricular refractoriness is rapidly changing. The circadian variation in refractory periods may be associated with a circadian variation in other electrophysiological properties, such as conduction velocity,48 which also may promote the emergence of reentrant circuits and arrhythmias.
Effects of ß-Blockade On Ventricular
Refractoriness
ß-Blockade abolished the circadian variation in
ventricular refractory periods and in particular abolished
the marked shortening in refractory periods associated with awakening
in the early morning hours. In our study, mean ventricular
refractory periods over 24 hours during ß-blockade were shorter than
during baseline testing, which may appear to contradict previous
findings.49 50 One explanation for this finding
probably
relates to the difference in stimulus intensities used during the two
phases of testing. During testing with ß-blockade, the mean stimulus
intensity used to perform ventricular stimulation was 0.9 V
(35%) higher than during baseline testing. Although all stimulation
was performed at twice the diastolic capture threshold both
at baseline and during ß-blockade, fixed increments in pacemaker
output settings may have resulted in overestimations of true capture
thresholds and thus shifted stimulation during ß-blockade to a higher
point on the strength-interval curve.
Another explanation for the apparent shortening in ventricular refractory periods during ß-blockade in the present study may relate to the setting in which these measurements were performed. In previous studies,49 50 refractory periods were measured invasively in the electrophysiology laboratory, where sympathetic tone would be expected to be high. In contrast, the present study was performed using noninvasive techniques while subjects were at rest, a setting in which sympathetic tone would be expected to be much lower and, thus, the effects of ß-blockade on ventricular refractoriness could differ.51
Potential Mechanisms for Circadian Variation in
Ventricular Refractory Periods
ß-Blockade eliminated the circadian
variation in refractory
periods, strongly suggesting that fluctuations in sympathetic tone are
mainly responsible for temporal changes in ventricular
refractoriness. Plasma epinephrine and
norepinephrine levels, however, were not independently
predictive of ventricular refractory periods after data
were adjusted according to the sleep-wake cycle. The absence of an
independent association in the present study between plasma
catecholamine levels and ventricular refractory
periods is consistent with the observation that sympathetic
outflow to the body is not uniform but rather is regional; therefore,
circulating norepinephrine levels may not reflect selective
cardiac sympathetic activity.52 53 54 It
has been shown
previously that the rate of regional sympathetic nerve discharge as
measured directly by microelectrodes may not correlate with plasma
norepinephrine concentrations.55
Although potassium levels are inversely related to action potential duration, the effects of hypokalemia on the ventricular effective refractory period have been variable in prior clinical and experimental studies.56 In the present study, a significant circadian variation in potassium levels was observed that is consistent with earlier findings.57 However, potassium levels were not independently predictive of ventricular refractory periods; thus, our data do not support a direct relation between the circadian variation in potassium levels and ventricular refractoriness.
Previous Studies of Circadian Variation in
Ventricular Refractoriness
To our knowledge, only one prior study has
examined the circadian
variation in cardiac electrophysiological
parameters.58 In that study, however, the
circadian variation in ventricular refractory periods was
not as great, refractory period determinations were not performed every
hour, marked refractory period shortening in the morning was not
demonstrated, and the relation of ventricular refractory
periods to the hour of waking was not investigated. In addition,
temporary transvenous catheters were used, raising the possibility that
catheter migration may have resulted in refractory period measurements
being performed at different sites in the ventricle. Furthermore, the
methods used to perform ventricular stimulation and
refractory period measurements were not detailed. No attempt was made
to correlate ventricular refractory periods with potassium
or catecholamine levels.
Ventricular refractory periods showed a substantial circadian variation in the present study, in which refractory periods were determined at a pulse width of 0.6 ms. This is a shorter pulse width than that used in prior studies in the clinical electrophysiology laboratory,24 25 in which refractory periods were 20 to 30 ms shorter than the morning refractory periods in the present study.
Limitations
A significant limitation of this study is that
subjects had no
structural heart disease; thus, these results can only be extrapolated
to patients with structural cardiac abnormalities. Although subjects in
this study had permanent pacemakers and cannot truly be considered
"normal," an invasive methodology using temporary transvenous
catheters would have had even greater limitations, including catheter
microdisplacement resulting in determinations of
ventricular refractory periods at different sites in the
ventricle, perturbation of the physiological state
caused by catheter insertion, and potential complications of an
invasive protocol in volunteers. Because permanent pacemaker leads were
used for ventricular stimulation, we were not able to
measure ventricular refractory periods at different
locations in the ventricle; thus, a potential relation between the
circadian variation in refractoriness and the dispersion of
refractoriness could not be explored.
The effects of acute ß-blockade on temporal changes in ventricular refractoriness were studied, and these results may not apply in the setting of long-term ß-blocker administration because of ß-receptor upregulation. It was also recognized that in the two subjects with possible sinus node dysfunction who underwent testing during ß-blockade, the use of isoproterenol to estimate the extent of ß-blockade may have limitations. However, both of these subjects had normal chronotropic responses during tilt table testing.
Although this study was not designed to evaluate the effects
of
-adrenergic or vagal tone on the circadian variation in
ventricular refractory periods, the elimination of the
circadian pattern after ß-blockade suggests that other autonomic
influences truly must be small. Electroencephalographic monitoring was
not performed to document the stages of sleep, and we cannot comment on
the potential relations between these stages and
ventricular refractoriness.
Conclusions
The results of this study suggest that in
individuals
without structural heart disease, a substantial circadian variation
exists in ventricular refractory periods and that this
circadian variation is abolished by ß-blockade. These findings are
consistent with the hypothesis that the circadian variation in
ventricular refractoriness is due to fluctuations in
ß-adrenergic tone. If a circadian variation in
ventricular refractoriness exists or is accentuated in
patients with underlying heart disease, then the elimination of the
circadian variation in ventricular refractoriness by
ß-blockade may be one potential mechanism for the protective effects
of ß-blockers against sudden cardiac death.
|
Acknowledgments |
|---|
This study was supported in part by grant RR-00048 from the National Center for Research Studies, National Institutes of Health, and by a grant from Siemens-Pacesetter Inc. We wish to express our thanks to Lynn Mohr and George Eisenger of Pacesetter Systems, Inc, for their technical assistance in designing this protocol.
Received January 30, 1995; revision received April 3, 1995; accepted April 8, 1995.
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References |
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