(Circulation. 2001;103:806.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Diurnal Variation in Endothelium-Dependent Vasodilatation Is Not Apparent in Coronary Artery Disease
From the Alfred and Baker Medical Unit, Alfred Hospital and Baker Medical Research Institute, Prahran, Victoria, Australia.
Correspondence to Jaye P.F. Chin-Dusting, PhD, Alfred and Baker Medical Unit, Baker Medical Research Institute, PO Box 6492, St Kilda Rd Central, Melbourne, Victoria 8008, Australia. E-mail j.chin{at}alfred.org.au
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Abstract |
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Background—Acute coronary syndromes present with an increased incidence from 6:00 AM to 12:00 noon. Whether endothelial function follows a diurnal rhythm and whether this rhythm is impaired in coronary artery disease (CAD) has not previously been studied.
Methods and Results—Diurnal variation in endothelium-dependent vasodilatation was examined in 10 CAD patients and 10 control subjects. Forearm blood flow responses to acetylcholine, sodium nitroprusside, and NG-monomethyl-L-arginine were determined by plethysmography at 8:00 AM, 2:00 PM, and 8:00 PM. Heart rate, blood pressure, plasma cortisol, and inflammatory markers were also determined. Heart rate and the low-frequency component of heart rate variability were greatest in the morning in control subjects, suggesting a diurnal variation in sympathetic activity. Basal forearm blood flows were significantly reduced in control subjects at 8:00 PM compared with 8:00 AM and 2:00 PM (1.2±0.2 versus 2.1±0.2 [8:00 AM] and 2.1±0.3 [2:00 PM] mL · 100 mL-1 · min-1; P<0.05) but unchanged in the CAD group. Acetylcholine (37 µg/min) responses were greater at 8:00 AM than at 8:00 PM in control subjects (12.5±3.7 versus 19.6±2.9 mL · 100 mL-1 · min-1, respectively; P<0.05), but these responses were not time dependent in the CAD group. Responses to sodium nitroprusside were similar at all time points and between those with and without CAD.
Conclusions—Thus, normal volunteers have a diurnal variation in their endothelium-dependent vasodilatation that may counteract other, potentially adverse, diurnal variations in hemodynamic and other parameters. In contrast, CAD patients who had presented with acute coronary syndromes showed a loss of this protective mechanism.
Key Words: endothelium • vasodilation • circadian rhythm • coronary disease
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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There are numerous studies demonstrating altered endothelium function in patients with coronary artery disease (CAD)1 2 3 4 and also in those at increased risk of CAD.5 The majority of these studies have evaluated vasodilator responses to pharmacological agonists or hemodynamic changes (such as shear stress) that elicit vasodilatation through endothelium-derived processes. The links between endothelial dysfunction, atherosclerosis, and clinical presentation could result from a number of the consequences of disordered endothelium function. Thus, in addition to shifting the balance between vasoconstriction and vasodilatation, there may be important effects on cell adhesion, thrombosis, and fibrinolysis.6 7
A number of cardiovascular diseases show a circadian
variation in their times of presentation. Thus, the onset of myocardial
infarction is 
1.3 times greater in the period from 6:00
AM to 12:00 noon than the
average occurrence during the remainder of the
day.8 A similar diurnal
variation has been found for the presentation of cerebrovascular
events,9 sudden cardiac
death,10 and pulmonary
emboli.11 An increased
incidence of cardiovascular events during the morning could be due to
an increase in pro-occlusive factors during this time or a reduction in
protective mechanisms. Hemodynamic changes may increase the chance of
plaque rupture in coronary arteries harboring atheromatous plaques.
Increases in coagulation and decreases in fibrinolysis may also
contribute to the circadian pattern, and indeed 1 study shows blood to
be hyperthrombotic and hypofibrinolytic at 8:00
AM versus 8:00
PM.12
Platelets have also been shown to be hyperaggregable in the early
morning.13 As discussed,
there is evidence to implicate endothelial dysfunction in the
development and presentation of CAD. However, information on diurnal
variation in endothelial function is not available. Alteration in
endothelium function during the day may contribute to the overall risk
of CAD as well as to its time of presentation.
In the present study, we report on diurnal variation in endothelium-dependent vasodilator function in normal subjects and in patients with CAD. In addition, we have documented a number of other parameters previously shown to exhibit diurnal variation, including an assessment of sympathetic activity, as well as inflammatory markers recently shown to relate to endothelial function.14
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Subjects
Ten male patients with angiographically proven CAD (aged 51.0±3.4 years) and a control group (n=10, all males, aged 56.0±2.1 years) were recruited for the study. All CAD patients were studied at least 3 months after an admission to the hospital with either an acute myocardial infarction or unstable angina. Five patients had normal left ventricular function; the remainder had, at most, moderate reduction in function. Six of the patients had predominantly single-vessel disease treated with angioplasty/stent; 1 patient had severe triple-vessel disease and underwent CABG. The remaining 3 patients had at least a 50% stenosis in the culprit vessel and were treated medically. The healthy volunteers had no history of cardiovascular disease.
The present study was approved by the Alfred Group of Hospitals Ethics Committee, and written informed consent was obtained from all participants.
Experimental Protocol
Subjects were studied at 8:00
AM and 2:00
PM and at 2:00
PM and 8:00
PM on 2 occasions separated
by at least 2 weeks. Subjects were randomly allotted to undergo their
first study beginning at either 8:00
AM or 2:00
PM. Vascular reactivity,
spectral analysis, biochemical parameters, and inflammatory markers
were monitored at each time point. Lipid-lowering, antihypertensive,
and long-acting antianginal medication was stopped 2 weeks and aspirin
was stopped 5 days before each study day.
On arrival, the brachial artery in the nondominant arm was cannulated (3F, 5-cm catheter, Cook) under aseptic conditions, and local anesthesia (1% lidocaine) was administered for intra-arterial pressure recording and drug infusion. Arterial blood pressure was recorded with an AE 840 physiological pressure transducer throughout the course of each experiment. Lead II of the ECG was monitored throughout. After arterial cannulation, a 10-minute rest period was followed by 20 minutes of continuous pulse and blood pressure recordings for spectral analysis of heart rate variability (see below). Arterial blood was then withdrawn for cholesterol, triglyceride, glucose, cortisol, C-reactive protein (CRP), and interleukin (IL)-6 assessment.
Forearm Venous Occlusion
Plethysmography
Forearm blood flow was measured by use of venous
occlusion plethysmography with a double-strand alloy-filled (gallium
and indium) strain gauge (Medasonic), with venous occlusion at 40 to 50
mm Hg for 10 of every 20 seconds. Hand blood flow was occluded by a
wrist cuff inflated to 200 mm Hg. All patients came to the laboratory
having fasted for 6 hours before the study. At the completion of the
first part of the study, ie, after the first time point, they were
given a light nonfatty meal.
Vasodilator responses to acetylcholine (ACh, 9.25 and 37 µg/min) and sodium nitroprusside (SNP, 0.4 and 1.6 µg/min) were determined at each time point. The NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA, 4 µmol/min) was then infused. For each drug, infusion was at 2 mL/min until the response over 3 flow measurements reached a plateau (or until a maximum of 7 minutes). Rest periods of 5 minutes between doses and drugs were observed. Normal saline (0.9% [wt/vol]) was infused during rest periods.
Spectral Analysis
Heart period variability was assessed from lead II of
the ECG over a 20-minute period under resting conditions before the
vascular reactivity studies. The ECG was digitized at 1000 Hz with use
of a 486/50 IBM-compatible PC and a data-acquisition system
incorporating a 12-bit analog-to-digital converter (McPherson
Scientific). The data-acquisition system used a variable-threshold
peak-detection technique from which the RR interval was derived. Heart
period segments of 128-second duration were sampled at 2 Hz to create
256-point data sets. For each 20-minute recording, 16 sets of 256
points overlapping by half were processed. The linear trend was removed
from each data set to eliminate its contribution to low-frequency
power, and a Hanning window in the time domain was used to
attenuate "spectral leakage." Spectral analysis was performed by
use of a direct fast Fourier transform. The frequency resolution was
0.0078 Hz, and the highest frequency evaluated was 0.5 Hz. The spectra
obtained for different data sets were averaged to reduce variance and
to sharpen reproducible spectral peaks. Power was calculated in the
band range of 0.07 to 0.14 Hz (0.1 Hz or low-frequency power) and 0.14
to 0.4 Hz (respiratory or high-frequency power).
Biochemical Measurements
Cortisol measurements were performed by using an
Abbott TDxFLx analyzer; cholesterol, triglyceride, and glucose levels
were analyzed with a Kodak Ektachem DT 60
analyzer.
Inflammatory Markers
IL-6 measurements were performed with an Immulite
IL-6 kit manufactured by Euro/DPC LTD. CRP was measured by using the
revised CRP flex reagent cartridge (Dade Behring) according to a
particle-enhanced turbidometric immunoassay
technique.
Data Analysis
Data are presented as mean±SEM. Summary statistics
were compared by paired or unpaired Student
t test where appropriate.
Comparison of flows between different doses and time points was
performed by 2-way repeated-measures ANOVA followed by post hoc
t tests with the appropriate
corrections. The level of statistical significance used was
P<0.05.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Clinical profiles for CAD patients and control subjects are shown in Tables 1
and 2.
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Analysis of the 2:00 PM data demonstrated no significant differences between the 2 study days for any of the variables. The 95% CIs for the within-subject differences were -67.1 to 39.9 nmol/L for cortisol, -1.56 to 1.76 mg/dL for CRP, and -0.90 to 0.11, -1.32 to 3.58, -1.13 to 0.91, and -0.48 to 0.48 mL · 100 mL-1 · min-1 for forearm blood flow at rest, after ACh, after SNP, and after L-NMMA, respectively. There was also no evidence of a significant order effect; therefore, the 2:00 PM data were averaged from the 2 study days, and the mean value was used in subsequent data presentation and analysis.
Biochemical Parameters
As expected, cortisol levels were significantly higher
in both groups in the morning compared with the rest of the day. Thus,
values at 8:00 AM, 2:00
PM, and 8:00
PM were 320±30, 229±29,
and 148±46 nmol/L (1-way repeated-measures ANOVA,
P<0.03) in the control group
and 355±24, 244±27, and 130±19 nmol/L (1-way repeated-measures
ANOVA, P<0.001) in the CAD
group. There were no differences between those with and without CAD.
Cholesterol and triglyceride levels were stable during the course of
the day, whereas glucose levels were significantly lower at 8:00
PM (1-way repeated-measures
ANOVA, P<0.01) in both groups.
There were no significant differences between control and CAD subjects
in any of these biochemical parameters at each comparable time point
(Table 3).
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Inflammatory Markers
IL-6 values were below the detection limit of the assay
(5 pg/mL) in all patients at all time points except in 2 CAD patients
at different times (7.1 and 8.0 pg/mL). CRP was detected in all
subjects but showed no significant diurnal variation. Values were
higher in the CAD group than in the control group at all 3 time points,
with mean values of 5.35±1.50 and 2.39±0.52 mg/dL
(P<0.05), respectively.
Respective values for control subjects and CAD patients were 2.78±1.04
and 4.58±1.32 mg/dL at 8:00
AM, 2.60±0.62 and
5.73±1.67 mg/dL at 2:00
PM, and 1.63±0.17 and
6.17±1.63 mg/dL (P<0.05) at
8:00
PM.
Blood Pressure and Heart Rate
In the control group, the resting heart rate was
highest at 8:00 AM and fell
later in the day (P<0.05),
whereas in the CAD group, the heart rate was similar at all time points
(Figure 1). In the control group, systolic blood pressure, on
the other hand, was lower at 8:00
AM than later in the day
(P<0.05), whereas there was no
change in the CAD group. Both systolic and diastolic blood pressures
were higher in the CAD group compared with the control group
(Figure 1).
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When expressed as a percentage of total power, there was a
fall during the course of the day for the low-frequency component of
RR-interval variability in the control group
(P<0.05,
Figure 2), with no change for the high frequency component
(Figure 2). Neither showed any diurnal variation in the CAD
group. Similarly, the ratio of low to high frequency for RR-interval
variability was highest at 8:00
AM for the control group
but showed no diurnal variation in the CAD group
(P<0.05,
Figure 2).
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Forearm Vascular Reactivity
Basal forearm blood flows are as shown in
Figure 3. Basal flows were significantly lower at 8:00
PM
(P<0.05) than at 8:00
AM and 2:00
PM in the control group.
Correspondingly, basal forearm vascular resistance was significantly
higher at 8:00 PM than at
8:00 AM and 2:00
PM. In the CAD patients,
basal flows and vascular resistance were similar at all 3 time points.
At 8:00 PM, basal forearm
blood flow was significantly higher in the CAD group than in the
control group (3.19±0.59 versus 1.15±0.15 mL · 100
mL-1 · min-1,
P<0.05). There was no
difference in basal flows between the 2 groups at the other time
points.
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In the control group, increases in forearm blood flow to ACh
infusion were significantly less at 8:00
PM than at 8:00
AM (2-way repeated-measures
ANOVA followed by multiple comparisons,
P<0.05;
Figure 4). There was no difference for the CAD group in the
response to ACh among the 3 study times
(Figure 4). The vasodilator response to ACh tended to be
lower in the CAD group than in the control group at both 8:00
AM
(P=0.074) and 2:00
PM, although this was
statistically not significant.
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Blood flow increases to SNP were similar between control and
CAD groups at all time points and showed no diurnal variation in either
group
(Figure 5). In the control group, L-NMMA significantly
reduced forearm blood flow at both 8:00
AM and 2:00
PM but not at 8:00
PM (by paired
t test). In the CAD group,
there was no diurnal variation in the responses to L-NMMA
(Figure 6).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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A diurnal variation in the presentation of cardiovascular clinical events, including acute myocardial infarction, is well established,8 and a number of biochemical, hemodynamic, and hematologic parameters have also been shown to undergo similar time-dependent changes.12 13 15 The principal findings of the present study are that endothelium-dependent vasodilatation is also subject to diurnal variation and that this differs between normal male volunteers and those with established CAD. These changes may contribute to the diurnal pattern in the clinical presentation of acute coronary syndromes.
Changes in plasma cortisol concentration indicated an underlying diurnal rhythm for both asymptomatic control subjects and patients with CAD, with levels in the evening being <50% the levels of the early morning. Plasma glucose levels were also lower in the evenings. There were no differences in cortisol or glucose concentrations between normal control subjects and patients with CAD. During the day, normal volunteers also demonstrated a progressive fall in heart rate and in the proportion of low-frequency power in RR variability that was consistent with higher sympathetic activity during the morning.16 A diurnal variation in sympathetic activity is well established.15 However, systolic blood pressure was lowest in the morning. In contrast to the normal volunteers, subjects with CAD did not show similar diurnal changes in either heart rate or low-frequency heart rate variability. Previous studies have shown that heart rate variability differs more from day to night in those without CAD compared with those with chronic stable angina.17
The difference between normal subjects and those with CAD
seems unlikely to be due to the effects of medication, inasmuch as
-blockers and calcium antagonists have recently been shown to have
no effect on endothelial
function,18 and the effect of
ACE inhibitors is
controversial.18 19
Furthermore, these medications were stopped 2 weeks before the study.
However, the relatively low cholesterol in the CAD group may indicate
that there were residual effects of lipid-lowering therapy in the 7
subjects previously treated. However, there were no differences between
the CAD and control groups at the time of study.
Inflammatory markers, including both CRP and IL-6, have been shown to be elevated in a number of coronary syndromes and to be predictive of future events.20 21 22 Interestingly a relationship between such markers and endothelial function has recently been noted.14 In the present study, CRP levels were higher in the CAD group, in line with previous findings.22 IL-6 levels were undetectable in almost all subjects, which was probably attributable to the fact that CAD subjects were studied several months after their acute events. There was, as expected from the known plasma half-life (19 hours),21 no diurnal variation in CRP levels that could directly contribute to diurnal differences in endothelial function between CAD patients and control subjects.
Normal subjects showed a greater increase in forearm blood flow to the endothelium-dependent dilator ACh at 8:00 AM than at 8:00 PM. In contrast, there was no diurnal difference in the CAD group. The vasodilator response to ACh tended to be lower in the CAD group compared with the control group at both 8:00 AM and 2:00 PM, although this was statistically not significant. The trend is in keeping with an established association of CAD with dampened endothelium-dependent vasodilatation.4 23 Responses to the endothelium-independent dilator SNP were similar at all 3 time points, both within and between the 2 groups. It is well known that responses to nitrate donors are similar between atherosclerotic and disease-free arteries.3 Because basal flows were significantly lower at 8:00 PM than at the other time points in the control population, it is possible that the depressed response to ACh at this time reflects the lower basal flow observed in this group. However, if this were the case, the same depressed response would have been expected for SNP; this was in fact not observed.
Normal volunteers showed a reduced response to L-NMMA at 8:00 PM compared with 8:00 AM, whereas there was no diurnal variation in the responses to this drug in the CAD group. These results are consistent with an increased basal and evoked endothelial vasodilator function in the morning in normal subjects but not in patients with CAD. As discussed above, these results may be confounded by the significantly lower basal blood flow measurement at 8:00 PM in the control population.
Endothelial function was assessed in terms of
vasodilatation, which was believed to be due to release from the
endothelium of NO.24 The
changes observed may be due to alteration in the release and/or the
biological action of NO and could contribute in a number of ways to
both the development of atherosclerosis and to its conversion to
clinical events. These include changes in the propensity of the
endothelium to permit monocyte and leukocyte attraction and
penetration,6 changes in
thrombosis and fibrinolysis, and changes in shifting the balance
between constriction and
dilatation.25 Several of
these mechanisms could also influence the time of onset of clinical
presentation. In the present study, information on the time of
presentation was accurately available only in regard to the initial
presentation at the emergency department. This occurred between 6:00
AM and 2:00
PM in 6 of the 10 subjects.
Clearly, the onset of symptoms occurred earlier than the time of
presentation. Therefore, these data are consistent with previous
studies8 showing an 30%
increase in the onset of symptoms between 6:00
AM and 12:00 noon than
would be expected.
Changes in endothelium function during the course of the day could be secondary to a number of other factors. Endothelial function is sensitive to plasma cholesterol concentrations over a wide range.26 However, there was no change in cholesterol concentration during the course of the day in either group. Endothelial function is also sensitive to triglyceride-rich lipoproteins.27 Care was taken in the present study to eliminate the confounding effects of meal consumption, and there were no systematic changes in plasma triglycerides during the day. The endothelium is sensitive to shear stress, which is dependent on blood flow and viscosity, and a diurnal variation in shear could have contributed to the changes seen. Although plasma viscosity was not measured in the present study, several earlier studies have shown that the hematocrit falls during the course of the day, so that early morning increases in viscosity are plausible and could contribute to the increase in shear stress.28
There have been several previous studies in which basal nutritive blood flow to the limbs has been measured at various times of the day in normal volunteers as well as in specific disease groups. These studies have reported morning blood flow to be less than flow in the early evening29 for there to be no diurnal variation30 and for flow during sleep to be greater than during the awake hours.31 The reasons for the different findings are unclear but likely result from differences in subject selection, particularly regarding age and perhaps sex, as well as differences in the particular protocols followed. In addition to finding a lower morning basal flow, the study of Panza et al29 also differed from the present study in finding that the absolute flow after SNP infusion was significantly greater in the evening than in the morning.
In conclusion, the present study has demonstrated a diurnal variation in endothelium-dependent vasodilatation with enhanced activity evident in the earlier part of the day in normal subjects but not in those who had presented with acute coronary syndromes. Enhanced endothelial function during the earlier part of the day may normally act to counteract some of the potentially adverse consequences of the diurnal variation in hemodynamic parameters and in thrombosis and fibrinolysis. Further studies are required to establish whether the loss of diurnal variation in endothelial function also contributes to the development of atherosclerosis as well as to the timing of its clinical presentation.
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Acknowledgments |
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This work was supported by a National Health and Medical Research Council grant to the Baker Medical Research Institute and a Center for Clinical Excellence grant to the Alfred and Baker Medical Unit. Dr Shaw is supported by a National Heart Foundation medical postgraduate scholarship. The authors would like to thank Leonie Johnson and Jenny Starr for their help with the experiments.
Received July 19, 2000; revision received October 6, 2000; accepted October 6, 2000.
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M. E. Otto, A. Svatikova, R. B. d. M. Barretto, S. Santos, M. Hoffmann, B. Khandheria, and V. Somers Early Morning Attenuation of Endothelial Function in Healthy Humans Circulation, June 1, 2004; 109(21): 2507 - 2510. [Abstract] [Full Text] [PDF]
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F. A.J.L. Scheer, G. A. Van Montfrans, E. J.W. van Someren, G. Mairuhu, and R. M. Buijs Daily Nighttime Melatonin Reduces Blood Pressure in Male Patients With Essential Hypertension Hypertension, February 1, 2004; 43(2): 192 - 197. [Abstract] [Full Text] [PDF]
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M. L. Hijmering, E. S. G. Stroes, J. Olijhoek, B. A. Hutten, P. J. Blankestijn, and T. J. Rabelink Sympathetic activation markedly reduces endothelium-dependent, flow-mediated vasodilation J. Am. Coll. Cardiol., February 20, 2002; 39(4): 683 - 688. [Abstract] [Full Text] [PDF]
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