Silent Ischemic Episodes Research Articles

The role of silent ischemia, the arrhythmic substrate and the short-long sequence in the genesis of sudden cardiac death

To study the role of silent ischemia and the arrhythmic substrate in the genesis of sudden cardiac death, 67 patients were studied (mean age 62 ± 12 years). Of these, 14 patients (Group 1) had an in-hospital episode of ventricular tachycardia or fibrillation while wearing a 24 h Holter ambulatory electrocardiographic (ECG) monitor, 33 (Group II) had a documented episode of sustained ventricular tachycardia or fibrillation, or both, and 20 (Group III) had angina pectoris but no ventricular tachycardia or fibrillation. Eight Group I survivors underwent programmed electrical stimulation or ECG signal averaging, or both. All Group II patients underwent 24 h Holter monitoring and ECG signal averaging to detect late potentials before programmed electrical stimulation. Group III patients underwent both 24 h Holter recording and coronary angiography. The 24 h ECG tapes were analyzed for ST segment changes, prematurity index and characteristics of ventricular premature depolarizations. Any ST depression ≥1mm for >30 s was considered to be a reflection of silent ischemia, and the induction of ventricular tachycardia or fibrillation by programmed electrical stimulation or the presence of late potentials, or both, was considered to be a reflection of the arrhythmia substrate.Silent ischemia preceded ventricular tachycardia in only 2 (14%) of the 14 Group I patients. The prematurity index was <1 in only 18% of ventricular tachycardia episodes. However, 14 (64%) of 22 episodes of ventricular tachycardia in 9 (64%) of the 14 patients were initiated by a ventricular premature depolarization preceded by a short-long sequence (sinus beat-ventricular premature depolarization-sinus beat) with a ratio of 0.5 ± 0.1. Six (75%) of eight in-hospital survivors of ventricular tachycardia or fibrillation (Group 1) had an arrhythmic substrate. A significantly (p < 0.0001) higher percent of the 33 Group II patients had an arrhythmic substrate (93%) than had silent ischemic episodes (45%). Silent ischemia resulted in ventricular tachycardia in only 1(7%) of 15 Group II patients. There was no significant difference between the incidence of silent ischemia (45% versus 35%) and the extent of coronary artery disease between Groups II and III.It is concluded that: 1) Silent ischemia was not a major determinant of ventricular tachycardia. 2) Although silent ischemia was common in survivors of ventricular tachycardia or fibrillation, its incidence was not significantly different from that in patients with angina pectoris and no sustained ventricular arrhythmias. 3) A high percent of patients (75% to 93%) with ventricular tachycardia and fibrillation have an arrhythmic substrate. 4) In the absence of acute myocardial infarction, sudden cardiac death is frequently triggered by a ventricular premature depolarization, with a preceding short-long cycle that likely produces dispersion of refractoriness in the arrhythmic substrate.

Cardiovascular reactivity and silent ischemia in response to mental stress in symptomatic and asymptomatic coronary artery disease patients: results of a pilot study.

The current study was designed to examine cardiovascular reactivity to psychological tasks and its relationship to provocation of ischemia in asymptomatic coronary artery disease (CAD) patients with documented silent ischemia and those with painful ischemia. ECG, heart rate, and blood pressure responses to mental stress were collected for 13 patients with coronary artery disease (CAD) and for 6 healthy control subjects. Six of the CAD patients were asymptomatic (documented silent ischemia and no history of angina), while the remaining 7 were symptomatic (history of angina). Three types of mental stress were employed: white noise (a passive stressor), digits repeated backwards (an active stressor), and a math task plus white noise (active + passive stressor). Results indicate that significant increases in heart rate and blood pressure, but not silent ischemic episodes, were induced by the mental stress tasks. In addition, patients with documented exercise-induced and ambulant silent ischemia showed trends of blunted autonomic responsiveness to the stressors. On the digits backwards task, the CAD patients with silent ischemia showed significantly lower diastolic blood pressure responses compared with controls or angina patients. Findings suggest that ischemic episodes are not easily induced by brief mental stress. However, results indicate that asymptomatic CAD patients with silent ischemia may be lacking in autonomic responsiveness, particularly in terms of peripheral resistance, to mental stress in comparison with health controls and symptomatic ischemic patients. Further investigation is needed to explore how patients with silent ischemia typically respond autonomically to mental stress and how blunted reactivity may relate to the provocation of unrecognized ischemic episodes.

NORADRENERGIC ACTIVITY AND SILENT ISCHAEMIA IN HYPERTENSIVE PATIENTS WITH STABLE ANGINA: EFFECT OF METOPROLOL

30 patients (10 normotensive, 20 hypertensive) with stable angina and positive treadmill exercise tests entered a double-blind, placebo-controlled crossover trial of metoprolol, 100 mg twice daily. At the end of each treatment phase, blood pressure was monitored for 24 h and Holter and real-time electrocardiographic (ECG) monitoring were carried out and an activity diary kept for 48 h. Blood samples for catecholamine measurement were taken after 30 min supine, 60 min standing, and at the first silent ischaemic event, triggered by the real-time ECG monitor, by means of an ambulatory blood withdrawal pump. Metoprolol lowered blood pressure and heart rate in both normotensive and hypertensive subjects, and reduced the frequency and duration of silent ischaemic episodes in hypertensive subjects. Plasma noradrenaline measured during silent ischaemia while the patients were resting was significantly higher than the control supine level without ischaemia. These findings suggest that noradrenergic hyperactivity may have a role in coronary vasoconstriction and that treatment which neutralises sympathetic tone may be especially beneficial in treatment of silent ischaemia in hypertensive patients.

Effects of Metoprolol, Nifedipine and Their Combination on Total Ischemic Activity in Effort and Mixed Angina

In a randomized double-blind study the effect of metoprolol, nifedipine and their combined therapy were investigated on total ischemic activity detected by ambulatory monitoring. The study was performed in 2 groups of patients, who were defined by clinical history as classical effort-induced angina (group 1 ; n = 16) and mixed angina (group 2; n = 25) to assess possible differences in pathophysiology and guidelines to therapy. In group 1, metoprolol significantly reduced the frequency of total and silent ischemic episodes (77 and 71 % respectively, p < 0.05) and reduced the durations of total and silent ischemia (73 and 61 %, respectively; p < 0.05). Nifedipine was without any statistically significant effect. The combined therapy reduced total ischemic events (77%; p < 0.05), silent ischemia (76%; p < 0.05) and durations of total and silent ischemia (78 and 71 %, respectively; p < 0.05). In group 2 there was a trend toward a reduction in the frequency of total ischemia, silent ischemia and duration of ischemia during therapy with metoprolol (36, 33 and 32%, respectively; NS). In contrast, an insignificant increase in total ischemia, asymptomatic ischemia and duration of asymptomatic ischemia was noted during nifedipine therapy (24, 35 and 8%, respectively; NS). Combination therapy significantly reduced total ischemic episodes, silent episodes and duration of ischemia (59, 65 and 67%; p < 0.05). Assessment of heart rate at onset of ischemia during daily life and during exercise testing indicate reductions in myocardial oxygen supply as a major determinant for transient myocardial ischemia out of hospital in both effort and mixed angina, and no differences in pathogenetic mechanisms between the 2 groups of patients could be observed. Therefore, the division into effort-induced angina and mixed angina seems arbitrary and gave no guideline to a specific therapy as metoprolol monotherapy and combined therapy of metoprolol and nifedipine were preferable in both groups.

Prognostic significance of ischemic episodes in patients with previous myocardial infarction

This study assessed the prognostic significance of ischemic changes during daily activity as recorded by ambulatory electrocardiographic monitoring in a group of 224 low-risk postinfarction patients. Of the 224 patients studied, 74 (33%) had transient ischemic episodes on Holter monitoring. During the 28 months of follow-up the frequency of cardiac events (cardiac death, reinfarction, hospitalization for unstable angina, balloon angioplasty or coronary bypass surgery) was 51% among those with ischemic episodes on Holter monitoring, compared with 12% in those without such changes (p < 0.0001). The 74 patients with positive results in their exercise tests and Holter monitoring had a 51% event rate, compared with 20% among the 44 patients with a positive exercise test result but negative Holter results (p < 0.001). The event rate in those without ischemic changes either on the exercise test or on Holter was only 8.5%. Among patients with good (>40%) or reduced (<40%) left ventricular ejection fraction, those with transient ST depression on Holter had a significantly higher cardiac event rate compared with those without it. A similar event rate was found in patients with only silent, only symptomatic and with silent and symptomatic ischemic episodes.

CIRCADIAN VARIATION OF TOTAL ISCHAEMIC BURDEN AND ITS ALTERATION WITH ANTI-ANGINAL AGENTS

6264 hours of ambulatory ST segment monitoring of 150 unselected patients with proven coronary artery disease, who were off all routine anti-anginal treatments, showed 598 ischaemic episodes, of which 446 (75%) were silent (symptom-free). Most (68%) ischaemic episodes occurred between 0730 and 1930, with a peak in the morning and a lesser peak in the evening. Two subgroups were studied further in double-blind controlled trials: 33 patients had a total of 1313 hours of ST segment monitoring while treated with nifedipine; and 41 patients a total of 1581 hours while treated with atenolol. Nifedipine did not alter the circadian pattern of ischaemic episodes; atenolol abolished the morning peak, and the peak incidence of ischaemia then occurred in the evening. Circadian patterns for total duration of ischaemic episodes corresponded closely to those of episodes of ischaemia, and were similarly altered by treatment. The circadian pattern of silent ischaemic episodes and their total duration were very similar to those of total ischaemia for the group as a whole and the different subgroups. This circadian distribution of ischaemic episodes and the observed changes with treatment resemble the reported circadian variation of acute myocardial infarction and sudden death.

The combination of antianginal drugs: Effects and indications

Today, three classes of drugs, all acting differently on the myocardium, the coronary circulation, and the peripheral circulation, that is, on the determinants for myocardial oxygen consumption (heart rate, contractility, and wall tension), are at the physician's disposition for anti-ischemic medical treatment: nitrates, beta-receptor blocking agents and Ca antagonists. All three drugs have been proven to exhibit a marked antianginal effect when given alone, as demonstrated both by an improvement in exercise performance as well as in perfusion and a significant decrease in symptomatic and silent ischemic episodes. Treatment should cover the total ischemic burden, which can be assessed today more accurately by Holter monitoring than with exercise tests alone. It has been shown in patients with stable angina that the majority of ischemic episodes are silent (over 75%); therefore, the question arose as to whether medical anti-ischemic treatment should aim at the prevention not only of symptomatic, but also of silent episodes. Furthermore, ischemia was revealed to be not only a marker for the presence of high-grade life-threatening obstructions, but also to have prognostic implications, not only in symptomatic, but also in asymptomatic episodes. In addition, ischemia can lead to life-threatening arrhythmia and irreversible myocardial damage, especially localized fibrosis. To what extent this is prevented by vigorous anti-ischemic treatment is still unanswered; however, as pathophysiologically symptomatic and asymptomatic ischemic episodes behave similarly, the latter should be included in treatment. The combinations of drugs, especially of nitrates and beta blockers, Ca antagonists and beta blockers, and also nitrates and Ca antagonists result in a further improvement in exercise performance and a reduction in ischemic episodes, allow the dose to be reduced, and minimize side effects. In addition, as is indicated from their hemodynamics, in special clinical situations, combinations might be preferable. Whether treatment should primarily reduce sympathetic drive or, rather, be directed towards vasodilation depends on the type of angina and the individual need. Hence, combining drugs in treating angina pectoris represents a true therapeutic challenge for the physician.

Clinical outcome of silent myocardial ischemia

Asymptomatic coronary artery disease can be detected by an abnormal electrocardiogram at rest, by a positive exercise test result unaccompanied by pain, or by the demonstration of silent ischemic episodes during daily activities. However, the clinical outcome of patients with silent myocardial ischemia has not yet been clearly defined. In a study of 356 patients with documented coronary disease—211 of whom had previous myocardial infarction—the prognostic information of spontaneous ST-segment depression was found to be independent of that associated with a positive exercise test result, ejection fraction, and extent of arteriographically documented coronary artery disease. Patients with asymptomatic ischemia had a higher coronary event rate than those without ischemia. Cardiac event rates followed a similar pattern for patients with silent, symptomatic and mixed ischemia—whether or not there was previous myocardial infarction.

Transdermal nitroglycerin patches for silent myocardial ischemia during antianginal treatment

Because silent ischemia is not associated with an increase in heart rate and, being asymptomatic, its treatment requires constant therapeutic plasma levels of the drug used, a transdermal nitroglycerin patch (Deponit ®) was selected for treatment of this condition. Eight patients with documented silent ischemia were studied. All patients also had angina on effort treated with calcium antagonists (n = 8) and β blockers (n = 6). They were evaluated by 24-hour ambulatory electrocardiographic monitoring. The transdermal nitroglycerin patch, 20 to 30 mg/ 24 hours, reduced the number of silent ischemic episodes from 9.25 ± 5.52 to 2.4 ± 2.0 episodes per 24 hours (p < 0.001). The maximal ST-segment depression was reduced from 3.1 ± 0.7 to 0.9 ± 0.7 mm (p < 0.001). Ventricular premature beats were significantly reduced, by 50%. Symptomatic ischemic episodes were completely suppressed. Thus, transdermal nitroglycerin, in moderate doses, is effective in suppressing silent ischemia in patients with angina pectoris who have silent ischemic episodes despite treatment with other antianginal agents.

Silent Myocardial Ischemia

Silent myocardial ischemia is increasingly recognized as a common phenomenon in a variety of people with coronary artery disease. The natural history is poorly understood, but available data suggest that silent ischemia adversely affects prognosis in all groups studied. Based on this information, we believe that efforts should be directed at detecting and aggressively treating silent ischemic episodes.

Beta-adrenergic blockers in silent myocardial ischemia

Factors contributing to the development of exercise induced painful ischemia, such as actions of the central nervous system and catecholamines, have been well identified, but the mechanisms by which nonexercise-related silent episodes of ischemia are provoked are unknown. Possible mechanisms receiving much study in recent years are those having the potential to influence the myocardial oxygen supply-demand relation. Beta-adrenergic receptor stimulations, by increasing myocardial oxygen demand through augmentation of heart rate and contractility ( β 1), may mediate responses that cause ischemia or perpetuate ischemic episodes induced by other means. Other receptors ( β 2) may mediate coronary and peripheral vascular constriction, limiting myocardial oxygen supply and further increasing myocardial oxygen demand. Studies have investigated the effect of β blockade on ischemic episodes in patients with a variety of clinical forms of coronary heart disease. Beta blockade has been shown to reduce the frequency and duration of silent and painful ischemic episodes in patients with effort angina and rest angina. The data suggest that heart rate and perhaps other changes observed with use of β blockade play an important role in silent ischemia; heart rate at specific times throughout the day, particularly in the late a.m., and the increase in heart rate seen in conjunction with silent ischemic episodes are all decreased with administration of β blockade. Results of a recent study focusing only on silent ischemia showed that β-blocker treatment with metoprolol, compared with placebo, significantly reduced total silent ischemic time (frequency and duration of episodes) in all periods examined.

Antianginal Drug Therapy for Silent Myocardial Ischemia

Many of the available nitrate preparations, beta-adrenergic blockers, and calcium antagonists appear to be useful in patients with painful and silent ischemic episodes detected on the ECG (Table 1). More controlled studies need to be done using standardized methodologies for assessing silent myocardial ischemia, to evaluate and compare the different antianginal medications. It is fortunate, however, that the nitrates, beta-blockers, and calcium antagonists, used alone and in combination, appear to have favorable effects not only on painful ischemic episodes but also on those ischemic episodes not associated with pain.

Association between silent myocardial ischemia and prognosis: Insensitivity of angina pectoris as a marker of coronary artery disease activity

The clinical syndrome of angina pectoris was accurately described over 200 years ago by Sir William Heberden. However, in recent years, we have learned that many episodes of myocardial ischemia occur that are not accompanied by symptoms of angina pectoris. These silent ischemic episodes may be detected either during exercise testing, using electrocardiographic criteria that can be combined with scintigraphic studies evaluating myocardial blood flow (thallium perfusion studies) or left ventricular function (gated blood pool scans). In addition, continuous electrocardiographic (Holter) monitoring can be used for the detection of transient ST-segment changes; these changes on Holter monitoring have been correlated with abnormalities of myocardial perfusion and function, indicating that they represent true ischemic events. Studies have shown that patients with coronary artery disease who have evidence of ongoing ischemia, whether symptomatic or silent, have an increased risk for experiencing subsequent cardiac events than patients without evidence of ischemia. Many studies have demonstrated that ischemia during an exercise study after myocardial infarction identifies patients at high risk for recurrent cardiac events, whether or not the ischemia is associated with angina pectoris. Holter monitoring has allowed for the detection of ischemic events out of hospital in ambulatory patients. Studies in stable angina patients have shown that there are many asymptomatic episodes in this setting, which are often occurring at low heart rates during activities of everyday life, without an apparent significant increase in myocardial oxygen demands, and these episodes may even be precipitated by mental stress. Several studies have suggested that the presence of ongoing silent ischemia in unstable angina patients and postinfarction patients can identify those at higher risk for cardiac events. The results of these studies will be discussed. The treatment of coronary artery disease has been for the most part symptomatic, with the primary goal of relieving symptoms of angina pectoris. Several exceptions include patients with left main disease or severe proximal 3-vessel disease, who have extensive amounts of myocardium at risk and who are generally referred for bypass surgery. These new data indicating that the presence and severity of asymptomatic ischemia have adverse prognostic implications suggest that therapy should be directed at reducing the total ischemic profile, i.e., symptomatic and asymptomatic episodes. Guidelines for appropriate screening and therapeutic strategies will be discussed.

Silent myocardial ischemia perspectives

Except for hibernating myocardium, other manifestations of silent ischemia appear to be favorably affected by the usual therapeutic approaches to patients with suspected or documented coronary heart disease. However, it appears that in severe stable angina and unstable angina pharmacologic therapy may not be effective in controlling all or nearly all episodes of silent ischemia. There is no data to determine indications for or efficacy of therapy directed primarily at silent ischemia. Although elimination of silent ischemia would seem to be a desirable goal, there are no data to support that it can be achieved or that it is a clinically practical approach to treatment of patients.

Effects of titrated beta blockade (metoprolol) on silent myocardial ischemia in ambulatory patients with coronary artery disease

This study investigates effects of β-adrenergic blockade on total silent ischemic time assessed by ambulatory electrocardiographs monitoring and its relation to heart rate and time of day in ambulatory men with coronary artery disease. Metoprolol, when titrated to optimal dose in a controlled trial in 9 patients, reduced both total silent ischemic time (from 156 ± 65 to 20 ± 15 minutes, p = 0.04) and frequency of silent ischemic episodes (from 8 ± 2 to 2 ± 2 episodes, p = 0.03) compared with placebo. Mean daily heart rate was reduced, from 82 ± 2 beats/min during placebo to 58 ± 1 beats/min, as was heart rate at onset of 1 mm of ST-segment depression (106 ± 2 to 74 ± 4 beats/min, both p < 0.001). Heart rate increased 10 ± 1 beats/min during silent ischemia with placebo therapy, but increased only 4 ± 1 beats/min during metoprolol treatment (p < 0.03). During placebo administration the largest proportion of silent ischemic time occurred between 0600 and 1200 hours. Metoprolol attenuated this circadian variation in silent ischemia while reducing (p < 0.05) total silent ischemic time in all periods. Thus, β-adrenergic blockade reduces the frequency of silent myocardial ischemic episodes and total silent ischemic time, while mean daily heart rate and heart rate at onset of ischemia and maximal ischemia decrease. Metoprolol treatment also attenuates circadian variation of silent ischemia. These data may be interpreted to suggest that β-adrenergic activation operates in the pathogenesis of silent myocardial ischemia and its circadian variation.

Choice of therapy in chronic ischemic heart disease

The choice of therapy in chronic ischemic heart disease depends on identifying the underlying mechanism. Ambulatory monitoring provides a means of identifying those patients in whom increased myocardial oxygen demand is the most important mechanism and who will respond to a β blocker. In contrast, those patients with coronary spasm are best treated with a calcium antagonist. The history of angina pectoris and the time of onset may, in itself, be misleading. Detailed ambulatory monitoring studies show that nocturnal angina is frequently due to increased myocardial oxygen demand and in such circumstances should be treated by careful control of the heart rate using a β blocker without intrinsic sympathomimetic activity. Other factors that will influence the choice of medical therapy must be considered. Smoking is particularly important because it not only acts detrimentally in terms of increased myocardial oxygen demand, but may also interfere with the metabolism of those antianginal agents that are metabolized in the liver. The importance of silent myocardial ischemia has been emphasized recently, and studies using ambulatory pulmonary artery monitoring have shown that silent ischemic episodes have the same significance in terms of hemodynamic effects as painful ischemic episodes. The therapeutic and prognostic implications of these findings need to be explored.

Antianginal drug therapy for silent myocardial ischemia

Many of the available nitrate preparations, beta-adrenergic blockers, and calcium antagonists appear to be useful in patients with painful and silent ischemic episodes detected on the ECG (Table 1). More controlled studies need to be done using standardized methodologies for assessing silent myocardial ischemia, to evaluate and compare the different antianginal medications. It is fortunate, however, that the nitrates, beta-blockers, and calcium antagonists, used alone and in combination, appear to have favorable effects not only on painful ischemic episodes but also on those ischemic episodes not associated with pain.

Characteristics of silent myocardial ischemia during out-of-hospital activities in asymptomatic angiographically documented coronary artery disease

Ambulatory electrocardiographic monitoring is useful in documenting characteristics of both painful and silent myocardial ischemia occurring during out-of-hospital activities in patients with angina and coronary artery disease (CAD), but few data are available concerning silent myocardial ischemia during ambulatory electrocardiographic monitoring in asymptomatic patients with CAD. Accordingly, 480 hours of ambulatory electrocardiographic monitoring were recorded in 10 asymptomatic patients with CAD not receiving cardiac drugs (48 hours/patient). All 10 patients had silent myocardial ischemia on treadmill exercise testing, with initial ST-segment depression at 2 to 6 minutes in 7 patients and more than 6 minutes In 3 patients. During ambulatory electrocardiographic monitoring, 64 episodes of silent myocardial ischemia (1 mm of ST-segment depression for at least 1 minute) were recorded, ranging from 1 to 17 episodes/patient/48 hours. Of the 64 silent myocardial ischemic episodes, 30 (47%) occurred between 6 AM and noon. Duration of silent myocardial ischemia was 798 minutes (range 1 to 80). ST-segment depression ranged from 1 to 4.5 mm. Heart rate at onset of the episodes on ambulatory electrocardiographic monitoring ranged from 65 to 150 beats/min (mean 98), which was significantly less than that during treadmill exercise testing in the same patients (mean 120). At cardiac catheterization, 7 patients had 2- or 3-vessel CAD and 3 had 1-vessel CAD. Thus, silent myocardial ischemia is common during daily life in asymptomatic CAD patients with positive treadmill exercise tests.

Management of the total ischemic burden in angina pectoris

Recent reports suggest that neither the severity nor control of angina influences prognosis in patients with coronary heart disease. One possible explanation for such findings is that episodes of angina are only a small fraction of the daily ischemic episodes occurring in these patients. Silent episodes represent most of the ischemic burden in many patients with coronary disease who have positive exercise test results despite the absence of pain. Silent episodes also represent most of the ischemic burden in patients with either stable or unstable angina. Since silent episodes may have prognostic significance, a major goal of therapy should be the modification of both silent and painful ischemic episodes. Currently available pharmacotherapy has the potential to reduce the total ischemic burden caused by both painful and painless attacks and, thereby, alter prognosis.

Silent myocardial ischemia during daily activities in asymptomatic men with positive exercise test responses

The usefulness of prolonged ambulatory electrocardiographic monitoring (AEM) for detecting ischemia was investigated in 17 asymptomatic men who had ischemic-type ST-segment depression (greater than or equal to 2.0 mm) during treadmill exercise testing. No patient took anti-ischemic medications and all patients underwent coronary angiography. A total of 1,154 hours (range 64 to 72 hours/patient) of high-quality AEM recordings was obtained. Silent ischemia (episodes of asymptomatic ischemic-type ST depression of 60 seconds or longer) occurred in 11 patients during daily activity detected by AEM. In 6 other patients, no myocardial ischemic episodes were found. But 1 of these patients withdrew after only 24 hours of AEM and the remaining 5 had no significant coronary artery disease (CAD). All 11 patients who had silent ischemia had significant CAD (at least 50% stenosis) on angiography. There was wide intrapatient variability in the frequency of silent ischemic episodes. Silent ischemia was identified in 6 of these 11 patients after 24 hours of AEM, in 2 after 48 hours and in 3 after 72 hours. Thus, asymptomatic men with positive exercise test responses and CAD have silent ischemic episodes during daily activity. AEM may be useful in helping to predict which patients with asymptomatic positive exercise test responses have CAD; however, extended AEM periods are required.