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Circulation. 1995;92:1737-1742

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(Circulation. 1995;92:1737-1742.)
© 1995 American Heart Association, Inc.

Articles

Early Morning Reduction in Ischemic Threshold in Patients With Unstable Angina and Significant Coronary Disease

Jaume Figueras, MD; Rosa Maria Lidón, MD

From Unitat Coronària, Servei de Cardiologia, Hospital General Vall d'Hebron, Barcelona, Spain.

Correspondence to Jaume Figueras, MD, Unitat Coronària, Servei de Cardiologia, Hospital General Vall d'Hebron, P. Vall d'Hebron s/n, 08035 Barcelona, Spain.


*    Abstract
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Background The objective of this study was to investigate in patients with unstable angina and significant coronary stenosis (>70%) whether or not the morning peak of myocardial ishemia is associated with a reduction in the ischemic threshold. The morning increased incidence of ischemic episodes in stable angina appears to be attributable to a coincidence of several factors. Patients with unstable angina who remain at bed rest, however, also present a similar morning increased incidence of ischemia, but its mechanisms are not completely understood.

Methods and Results The ischemic threshold was assessed by atrial pacing at 7 to 8 AM and at 12 to 1 PM in 46 patients. In the 34 with a positive pacing response (ST segment shift >1.0 mm), ischemic threshold was lower at 7 to 8 AM than at 12 to 1 PM (131±16 versus 139±15 beats per minute, P<.001), whereas in the remaining 12 patients, the pacing response was negative. Moreover, 4 patients presented ST segment elevation during pacing in the morning but only 1 at noon and at a higher threshold. Baseline heart rate and diastolic blood pressure were higher at noon than in the morning (81±16 versus 76±13 beats per minute, P<.01, and 87±11 versus 82±10 mm Hg, P<.05).

Conclusions The morning lowering of ischemic threshold in the absence of increases in baseline blood pressure or heart rate suggests that a reduced coronary vasodilator capacity or an increased coronary tone may favor the increased incidence of ischemic events during this interval.


Key Words: angina • rest • ischemia • circadian rhythm


*    Introduction
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It is now widely recognized that ischemic episodes during daily activities tend to follow a circadian distribution, with a primary peak in the morning and often a secondary peak in the late afternoon.1 2 3 4 5 6 7 8 More recently, a similar distribution has been demonstrated in patients with unstable angina despite being at bed rest.9 10 11 Also, a comparable bimodal presentation has been documented in patients with vasospastic angina without significant coronary stenosis,7 11 12 13 although with an earlier morning peak.3 11 12

Even though the mechanisms that account for the morning peak in stable angina have not yet been clearly identified, a combination of factors such as increases in myocardial oxygen needs related to the morning increases in heart rate and blood pressure,14 15 an increase in platelet aggregability,16 17 18 19 a reduction of the thrombolytic capacity of the plasma caused by a rise of the tissue plasminogen activator inhibitor,20 and/or an increase in coronary arterial tone3 21 have been invocated as potential explanations. In patients with unstable angina who present recurrent episodes while being at bed rest and in whom changes in blood pressure or heart rate are likely to be much less accentuated than in patients with stable angina during normal daily activities,22 23 it is conceivable that the morning peak could relate to factors others than changes in myocardial oxygen demands. It is also possible, however, that the diurnal distribution of ischemic episodes could be dominated by more intrinsic alterations in the complicated plaque, such as unpredictable changes in the size of the thrombi or in the local release of vasoconstrictive substances. In patients with well-identified vasospastic angina, an increased coronary tone in the early morning, either spontaneous3 or induced by ergonovine,24 has been documented. Thus, a similar trend also might be operative in patients with unstable angina and significant coronary stenosis. Therefore, to indirectly assess the circadian changes in coronary tone or coronary vasodilator capacity in these patients, we investigated the possible differences in ischemic threshold as determined by atrial pacing between 7 and 8 AM and noon in patients with unstable angina and significant coronary stenosis.


*    Methods
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Patients
The patients included in this study were part of 383 consecutive patients admitted to our coronary care unit with the diagnosis of unstable angina from January 1984 through December 1988 in whom the prognostic value of coronary reserve, as measured by atrial pacing, was evaluated.25 Diagnosis of unstable angina was based on the presence of angina at rest or to minimal exertion associated with or not associated with increased frequency of episodes of exercise-induced angina. Other inclusion criteria were age <75 years and absence of heart failure (Killip class III or IV), left bundle branch block, atrial fibrillation, atrioventricular block >1st degree, associated cardiac disease, or previous coronary artery bypass surgery (see TableDown). The subset included in the present report was the 55 consecutive patients studied from February 1987 through March 1988 who met the following additional requirements: (1) presence of typical angina at rest while in the hospital associated with transient ECG changes (ST segment shift >1.0 mm or pseudopositivization of negative T waves), (2) absence of previous myocardial infarction, and (3) absence of elevated cardiac enzymes.


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  		Table 1. Clinical and Angiographic Data for Study Patients

Protocol
All patients were at bed rest for at least the first 3 to 4 days, under continuous ECG monitoring. Arterial blood pressure by cuff and heart rate were measured every 2 to 4 hours during their admission to the coronary care unit and during and after each episode of chest pain. Total creatine kinase, its MB fraction, and the glutamic oxalacetic transaminase were measured every 6 hours during the first 48 hours. A standard 12-lead ECG was taken on admission, daily thereafter, and during and after the episodes of chest pain. Coronary angiography was carried out within the first 10 days.

Atrial Pacing Test
Within the first 4 days, a 6F electrocatheter was introduced through the left subclavian vein and advanced into the coronary sinus to secure atrial pacing. Thereafter, pacing was started at a rate of 100 beats per minute and was subsequently increased by steps of 10 beats at 2-minute intervals. Pacing was discontinued when significant ST segment changes developed (>1.0 mm at 0.08 seconds after the J-point) or when a heart rate of 150 beats per minute was reached and maintained for 5 minutes. After each pacing step, stimulation was stopped for 10 to 15 seconds to allow recognition of possible ischemic changes in the ECG recorded on an eight-channel Elema Mingograf recorder (Siemens). The ECG changes were analyzed after the first 5 seconds to eliminate interference by nonischemic artifactual changes that we have observed in some patients. A positive pacing response was defined by the presence of significant ST segment changes (>1.0 mm shift), with or without pain, at a heart rate <150 beats per minute. Ischemic threshold was defined as the pacing rate that caused a 1.0-mm ST segment shift. This initial pacing was used to assess the prognostic value of the ischemic threshold for in-hospital complications.25 For the purpose of analyzing the possible morning and noon differences in ischemic threshold, however, two additional pacing procedures were performed on the next day: one between 7 and 8 AM and the other between 12 and 1 PM. Breakfast and lunch, respectively, were withheld until completion of the pacing test. Also, brisk awakening of patients in the morning before pacing was carefully avoided, and the procedure was always performed with the patient relaxed and comfortable. The patient was already familiar with the procedure, which had been performed the previous day. To allow comparison of pacing thresholds, a value of 170 beats per minute was arbitrarily assigned to each negative pacing response.

Medical treatment included an intravenous nitroglycerin infusion started after one to two episodes of angina at 15 to 20 µg/min and increased progressively according to recurrence of symptoms. Before the pacing test and in patients with frequent episodes, nifedipine 40 to 80 mg daily was administered but discontinued 12 hours before the morning pacing. After performance of the noon pacing, nifedipine was resumed and additional treatment, when needed, was administered (ß-adrenergic blocking agents and/or diltiazem). The two pacing tests were performed during nitroglycerin infusion and at the same dose. Calcium heparin was administered to all patients during the first days, at 4 AM and at 4 PM. Informed consent was obtained before patients entered the study.

Statistical Analysis
The {chi}2 test or the Fisher's exact test was used to assess the relationship between categoric variables; intergroup differences for continuous variables were assessed using the Student's t test for paired or unpaired samples. Data are expressed as mean±SD.


*    Results
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Clinical Data
The study included 55 patients, but 9 of them were subsequently excluded because of absence of significant coronary stenosis. In each of these 9 patients, the two pacing tests were negative. Of the remaining 46 patients, 30 (65.2%) had a history of exercise-induced angina longer than 1 month and 34 had a positive pacing test in the morning (group PP), whereas the remaining 12 had negative pacing (group NP). Patients in group PP were older than those in group NP (58.5±8.7 versus 50.1±7.3, years, P<.01) and had a comparable incidence of arterial hypertension and of diabetes mellitus but a higher number of in-hospital anginal episodes (3.7±4.3 versus 1.3±1.5, P<.01). Also, they tended to have more extensive coronary disease, since 58.8% had multivessel disease as opposed to 33.3% in group NP.

Ischemic Threshold
At noon, pacing also was negative in all patients from group NP. In those from group PP, ischemic threshold and double product during pacing at noon were significantly higher than in the morning (138.8±15.3 versus 131.2±15.9 beats per minute, P<.001, and 1976±307x10 versus 1821±359x10, P<.005; Figs 1Down and 2Down). Furthermore, in group PP in the morning, 4 patients developed ST segment elevation during pacing, whereas this was seen in only one of them at noon (Fig 3ADown and 3BDown). Also in this group, baseline heart rate and diastolic blood pressure before pacing were higher at noon than in the morning (80.6±15.7 versus 75.6±13.3 beats per minute, P<.001, and 86.8±11.1 versus 82.2±9.8 mm Hg, P<.05; Fig 4Down). In group NP, baseline diastolic blood pressure at noon also was higher than in the morning (89.7±12.6 versus 83.6±9.1 mm Hg, P<.05).



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  		Figure 1. Bar graph shows heart rate at control prepacing and at ischemic threshold in the morning and at noon in patients with positive pacing. Both control (*P<.01) and ischemic threshold (**P<.0001) values were significantly lower in the morning than at noon.



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  		Figure 2. Bar graph shows double product (heart ratexsystolic blood pressure) at control and at the ischemic threshold in the morning and at noon pacing tests in the group of patients with positive pacing. For heart rate, control (*P<.05) and ischemic threshold (**P<.005) values were significantly lower in the morning pacing.




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  		Figure 3. ECG recordings before and during pacing in a 48-year-old man in the morning (A, 08:00) and at noon (B, 12:45). In the morning pacing there was a prompt ST elevation at a heart rate (HR) of 100 beats per minute. In this case, ischemia was spontaneously reversed 1 minute later despite maintenance of the same pacing rate ("walk-through phenomenon"). At noon, however, pacing was only positive at 140 beats per minute. Baseline blood pressure (BP) was comparable at both intervals, but heart rate was higher at noon.



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  		Figure 4. Bar graph shows diastolic blood pressure at control prepacing (open bars, *P<.05) and at the ischemic threshold (closed bars, NS) in the morning and at noon. Note that control values were lower in the morning than at noon.


*    Discussion
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*Discussion
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The main contribution of the present work is the demonstration that in patients with unstable angina and significant coronary artery disease who remain at bed rest, there is a reduction of the ischemic threshold in the morning when compared with that at noon. As in patients with acute myocardial infarction1 2 4 8 or stable angina,6 7 26 27 it has been demonstrated recently that in patients with unstable angina there is also an increase in the frequency of ischemic episodes in the morning.9 10 11 It also has been documented that in most of these episodes, changes in the heart rate before or at the onset of pain are very small and often nonexistent.22 23 28 29 Moreover, the heart rate attained during these episodes is much lower than the ischemic threshold measured by atrial pacing.9 23 Thus, there is a strong suggestion that decreases in coronary blood flow are responsible for the majority of these ischemic events.22 26 28 30 31 32 33 Hence, the possibility that they are facilitated by transient increases in coronary tone, either global or local, at the culprit stenosis has been entertained.9 28 30 33 In fact, an increased coronary vasoconstrictive sensitivity has been documented in these patients.33 34 35 In a previous work, we demonstrated that in 162 patients with unstable angina, significant coronary disease, and ECG changes during pain, the highest peak of anginal episodes occurred between 6 and 10 AM.11 In the current study, we found that the ischemic threshold at 7 to 8 AM was indeed lower than at 12 PM, when the incidence of attacks falls significantly.10 11 Aside from the possible increases in coronary tone, another potential explanation for the observed lowering of ischemic threshold in the morning could be an increased severity of stenosis caused by transient platelet aggregates, based on the increased aggregability observed during these hours in some studies16 17 18 19 but not in others.36 Although we afford no data to discard this contention, it would appear that this increase in platelet aggregability is essentially linked to adoption of the upright position rather than to awakening.18 On the other hand, antiaggregation therapy with aspirin did not reduce the incidence of anginal episodes.37 38 39 Perhaps a more relevant factor could be the morning reduction in fibrinolytic activity recently documented in hypertensive subjects36 similar to that in healthy men.40 Yet another possible explanation might be that the morning lowering of ischemic threshold, mainly expressed as heart rate threshold, could be secondary to a higher baseline arterial blood pressure. In our patients, however, who were at bed rest for several days, this was not the case, since systolic blood pressure, as the heart rate, tended to be lower in the morning that at noon. The higher blood pressure at noon, which perhaps was due to a higher sympathetic tone, could in turn lead to better coronary perfusion, possibly overriding the effects of increases in oxygen needs.

We hypothesize that there could be a trend toward a morning increase in coronary tone in patients with significant coronary stenosis and unstable angina similar to that observed in patients with vasospastic angina and nonsignificant stenosis,3 11 24 35 the main difference being the greater magnitude of coronary vasoconstriction and probably, the somewhat earlier peak in those without significant stenosis.11 12 The fact that in some patients the morning pacing not only was associated with a reduction of threshold but also with an elevation of the ST segment that reverted with cessation of pacing would lend additional support to the thought that coronary reserve was further curtailed in the morning. In patients with nonsignificant coronary stenosis, Yasue et al3 noted at angiography that coronary diameter was smaller in the early morning than in the afternoon and that this was associated with a lower ischemic threshold as measured by an exercise stress test. Likewise, the dose of ergonovine necessary to produce coronary spasm has been shown to be lower early in the morning than in the afternoon.24 Moreover, Ouyyumi et al41 recently have documented that in patients with stable angina there was also a decrease in ischemic threshold in the morning when compared with noon or afternoon times, and Panza et al42 have demonstrated a higher basal forearm vascular resistance and a greater vasodilator effect of phentolamine in the morning than in the afternoon in normal subjects. We have observed that in patients with normal atrioventricular conduction there is a significant prolongation of the effective refractory periods of the atria and the atrioventricular node at 7 to 9 AM in comparison to 12 PM, which suggests a heightened parasympathetic tone.43 Thus, it is tempting to relate this morning increase in parasympathetic tone with the increase in coronary tone herein alluded. We have demonstrated in a previous study with comparable unstable angina patients that the ischemic threshold was significantly lower at midnight than at noon.9 In that study, however, ischemic threshold was measured without nitroglycerin, and it was not measured at 7 to 8 AM, which is one of the intervals with highest incidence of angina.10 11 We have now documented that despite the use of nitroglycerin, there is also a significant difference in threshold between 7 to 8 AM and 12 PM. The reproducibility of pacing threshold at 12 PM in 154 similar patients with unstable angina23 in two tests performed 24 hours apart, as previously reported,23 stresses the value of the difference with the morning threshold herein reported.

Limitations
We speculate that changes in coronary tone, either global or local, account for changes in ischemic threshold, but we provide no direct evidence. Nevertheless, since coronary perfusion pressure, as roughly expressed by the arterial blood pressure, remained unchanged or tended to be lower in the morning, we think it is a reasonable assumption that the lower threshold was related to an increased coronary tone, although changes in blood viscosity, a reduced fibrinolytic capacity, or even the same reduction in blood pressure also could have played a role.

We acknowledge that the perfusion of intravenous nitroglycerin invariably altered the coronary tone in our patients and hence, our observations may not be extrapolated to patients untreated with vasodilators. We suspect, however, that this agent might have blunted the differences in threshold by proportionally exerting a more critical vasodilation in the morning, when the tone was presumably higher. The fact that the differences in threshold were present despite administration of nitroglycerin may indicate that the dose used was too low to block this phenomenon. On the other hand, it can be speculated that some tolerance to nitroglycerin had developed, thus permiting morning tone changes to remain apparent. Moreover, the fact that nifedipine was discontinued 12 hours before the morning pacing raises the possibility of a residual vasodilatory effect that could have increased the morning threshold in some patients. Although the anticoagulant effect of heparin appears to follow a circadian rhythm with minimum values attained in the early morning,44 it is doubful that subcutaneous administration at 4 AM would have decreased efficacy 4 to 5 hours later, when the morning threshold was evaluated. Finally, since interpretation of the ECG changes during pacing was not blinded, it cannot be excluded as a possible bias toward overinterpretation of the morning results.

Implications
Our findings on the importance of a morning increased coronary tone or a reduced coronary vasodilator capacity in patients with unstable angina to possibly account, at least in part, for the increased incidence of anginal episodes during this interval may serve to improve our understanding of the mechanisms involved in these ischemic events and in their circadian distribution. At the same time, they are consistent with the high effectiveness of intravenous nitroglycerin in limiting the ischemic attacks. They stress, furthermore, the need to increase the protection during the morning hours, particularly during the weaning period of intravenous nitroglycerin with parenteral coronary vasodilators.

Received January 9, 1995; revision received March 23, 1995; accepted March 26, 1995.


*    References
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