(Circulation. 1997;95:1185-1192.)
© 1997 American Heart Association, Inc.
Articles |
Pathophysiology of Transient Myocardial Ischemia in Acute Coronary Syndromes
Characterization by Continuous ST-Segment Monitoring
the Department of Cardiology, Royal Brompton Hospital, London, United Kingdom.
Correspondence to Dr D.J. Patel, Department of Cardiology, Harefield Hospital, Harefield, Middlesex UB9 6JH, United Kingdom.
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Abstract |
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Background Transient ischemia in stable coronary disease peaks in the morning, reflecting increased myocardial oxygen demand and coronary vasomotor tone after waking. In acute coronary syndromes, however, ischemia may result from transient thrombus formation or coronary spasm at the site of a ruptured plaque. We report on the pathophysiological mechanisms underlying transient ischemia in acute coronary syndromes despite optimal therapy, on the basis of analysis of heart rate changes preceding ischemia and its circadian variation.
Methods and Results Two hundred fifty-six patients with unstable angina or non–Q-wave myocardial infarction underwent continuous ST-segment monitoring for 48 hours while receiving maximal medical therapy. All ischemic episodes were characterized by their timing, duration, association with pain, and heart rate changes before the onset of ischemia. During 10 629 hours of monitoring, 44 patients (17.2%) had 176 episodes of transient ischemia. The mean heart rate at onset of ischemia was 68±12.8 bpm, and >55% of ischemic episodes were not preceded by a significant increase in heart rate. Ischemic activity had a single nocturnal peak, with 64% of all episodes occurring between 10 PM and 8 AM, this nocturnal preponderance being evident for episodes with or without a preceding increase in heart rate. The characteristics and timing of transient ischemia were similar in unstable angina and non–Q-wave myocardial infarction, but transient ischemia was more frequent (27.3% versus 15.1%; P<.05) and prolonged (median, 20 versus 13.5 minutes; P<.01) in non–Q-wave myocardial infarction.
Conclusions In acute coronary syndromes, transient ischemia has a low threshold, occurs predominantly without an increase in myocardial oxygen demand, and is present mainly at night rather than in the morning. These findings in patients receiving maximal medical therapy suggest significant pathophysiological differences underlying transient ischemia compared with stable coronary disease.
Key Words: angina • ischemia • coronary disease • circadian rhythm
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Introduction |
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Unstable angina and non–Q-wave myocardial infarction (MI) share a common underlying pathological substrate and are associated with an increased risk of death and infarction.1 2 3 An important marker of prognosis in these conditions is the presence of transient myocardial ischemia, detected by continuous ST-segment monitoring.4 5 6 7 8
Myocardial ischemia can be caused by several mechanisms, including increased myocardial oxygen demand in the presence of a severe fixed stenosis, coronary spasm due to local release of vasoactive mediators, and transient thrombus formation. The use of ambulatory ST-segment monitoring and analysis of heart rate changes before the onset of ischemia has established that most anginal episodes in patients with stable coronary disease are caused by increases in myocardial oxygen demand, with episodes of spontaneous vasospasm being relatively uncommon.9 10 11 12 The circadian distribution of ischemia in stable coronary disease shows a peak in the morning waking hours, particularly in the first few hours after waking and commencing activity, the period corresponding with increased sympathetic activation resulting in increased myocardial oxygen demand and raised coronary vasomotor tone.13 14 15
The determinants of myocardial ischemia are likely to differ in patients with unstable coronary syndromes as the underlying pathological substrate usually consists of plaque rupture with a varying degree of intracoronary thrombus formation.16 17 18 Transient thrombus formation can reduce coronary flow with resolution of ischemia occurring by spontaneous clot lysis or fragmentation. Furthermore, vasoactive substances released from the injured endothelium or from platelet activation could cause ischemia by inducing vasospasm at the site of the lesion.
Previous studies assessing the frequency and pathophysiology of transient ischemia in acute coronary syndromes used limited medical therapy during investigation or performed monitoring after stabilization in highly selected patients. The purpose of the present study was to investigate the frequency and pathophysiology of transient ischemia in patients admitted to coronary care units with acute coronary syndromes who were receiving presently recommended treatment for their condition.
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Methods |
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All data were collected as part of a randomized multicenter study comparing the effects of intravenous heparin and aspirin versus aspirin alone, in addition to maximal antianginal therapy in unstable angina.8 Patients were recruited between 1990 and 1992 at three district general hospitals, none of which had on-site facilities for coronary angiography. The study had received approval from the ethics committees of all participating centers, and all patients provided informed written consent.
Patients were included if they were between 30 and 75 years old and had presented with acute chest pain necessitating admission to the coronary care unit. Patients were included with new onset angina, sudden acceleration of previously stable angina, or angina within 1 month of MI. Although resting ECG changes for ischemia were not a prerequisite for inclusion, patients with evolving Q-wave MI, significant conduction abnormalities (left bundle-branch block, left ventricular hypertrophy, and strain pattern) or taking medication likely to affect interpretation of ST-segment changes were excluded.
Treatment was standardized at admission with oral aspirin 150 mg/d, an oral ß-blocker, diltiazem 60 mg three times a day, and intravenous glyceryl trinitrate unless specifically contraindicated, thus allowing assessment of transient ST-segment changes under conditions of treatment similar to those recommended in the guidelines of the American Heart Association. In addition, patients were randomized to receive either intravenous heparin or no heparin with anticoagulation titrated in the active group to maintain an activated partial thromboplastin time ratio of 1.5x to 2.5x control value. Study medication was administered at 8 AM for once-daily therapy or at 8 AM, 2 PM, and 10 PM for thrice-daily therapy. Throughout the period of monitoring, all patients were placed on bed rest.
Of 285 patients recruited into the study, 29 (10.2%) had increased cardiac enzymes with evolution of Q waves within 24 hours of presentation, consistent with acute transmural MI, and were excluded from the present analysis. A further 44 patients (15.4%) had cardiac enzyme elevation without development of Q waves (non–Q-wave MI group); the remaining 212 patients had unstable angina on the basis of clinical or ECG criteria. The latter two groups constitute the present study population.
Continuous ECG Monitoring
After admission to the coronary care unit and commencement of treatment, patients underwent 48 hours of ECG monitoring for ST-segment analysis. The Oxford Medilog II FM system was used with MR35 dual-channel recorders, which have a frequency response of 0.05 to 40 Hz. Tapes were analyzed by investigators who were blinded to the clinical data. Analysis was performed by visual review of the recordings at 60 to 120 times the normal speed on an Oxford MA20 analyzer. All potential episodes of transient ischemia were printed on paper, and ST-segment depression was measured manually. The automatic trend analysis was also examined for any further episodes, and representative ECG complexes were sampled from each episode to confirm that the ST-segment changes represented ischemia and to measure the depth of ST-segment depression. Significant ST depression was defined as horizontal or downsloping ST-segment deviation beginning at the J-point and of 
0.1-mV magnitude below the baseline at J-point plus 80 ms. ST elevation was defined as the development of upward ST-segment deviation of 0.2 mV above the isoelectric line at the J-point. Changes in the T-wave vector in isolation were not included in the definition of transient ischemia, and persistent depression of the isoelectric line also was not considered to represent ischemia. In addition to the frequency of ischemic activity, the duration of each episode was recorded as well as its association with chest pain.
Analysis of Heart Rate and Circadian Variation
An ECG strip obtained before the onset of ST-segment depression was printed for each of the episodes, and the heart rate at 10 minutes, 5 minutes, and 1 minute before and at the onset of ST-segment depression was calculated. The difference between the heart rate at each of the time points before ischemia and that at the onset of ischemia was calculated, with a >5 bpm increase in the 10 minutes before the onset of ischemia selected a priori to represent increased myocardial oxygen demand. The choice of this cutoff was based on previously published studies.10 11 12
To examine the circadian variation of ischemic activity, the frequency of occurrence of transient ischemic episodes was plotted in 2-hour time groups for the entire 24-hour period starting from midnight, based on the time of onset of ischemia. Episodes in unstable angina subjects were plotted in the same way for comparison with ischemic activity in non–Q-wave MI subjects. The temporal distribution of episodes associated with a predefined increase in heart rate was also compared to those without, and the circadian variation in duration of transient ischemia was plotted in the same way.
Statistical Methods
Mean heart rates at the three prespecified time intervals, before the onset of transient ischemia, were compared with the heart rate at the onset of ischemia by a paired sample t test. Comparisons between the proportion of episodes with or without a >5-beat preceding heart rate increase were made by 
2 analysis with Yates' correction for continuity. Circadian variation in ischemic activity was examined initially by 2 test for goodness of fit based on the two-hour grouping of episodes, assuming equal preponderance of ischemic activity in each time period. In view of the single nocturnal peak, the number of episodes at night, defined as the time period between 10 PM and 8 AM (10 hours), was compared with the number occurring in the daytime (14 hours) by a 2 analysis assuming equal frequency of ischemic activity in the two time periods. The expected frequencies were calculated from the mean hourly frequency of episodes and corrected for the difference in length of the two time periods. The same grouping of night and day was also used to compare the temporal variation in ischemic activity between unstable angina and non–Q-wave MI and for episodes with or without a preceding heart rate increase.
Baseline characteristics were compared with an unpaired t test and by 2 analysis for categorical data. Fisher's exact test was used for any count that was 
5 in number. All values are quoted as mean±SD or as the median value and range as appropriate. A two-sided probability value of <.05 was used to define statistical significance throughout, and the Bonferroni correction was used for multiple comparisons.
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Results |
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The mean age of the study population was 59.3 years, of whom 202 (78.9%) were men. One hundred forty-two patients (55%) had previous stable angina and 160 (62.5%) were taking either a ß-blocker, calcium antagonist, or long-acting nitrate at the time of admission. After admission, all patients received standardized antianginal therapy according to tolerability (ß-blocker, n=189 [74%]; diltiazem, n=197 [77%]; intravenous glyceryl trinitrate [GTN], n=250 [98%]), and 137 patients (54%) received intravenous heparin. There were no significant differences in the baseline characteristics between the patients with unstable angina and those with non–Q-wave MI or between those receiving or not receiving heparin therapy.
Frequency and Characteristics of Ischemic Episodes
The findings of continuous ST-segment monitoring are shown in Table 1
. During 10 629 hours of monitoring, 44 patients (17%) had at least one episode of transient ischemia, 80% of which were silent. Patients with non–Q-wave MI were more likely to have such episodes (P<.05), and these episodes were of a longer duration (P<.01) than episodes occurring in patients with unstable angina. Transient ischemic episodes with ST-segment elevation were relatively rare, with only nine such episodes recorded.
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Heart Rate Changes in Relation to Onset of Ischemia
Heart rate changes before and at the onset of ischemia are shown in Table 2. There were no differences before or at the onset of ischemia in patients with unstable angina versus those with non–Q-wave MI. The heart rate before or at the onset of silent ischemic episodes (68.5±9.8 bpm) compared with that during painful episodes (68.4±13.8 bpm) was not significantly different. The extent of heart rate change leading to ischemia is shown in Fig 1. In >55% of episodes, there was no significant increase in heart rate (>5 bpm) during the 10 minutes before the onset of ischemia.
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The mean heart rate at the onset of ischemia was significantly lower in those episodes without a preceding heart rate increase (62.0±9.6 bpm) than in episodes preceded by a heart rate rise of >5 bpm (75.7±12.8 bpm; P<.001). Episodes without a preceding heart rate rise were also of significantly longer duration (median, 16.5 minutes [range, 1 to 143 minutes]) than those with a preceding heart rate increase (median, 12 minutes [range, 2 to 1062 minutes]) (P<.01). In ischemic episodes with an increase in heart rate, the change in heart rate was progressive from 10 minutes before the onset of ischemia, with virtually no change occurring in the minute immediately preceding ST depression, emphasizing the importance of assessing heart rate several minutes before the onset of ischemia.
Eighteen of the patients had 4 episodes of transient ischemia. Seven of these subjects had episodes predominantly without a heart rate rise, and the remaining 11 had episodes both with and without a preceding heart rate increase. None of the patients with frequent ischemia had a predominance of increased heart rate–associated episodes.
Timing of Ischemic Events
The circadian distribution of transient ischemic episodes for the total group is shown in Fig 2 (top). More episodes occurred at night (10 PM to 8 AM; 113 episodes [64.2%]) than during the day (8 AM to 10 PM; 63 episodes [35.8%]) (P<.001). In particular, there was no increase in ischemic activity in the period from 8 AM, when patients were woken and received their oral medication and breakfast, to noon. The mean basal heart rate and its relation to the timing of medication are shown in Fig 2 (middle). There was no significant variation in heart rate throughout the 24-hour period, with no morning increase in heart rate. Ischemic activity occurred at a similar time in unstable angina and non–Q-wave MI, as shown in Fig 2 (bottom), with 65% (86) of the episodes occurring at night in unstable angina subjects and 61% (27) in non–Q-wave MI subjects (P=NS). The temporal distribution of the duration of ischemia (Fig 3) does not show any obvious pattern, and episodes occurring at night (median, 14 minutes) were not significantly longer than daytime episodes (median, 15 minutes) (P=NS). Episodes were also more likely to occur at night, whether silent or symptomatic (Fig 4).
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Fig 5 demonstrates that the overall circadian variation in heart rate at the onset of ischemia was small, although there was a slight reduction in the early morning. The mean heart rate at the onset of ischemia in the day (70.2±12.3 bpm) was not significantly different from that in the night (67.3±13.6 bpm). The magnitude of heart rate change in the preceding 10 minutes is also plotted in Fig 5 (bottom) and shows a similar circadian variation to the heart rate at onset, with a mean heart rate increase preceding ischemia for daytime episodes of 7.80±8.25 bpm, compared with 6.30±10.34 bpm for nocturnal episodes (P=NS). The temporal distribution of episodes, with or without a heart rate rise, in relation to the mean basal heart rate is shown in Fig 6. Both types of episode had a similar temporal distribution to the overall ischemic activity, with a single nocturnal peak and no increase in the morning. The number of episodes associated with increased heart rate at night (41 [56.2%]) was similar to the number for those without such an increase (63 [68.5%]) (P=NS).
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Effect of Heparin Randomization
There was no significant difference in ischemic activity between patients receiving heparin and those who were not with respect to duration and timing of episodes or in terms of the heart rate changes before and at the onset of ischemia. Fig 7 shows that the circadian distribution of episodes was similar in patients receiving heparin treatment and those who were not.
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Discussion |
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Transient myocardial ischemia in acute coronary syndromes is a marker of adverse prognosis,4 5 6 7 8 although its underlying pathophysiological basis is not fully understood. The purpose of the present study was to explore the mechanisms involved in the genesis of transient ischemia in acute coronary syndromes on the basis of our knowledge of the mechanisms responsible for ischemia in stable coronary disease.
Our results show that patterns of transient ischemia in acute coronary syndromes, despite optimal drug therapy, differ markedly from ischemic activity in stable coronary disease.9 10 11 12 13 14 15 Ischemia is provoked at lower heart rates and is seldom preceded by an increase in heart rate, a surrogate measure of myocardial oxygen demand. Transient ischemic activity in patients with acute coronary syndromes admitted to the hospital and treated with maximal medical therapy also has a distinctive circadian pattern, which differs from that seen in stable coronary disease,12 13 14 15 with a nocturnal peak between 10 PM and 8 AM and without a morning peak of activity after awakening.
Lack of Alteration in Myocardial Oxygen Demand
The importance of alterations in myocardial oxygen demand causing transient ischemia during daily life has now been established in several studies.9 10 11 12 More than 80% of transient ischemic episodes during daily life in patients with stable angina are preceded by an increase in myocardial oxygen demand, as measured by fluctuations in heart rate and blood pressure. Primary changes in coronary perfusion, either as a result of altered coronary vasomotor tone or intraluminal thrombus, do not appear to play a major role in the genesis of ischemia in stable angina.10 In contrast, in unstable angina and non–Q-wave MI, acute plaque rupture is the characteristic pathological finding,16 17 and coronary spasm or transient coronary thrombosis18 are thus more likely to occur than in stable coronary disease. However, patients with unstable angina commonly have severe coronary luminal narrowing, often affecting more than one coronary artery,5 19 and may therefore also experience ischemia as a result of fixed obstruction to coronary flow, albeit at a lower threshold than in stable angina. Thus, in patients with unstable angina, myocardial ischemia may potentially be caused by mechanisms similar to those that operate in stable angina or by primary changes in coronary flow due to coronary spasm or thrombosis. Identification of the precise underlying pathophysiology would enable the use of tailored therapy: bed rest and ß-blocker therapy for demand-driven episodes and antispasmolytic, antiplatelet, or antithrombotic drugs for supply-mediated episodes. Furthermore, demonstration of the differences in the initiating mechanism of ischemia may have prognostic implications.
The majority of ischemic episodes in the present study occurred without an increase in heart rate in the 10 minutes before the onset of ischemia. Even when the heart rate rose, the magnitude of the change was small. Thus, large fluctuations in myocardial oxygen demand did not occur before the onset of ischemia. Heart rate changes before ischemia were similar in unstable angina and non–Q-wave MI, in keeping with a common underlying pathological substrate.16 20 Our results are consistent with those of Chierchia et al,21 who, in a study of silent and symptomatic ischemia, showed a fall in coronary perfusion before the onset of ischemia. That study, however, included only highly selected patients, and the vast majority of ischemic episodes were denoted by transient T-wave changes and thus were unrepresentative of typical ischemic activity in unstable angina. Our findings are also supported by a report by Langer et al5 of patients with unstable angina in whom no significant rise in rate-pressure product occurred in the 10 minutes before the onset of ischemia but a small increase was noted compared with a 2-hour baseline. Those results may reflect in part the efficacy of combination drug therapy in reducing myocardial oxygen demand but also suggest that residual ischemic activity despite medical therapy may have a different pathophysiological basis.
The heart rate at the onset of myocardial ischemia in the present study was low in both unstable angina and non–Q-wave MI (<75 bpm in 72% of the episodes and 100 bpm in only 4). Previous reports on such patients have reported higher heart rates at the onset of ischemia; however, the basal heart rate has also been higher.5 22 The low heart rate at baseline and at the onset of ischemia and the relatively small fluctuations preceding it are a reflection of the greater use of ß-blockers and diltiazem in our subjects. ß-Blockers were tolerated by 74% and oral diltiazem by 77%, while 98% were able to tolerate intravenous GTN during the period of the study. This high compliance with anti-ischemic therapy accounts at least in part for the low frequency of ischemic activity that we detected, although variation in the selection criteria and extent of underlying coronary disease may have also contributed to the observed differences.
The low ischemic threshold nevertheless suggests the presence of a critical underlying coronary lesion, because even in the episodes preceded by an increase in myocardial oxygen demand, the heart rate at the onset of ischemia was lower than generally reported in studies of transient ischemic activity in stable coronary disease.10 11
Timing of Ischemic Events
Although the circadian variation of symptomatic anginal pain has been reported,23 24 the distribution of silent as well as symptomatic transient ischemic activity in acute coronary syndromes has not been reported previously. Our results show that ischemia, whether symptomatic or silent, is more common at night in acute coronary syndromes despite optimal medical therapy. This nocturnal predominance in ischemic activity contrasts with the well-recognized morning peak in the onset of MI,25 sudden death,26 and unstable angina.27 28 These initiating events, representing the acute rupture of a plaque, are likely to be caused by surges in heart rate and blood pressure resulting in increased shear stress across vulnerable plaques. These surges also represent an increase in myocardial oxygen demand and account for the increased peak in transient ischemic activity during this time period in patients with stable coronary disease.12 13 14 15 A lack of a morning peak in ischemic activity might be the expected finding in patients who are hospitalized, restricted to bed rest, and treated with ß-blockers. Our results, however, indicate that ischemic activity in acute coronary syndromes is not distributed uniformly throughout the day but has a distinct nocturnal peak between 10 PM and 8 AM and no characteristic morning peak between 8 AM and noon. This suggests that although the initiation of acute coronary syndromes mirrors surges in myocardial oxygen demand, subsequent ischemic activity is not related to changes in myocardial demand, and other mechanisms need to be considered.
Circadian variations of platelet aggregability29 and endogenous fibrinolytic activity30 31 have been widely reported, and increased platelet aggregation occurs between 6 AM and noon.29 Sympathetic activation is probably responsible for the circadian variation in platelet function because it is induced by physical activity, occurs after adopting upright posture, and is abolished by remaining inactive and supine.32 Endogenous fibrinolytic activity, however, is lowest in the night and the early hours of the morning,30 31 33 similar to the peak of ischemia shown in the present study, and occurs earlier than the normal time of awakening. This association is supported by the findings of Masuda et al,33 who demonstrated a peak of ischemic activity at night in patients with variant angina that coincided with a nadir in fibrinolytic activity. Free-radical generation is also greatest at this time of the night,34 consistent with the possibility of increased risk of thrombosis at this time. Thus, the nocturnal peak of ischemic activity in acute coronary syndromes may reflect transient reductions in coronary flow as a consequence of transient thrombus formation.
Alteration in coronary vasomotor tone could also account for our observations because increased coronary tone in the night is considered to be the cause of a lower ischemic threshold at this time in stable coronary disease.35 Although the heart rate at the onset of ischemia and the magnitude of heart rate change preceding ischemia were lower at night (Fig 6
), the results were not statistically significant. This may reflect either the effect of ß-blockers and vasodilators in minimizing fluctuations in vasomotor tone or possibly a true lack of reactivity due to the extent of endothelial injury.
Limitations
We have relied solely on heart rate activity as a surrogate measure of myocardial oxygen consumption. Although changes in myocardial oxygen demand can result from alteration in blood pressure alone, it is generally accepted that such isolated changes in blood pressure are not common, and heart rate changes almost invariably accompany blood pressure fluctuations. The overall level of ischemic activity reported here is lower than in previous studies, but this probably reflects differences in patient selection and use of drug therapy rather than any real difference in pathophysiology. The broad entry criteria and the standardized treatment regimen of the present study are in accordance with current clinical practice and increase the clinical applicability of our observations.
Clearly our study does not report on the "natural" history of ischemic activity in acute coronary syndromes but rather on the characteristics of transient ischemia in such patients treated with maximal medical therapy on strict bed rest. It is possible, therefore, that the nocturnal preponderance of ischemia that we detected is a result of a trough of drug therapy at night. However, the absence of a rise in basal heart rate (Fig 2, middle) at night does not suggest a significant decrease in ß-blocker or diltiazem levels. Furthermore, heparin allocation did not affect the circadian distribution of transient ischemia (Fig 7), and although a circadian variation in the biological effects of heparin has been reported, the majority of studies show increased rather than decreased anticoagulant efficacy at night.36
Bed rest probably accounts for the abolition of the normal increase in heart rate after awakening, but not the nocturnal peak of ischemia. It is conceivable, however, that increased nocturnal ischemic activity might relate to altered sleeping patterns as a consequence of hospitalization. Review of the case notes of all patients with ischemia suggested, however, that the majority of patients were asleep during the night and awake during the day, with only 27% (12 of 44) reporting any sleep disturbance. Most ischemic activity was silent, and no patient was awake during these silent episodes. When experiencing painful episodes, the majority of patients (63%) were awoken by the pain, rather than being awake when pain occurred. Poor-quality sleep could have induced ischemia, but prospective data regarding rapid eye movement status or specific questioning regarding dreams or nightmares was not undertaken.
Therapeutic and Prognostic Implications
The lack of alteration in myocardial oxygen demand preceding ischemia after optimal medical therapy suggests that current multiple-drug regimens are highly effective in treating this potential cause of ischemia. The residual ischemic activity detected is probably related to alterations in coronary flow due to transient coronary thrombosis or vasoconstriction, and treatment should be directed against these mechanisms rather than at further attempts to reduce myocardial oxygen demand. When timing such treatment, it is important to bear in mind that the majority of ischemic activity we detected was nocturnal. Continuous ST-segment monitoring may be useful in assessing the efficacy of medical therapy and in establishing prognosis; the prognostic significance of supply-driven episodes of transient ischemia needs additional evaluation in larger numbers of patients.
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Acknowledgments |
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Dr Patel has been supported as a clinical research fellow by the Augustus Newman Foundation and Dr Knight by a British Heart Foundation Junior Research Fellowship during the period of this research. We would like to thank Dr William Hubbard, Dr Rod Thomas, Margaret Wicks, Dr George C. Sutton, and Dr Gordon Hendry and their coronary care staff for help in recruiting patients. We are also grateful for the advice given by Drs David Cunningham and Bharat Thakrar concerning data analysis.
Received April 18, 1996; revision received October 14, 1996; accepted October 21, 1996.
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