CLINICAL STUDIES
Circadian activity of the endogenous fibrinolytic system in stable coronary artery disease: effects of beta-adrenoreceptor blockers and angiotensin-converting enzyme inhibitors
Jeremy W. Sayer, BSc, MB, MRCPa,b,
Charles Gutteridge, MD, FRCPatha,b,
Denise Syndercombe-Court, PhDa,b,
Paul Wilkinson, MB, MRCPa,b and
Adam D. Timmis, MD, FRCPa,b
a Department of Cardiology, Royal Hospitals Trust, Environmental Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom
b Department of Haematology, Royal Hospitals Trust, Environmental Epidemiology Unit, London School of Hygiene and Tropical Medicine, London, United Kingdom
Manuscript received October 28, 1997;
revised manuscript received July 30, 1998,
accepted August 20, 1998.
Address for correspondence: Dr. Adam D. Timmis, Royal Hospitals Trust (London Chest Hospital), Bonner Road, London, United Kingdom E2 9JX
adam{at}timmis-lch.demon.co.uk
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Abstract
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Objectives. To examine circadian changes in the sympathovagal balance, the activity of the renin-angiotensin system and hemostatic variables in patients with stable coronary artery disease, and the effects of beta-adrenoceptor blockade and angiotensin-converting enzyme inhibition.
Background. Sympathovagal balance and key components of the fibrinolytic system show circadian variability. The effects of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors on these autonomic and hemostatic rhythms are not well defined.
Methods. Twenty patients with coronary artery disease underwent 24-h Holter monitoring for heart rate variability and blood sampling (6 hourly for 24 hours) after three consecutive treatment phases, (firstly with placebo, then bisoprolol, and finally quinapril). The effects on sympathovagal balance, hemostatic variables and the renin-angiotensin system activity were measured.
Results. The fibrinolytic capacity showed marked circadian variation at the end of the placebo phase (p = 0.002), plasminogen activator inhibitor-1 (PAI-1) activity peaking at 06.00 AM when tissue plasminogen activator (tPA) activity was at its nadir. Sympathovagal balance showed a sharp increase at approximately the same time but plasma renin activity did not rise until later in the day. Inspection of the 24-h profiles suggested that bisoprolol reduced sympathovagal balance and the morning peak of PAI-1 activity and antigen, with a small increase in tPA activity, although these changes were not significant. Quinapril produced a substantial rise in renin (p = 0.01) but did not significantly affect either PAI-1 or tPA. Sympathovagal balance was unaffected by quinapril.
Conclusions. In patients with stable coronary artery disease, angiotensin-converting enzyme inhibition with quinapril does not affect either sympathovagal balance or the endogenous fibrinolytic system. Our data suggest that the sympathoadrenal system may modify fibrinolytic activity, judged by the response to beta-adrenoreceptor blockade with bisoprolol.
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Abbreviations and Acronyms
| | ßTG | = beta-thromboglobulin | | PAI-1 | = plasminogen activator inhibitor-1 | | PF4 | = platelet factor 4 | | RAS | = renin-angiotensin system | | tPA | = tissue plasminogen activator | | vWF | = von Willebrand factor |
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The circadian rhythm of acute myocardial infarction is well documented. A significant excess of patients present during the second quarter of the day. Mechanisms remain unclear although considerable evidence points to a role for the sympathetic nervous system; thus, circadian variability of plasma catecholamines has long been recognized (1), and in patients with stable angina, the morning peak in ambulatory ischemia coincides with a peak in sympathetic activity (2,3). It is now apparent that the circadian rhythm of myocardial infarction is attenuated or abolished in patients taking beta-blockers (4,5), and in other groups with deranged autonomic function (6,7). A plausible mechanism accounting for these observations is that myocardial ischemia and plaque events are provoked by the heart rate and blood pressure responses to sympathetic stimulation which peaks during the second quarter of the day.
Other mechanisms may also contribute to the circadian rhythm of myocardial infarction. Key components of the endogenous fibrinolytic system show circadian variability (8–13), peak and trough plasma activities of plasminogen activator inhibitor-1 (PAI-1) and tissue plasminogen activator (tPA) combining to provide a relatively prothrombotic state in the morning (14) when the risk of thrombotic coronary occlusion is greatest. Factors responsible for regulating these fibrinolytic products of the vascular endothelium are unclear although there is some evidence for involvement of the renin-angiotensin system (RAS); thus, when RAS activation is simulated by angiotensin II infusion (15), or occurs pathophysiologically during myocardial infarction (16), plasma levels of PAI-1 increase, a response prevented by angiotensin-converting enzyme inhibition.
If the sympathetic and renin angiotensin systems interact to heighten the risk of infarction during the second quarter of the day, intervention with specific inhibitors would be expected to exert a protective effect by favorably influencing the hemodynamic and fibrinolytic environment. In the present study, this hypothesis was tested by examining circadian changes in sympathovagal balance, RAS activity and circulating hemostatic variables in patients with stable coronary artery disease, with particular reference to the effects of beta-adrenoceptor blockade with bisoprolol and angiotensin-converting enzyme inhibition with quinapril.
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Methods
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Patients.
Twenty patients aged 40–70 years with angiographically confirmed coronary artery disease were recruited (Table 1). All were either asymptomatic or had mild stable angina (Canadian class I-II), with well-preserved left ventricular function (ejection fraction > 50%). Exclusion criteria included diabetes, hypertension and current treatment with angiotensin-converting enzyme inhibitors. The study was approved by the East London and City Health Authority Research Ethics Committee, and all patients gave written informed consent. All patients completed the placebo run-in phase of the trial, but three did not complete the first treatment period with bisoprolol (personal reasons [n = 1], intercurrent illness [n = 1], bronchospasm [n = 1]) and three did not complete the second treatment period with quinapril (personal reasons [n = 2], intercurrent illness [n = 1]); thus, data for both treatment phases are for 17 patients.
Study protocol.
This was a single blind study. Patients first underwent a placebo run-in phase for four weeks and this was followed by two consecutive treatment periods first with bisoprolol and then with quinapril (each for four weeks). Bisoprolol was chosen for its ß1 cardioselective properties and quinapril for its high tissue angiotensin-converting enzyme binding capacity. Before the placebo run-in phase, aspirin and all vasoactive drugs except short-acting nitrates were stopped and not reintroduced until after the end of the study. Smokers were asked to refrain from smoking for 24 h before Holter monitoring until after the final blood sample on each admission.
Placebo run-in phase
Patients received one capsule of placebo in the morning, which was increased to two capsules at the end of the first week. After four weeks on placebo, the patients underwent 24-h ambulatory Holter monitoring using a Marquette Series 8000 recorder. This was followed by admission to a hospital at 9 AM. Blood was collected at 12 PM, 6 PM, 12 AM, and 6 AM for analysis of renin levels, tPA antigen and activity, PAI-1 antigen and activity, fibrinogen, von Willebrand factor (vWF), beta-thromboglobulin (ßTG) and platelet factor 4 (PF4).
First treatment period (bisoprolol)
At the end of the placebo run-in phase, placebo capsules were stopped and bisoprolol (10 mg daily) was substituted, with a dose increment to 20 mg daily after one week if the resting heart rate remained > 60 beats per minute. After four weeks on bisoprolol, Holter monitoring and blood sampling were repeated as described above.
Second treatment period (quinapril)
At the end of the bisoprolol treatment period, quinapril (10 mg daily) was substituted, increasing to 20 mg daily after one week if systolic blood pressure remained > 100 mmHg. After four weeks on quinapril, Holter monitoring and blood sampling were repeated as described above.
Heart rate variability.
All Holter recordings were analyzed by a single physician blinded to the identity and treatment phase of the patient. The recordings were analyzed for spectral and nonspectral measures of heart rate variability with Marquette heart rate variability software. The measures calculated were: amplitude of low (0.04–0.15 Hz) and high (0.15–0.40 Hz) frequency spectral analysis for each hour and 24 hour means, proportion of adjacent electrocardiographic R intervals (RR) intervals more than 50 ms different (pNN50), root-mean square of difference of successive RR intervals (rMSSD), mean of all 5-minute standard deviations or RR intervals (SD), standard deviation of 5-minute mean RR intervals (SDANN), and the standard deviation of all RR intervals (SDNN).
Blood sampling and analysis.
All samples were taken from the antecubital fossa after 3 h bed rest through a 21 gauge needle, using a tourniquet only briefly to gain venous access; the first 2 ml of blood were discarded. Blood was collected for renin measurement into 5-ml tubes containing sodium EDTA (Vacutainer, Becton Dickinson, Oxford, UK), fibrinogen and tPA antigen and activity into 5-ml tubes containing sodium citrate (Vacutainer, Becton Dickinson), and ßTG, PF4 and PAI-1 antigen and activity into tubes containing theophylline, adenosine and prostaglandin PGE1 (Diatubes, Becton Dickinson). The latter samples were centrifuged for 30 min at 2,500 g and 4°C. Only the mid-sample of the platelet-free plasma was decanted. The other samples were centrifuged at 2,500 g for 10 min at 4°C. Samples were collected into precooled tubes in iced water, and were kept cold until freezing at –40°C. Analyses were performed in a single batch within 9 months of initial sampling.
All assays were performed using commercially available kits on paired samples. Renin activity was measured by immunoradiometric assay (Nichols Institute Diagnostics, Geneva, Switzerland). Tissue plasminogen activator and PAI-1 antigen were measured by enzyme-linked immunosorbent assay (ELISA; Technoclone, Vienna, Austria) and tPA and PAI-1 activity were measured by a two-step indirect enzymatic assay (Technoclone, Vienna, Austria). Beta-thromboglobulin was measured by ELISA (Asserchrom ßTG, Diagnostica Stago, Asnieres-sur-Seine, France) but samples were discarded if there was evidence of in vitro platelet activation (ratio of ßTG:PF4 < 2 [17]). von Willebrand factor was measured by ELISA (Shield Diagnostics, Dundee, UK) and fibrinogen by the modified Clauss method (Immuno, Heidelberg, Germany).
To test for sample deterioration, log linear regression analysis was performed for all hematological variables against the time which had elapsed since their collection. No time-dependent changes in measured values were detected.
Statistical analysis.
Data are presented as mean ± standard deviation unless otherwise stated. Tests of circadian variation and comparisons of daily means and time profiles during the three treatment phases were based on repeated measures (two-way) analysis of variance, and subsequent adjustments for multiple testing were made using the Bonferroni method (18). Logarithmic transformation was performed on four variables (renin, PAI-1 antigen, ßTG and PF4) to normalize their skewed distribution. Quoted p-values correspond to comparison of all three treatment phases; p-values of 0.05 or less were regarded as significant.
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Results
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Efficacy of treatment.
Compliance rates, assessed by tablet counting, were: placebo 99%, bisoprolol 97%, quinapril 97%. Bisoprolol reduced heart rate compared with placebo (57 ± 11 versus 76 ± 7.6 beats per minute, p < 0.0001), and systolic and diastolic blood pressure measurements (114 ± 8.8 versus 124 ± 10.7 mmHg, p = 0.02; 67 ± 7.1 versus 76 ± 8.9 mmHg, p = 0.001). Quinapril produced small reductions in systolic and diastolic blood pressures (117 ± 17.3 versus 124 ± 10.7 mmHg, p = 0.16; 70 ± 11 versus 76 ± 8.9 mmHg, p = 0.05). The heart rate at the end of the quinapril treatment phase was no different than during the placebo phase (79 ± 11 beats per minute) but substantial elevation of 24-h mean plasma renin levels occurred (106 ± 182 versus 21.6 ± 17.4 µU ml–1, p < 0.0001).
Hematological factors.
Fibrinolytic system
All four key components of the endogenous fibrinolytic system (Fig. 1) showed circadian variation at the end of the placebo run-in phase (p = 0.002 in each case). Treatment with quinapril did not significantly affect these circadian rhythms. The effect of bisoprolol also failed to reach statistical significance after correction for multiple comparisons; however, observation of the data in Fig. 1 suggests some attenuation of the morning peak of PAI-1 activity compared with placebo and a small increase in tPA activity throughout the 24-h period.
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Figure 1 Circadian variation of PAI-1 and tPA antigens and activities and the effect of treatment with beta-blocker (bisoprolol) and angiotensin-converting enzyme inhibitor (quinapril). Points represent mean values; figures are the standard deviation for each data point. P1 = placebo; BB = beta-blocker; ACEI = angiotensin-converting enzyme inhibitor.
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Platelet activity
Beta thromboglobulin showed no significant circadian variation after the placebo run-in phase (Fig. 2). Treatment with quinapril and bisoprolol tended to reduce plasma levels over the 24 h, although this effect was not statistically significant.
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Figure 2 Variation in ß-TG over 24 h and the effect of treatment with beta-blocker (bisoprolol) and angiotensin-converting enzyme inhibitor (quinapril). Points represent mean values; figures are the standard deviation for each data point. P1 = placebo; BB = beta-blocker; ACEI = angiotensin-converting enzyme inhibitor.
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von Willebrand factor and fibrinogen
These showed no significant circadian variation and were unaffected by bisoprolol or quinapril (Table 2).
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Table 2 von Willebrand Factor and Fibrinogen Levels at Baseline (Placebo) and After Treatment with Bisoprolol and Quinapril According to the Time of Day
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Autonomic function.
The ratio of the low to high frequency spectral components of heart rate variability showed significant circadian variation at the end of the placebo run-in phase (p = 0.002) with a sharp rise starting at around 5 AM and a nadir at midnight. Observation of the data in Fig. 3 shows evidence of a difference between treatment phases. Bisoprolol diminished the LF:HF ratio throughout the 24-h period and effectively abolished the morning increase. Again, however, this response to beta-blockade is not statistically significant following adjustment for multiple comparisons; nevertheless, bisoprolol did cause significant increases in many of the nonspectral measures of heart rate variability (Table 3). Quinapril had no appreciable influence on heart rate variability.
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Figure 3 Twenty-four hour variation of low frequency to high frequency ratio (LF:HF) at baseline (placebo) and after treatment with beta-blocker (bisoprolol) and angiotensin-converting enzyme inhibitor (quinapril). Points represent mean values; figures are the standard deviation for each data point. P1 = placebo; BB = beta-blocker; ACEI = angiotensin-converting enzyme inhibitor.
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Renin-angiotensin system.
There was again evidence of difference between the three treatment phases in mean level (p = 0.01) and diurnal pattern (p = 0.002) of plasma renin levels (Fig. 4). Placebo and bisoprolol phases were very similar, but angiotensin-converting enzyme inhibition led to a substantial increase in daily mean level, peaking at 12 PM.
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Figure 4 Variation in plasma renin over 24 h and the effect of treatment with beta-blocker (bisoprolol) and angiotensin-converting enzyme inhibitor (quinapril). Points represent mean values; figures are the standard deviation for each data point. P1 = placebo; BB = beta-blocker; ACEI = angiotensin-converting enzyme inhibitor.
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Discussion
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This study has shown that in stable patients with coronary artery disease, angiotensin-converting enzyme inhibition with quinapril affects neither the circadian rhythm of fibrinolytic activity nor the morning surge of sympathetic activity. Beta-adrenoceptor blockade with bisoprolol, on the other hand, reduces sympathetic activity and may also favorably influence the fibrinolytic system by reducing the relatively prothrombotic state that occurs around 6 AM when the risk of myocardial infarction is greatest. Quinapril and bisoprolol tends to reduce platelet activity as reflected by beta-thromboglobulin.
Circadian rhythms of sympathovagal balance and fibrinolytic activity.
Spectral analysis of heart rate variability following the placebo run-in period confirmed a significant circadian variation of sympathovagal balance (19) which increased sharply in the early morning (3). Key components of the fibrinolytic system showed a similar pattern, PAI-1 activity, PAI-1 antigen and tPA antigen (which binds to PAI-1) peaking at 6 AM when tPA activity was at its nadir, resulting in a relatively prothrombotic state at a time when the risk of myocardial infarction is greatest. Because pathogenic mechanisms of myocardial infarction involve plaque rupture and thrombosis (events influenced importantly by blood pressure and endogenous fibrinolytic state), it is possible to speculate that the circadian changes in sympathovagal balance and the fibrinolytic system which we and others have demonstrated account, at least in part, for the circadian rhythm of acute myocardial infarction.
Effects of beta-blockade on circadian rhythms.
Attenuation or absence of the circadian rhythm of acute myocardial infarction in patients taking beta-blockers has been reported by several investigators (4,5), suggesting that reductions in sympathetic activity might protect against plaque events during the period of heightened risk. Observation of Fig. 3 shows that bisoprolol reduced sympathovagal balance throughout the day, effectively abolishing the morning surge in activity. Bisoprolol may also have modified fibrinolytic activity, and there was a tendency for the morning surge in PAI-1 activity to be reduced while mean tPA activity increased throughout the 24-h period. These changes were small and lacked statistical significance, particularly with adjustment for multiple comparisons, although there is some debate about whether statistical inference is improved by Bonferroni adjustments (20–22); however, the flat contour of the PAI-1 activity curve after four weeks on bisoprolol contrasted strongly with the placebo curve, suggesting that there may indeed have been a response to beta-adrenoreceptor blockade.
In contrast to PAI-1, the circadian rhythm of tPA activity was unaffected by bisoprolol, perhaps reflecting the fact that tPA is produced almost exclusively by the vascular endothelium while PAI-1 has, in addition, many nonendothelial sources (23) which may be more susceptible to the effects of beta-blockade; nevertheless, the effects of bisoprolol on fibrinolytic activity were potentially favorable and reduction in the morning surge of PAI-1 activity would be expected to reduce the risk of thrombotic coronary occlusion and complement the hemodynamic responses to beta-blockade in modifying the circadian rhythm of acute myocardial infarction.
Mechanisms whereby beta-blockade with bisoprolol might affect the fibrinolytic system are unclear and must remain speculative until factors regulating the endothelial production of PAI-1 and tPA are better understood. Certainly, there is no evidence for a direct effect of the sympathetic nervous system on endothelial function although indirect effects on the endothelial production of vasoactive substances, mediated by variations in blood flow and sheer stress, are well documented (24,25). The morning rise in sympathovagal balance and PAI-1 activity were approximately simultaneous. Because both were attenuated by bisoprolol, indirect effects of sympathetic activity on the vascular endothelium provide a potential mechanism for the circadian rhythm of PAI-1 activity and for the effects of bisoprolol.
Effects of angiotensin-converting enzyme inhibition.
At the end of the placebo run-in phase, circadian changes in plasma renin levels showed a strikingly different pattern from the changes in fibrinolytic activity; thus, plasma renin peaked at midday when PAI-1 and tPA activities were both relatively low. The phase delay between cycles of renin release and fibrinolytic activity must cast doubt on the importance of the RAS in regulating endothelial production of PAI-1 and tPA under basal conditions, doubt that is amplified by our finding that angiotensin-converting enzyme inhibition with quinapril, sufficient to increase plasma renin levels by over 450%, had no palpable effect on circadian rhythms or plasma activities of PAI-1 and tPA. While this finding appears to contradict previous experimental and clinical studies (16,26,27), it is almost certainly attributable to the fact that ours were stable patients without significant RAS activation, in contrast to previous studies in which the RAS was activated at the time of angiotensin-converting enzyme inhibition; thus, Hamdan et al. (27) reported that RAS activation in the balloon-injured rat aorta induced PAI-1 mRNA expression, a response suppressed by captopril, while others have reported that RAS activation in patients with myocardial infarction increased PAI-1 and tPA antigen levels, responses that are also suppressed by angiotensin-converting enzyme inhibition (16,26). Importantly, in one of these myocardial infarction studies (16), the effects of angiotensin-converting enzyme inhibition in a normal control group was reported. In this group, PAI-1 and tPA antigen levels were similar to the baseline data in our own patients and were unaffected by angiotensin-converting enzyme inhibition. It can be concluded, therefore, that when the RAS is activated, it provides a potent stimulus for endothelial production of PAI-1 (presumably mediated by angiotensin II), but under basal conditions, other factors which may include the sympathetic system, play a more important role in driving the circadian rhythms of the endogenous fibrinolytic system. While modifying these rhythms may contribute to the protective effects of beta-blockade in stable patients with coronary artery disease, the potential benefits of angiotensin-converting enzyme inhibition, currently under clinical investigation (28), are more plausibly attributable to direct effects on the endothelial production of nitric oxide and other components of the atherogenic process (29).
Effects of angiotensin-converting enzyme inhibition and beta-blockade on platelet function.
Angiotensin-converting enzyme inhibitors and beta-blockers may also have useful antiplatelet activity, judging by the small reductions in ßTG that followed treatment with quinapril and bisoprolol. Human platelets possess angiotensin II and beta-adrenergic receptors (28). Previous investigators have also reported inhibition of platelet activity by angiotensin-converting enzyme inhibitors (30,31) and less consistently by beta-blockers (32–35). Certainly, any antiplatelet effects of quinapril and bisoprolol would be potentially beneficial in patients with coronary artery disease by protecting against thrombosis in the event of plaque rupture. It is possible to speculate from our data that combination therapy might have useful additive effects given the different mechanisms of action of these drugs. Other components of the coagulation process measured in this study included fibrinogen and von Willebrand factor, neither of which were affected by angiotensin-converting enzyme inhibition or beta-blockade.
Conclusions.
No evidence was found of a regulatory role for the RAS in the endothelial production of PAI-1 or tPA under basal conditions in patients with coronary artery disease; however, this does not discount a role under conditions of RAS activation. Our data suggest that the sympathoadrenal system may influence fibrinolytic activity judging by responses to beta-adrenoreceptor blockade with bisoprolol which tends to reduce the relatively prothrombotic state that occurs in the early morning. Bisoprolol also reduces sympathoadrenal activity with predictable hemodynamic consequences. These combined hematological and hemodynamic responses to bisoprolol may account, at least in part, for the protective effects of beta-blockers, particularly in the early morning when the risk of infarction is greatest.
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Footnotes
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This study was partially funded by Wyeth Laboratories.
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Abstract
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