1. Introduction

Long-term electrocardiographic (ECG) recording is fundamental to detect and characterize episodes of myocardial ischemia in patients with suspected or documented coronary artery disease (CAD). Indeed, 70% to 80% of transient ischemic episodes are not associated with anginal chest pain or any other symptom (silent ischemia) [Cohn, 1988], and this is independent of the mechanisms responsible for the induction of ischemia. In clinical practice long-term ECG monitoring is principally achieved by Holter ECG recordings (H-ECG), which is the method used in the vast majority of studies and trials on silent ischemia in the medical literature. Detection of spontaneous ischemic episodes during normal daily life by H-ECG has been found to have relevant prognostic implications and can assist in therapeutic decisions. Indeed, H-ECG can also provide findings contributing to define the pathophysiologic mechanisms responsible for transient ischemia in individual patients.

2. Diagnostic Aspects of Silent Ischemia

Transient myocardial ischemia is most frequently subendocardial. Episodes of subendocardial ischemia are usually diagnosed on H-ECG recording when horizontal or downsloping ST segment depression >1 mm at 0.06-0.08 sec from the J point, lasting at least 1 minute, is detected [Cohn, 1988].

After the early technical difficulties in the correct reproduction of low-frequency ECG signal [Bragg-Remschel et al., 1982], modern technology has allowed reliable reproduction of the ST segment by H-ECG devices [Deanfield et al., 1984a]. Furthermore, the possibility to detect myocardial ischemia by H-ECG has been improved by monitoring two bipolar chest leads. Monitor leads should always include CM5, as it is the single lead with the highest sensitivity in relieving ST segment depression, independent of the location of myocardial ischemia [Quyyumi et al., 1986]. Recently, H-ECG recorders able to monitor three leads, and also a system which allows recording of 12 leads, have become available. Nevertheless, the usefulness of more than 2 bipolar leads for improving detection of subendocardial ischemia has been questioned [Shandling et al., 1992; Jiang et al., 1995]. In a study we found that the addition of a third H-ECG lead improved sensitivity for detecting subendocardial ischemia only from 94% to 96% [Lanza et al., 1994].

According to Bayes theorem, the probability that transient ST segment depression on H-ECG actually represents myocardial ischemia varies according to the clinical features of the patient, being as much as greater as higher is the pre-test likelihood of CAD. In fact, "ischemic" ST segment changes have been reported in 2% to 30% of asymptomatic apparently healthy subjects [Deanfield et al., 1984b; Armstrong et al., 1982; Quyyumi et al., 1983], but the vast majority of them will not have significant CAD. A greater severity of ST depression or the simultaneous presence of angina will increase the likelihood that the ECG alteration is actually caused by myocardial ischemia.

The ischemic meaning of ST depression on H-ECG is usually established with reference to the presence or absence of hemodynamically significant epicardial coronary artery stenosis at angiography. However, coronary angiography may not be the ideal "gold-standard" for the interpretation of ST segment depression, because myocardial ischemia can occur in the absence of coronary stenoses, as in microvascular angina or in subocclusive vasospastic angina.

Dynamic vectorcardiography has recently been proposed as an alternative to H-ECG for silent ischemia detection [Dellborg et al., 1995; Homvang et al. 1999]. Although this method is promising, its actual sensitivity and specificity in ischemia detection are hitherto still poorly known. Furthermore, clinical studies using dynamic vectorcardiography are limited and its advantages on H-ECG unclear.

2.1. Silent Ischemia Detection in Chronic Stable Angina

Although in patients with chronic stable angina the sensitivity of H-ECG in detecting myocardial ischemia has sometimes been reported to be similar to that of exercise testing [Quyyumi et al., 1987; Hoberg et al., 1990], it is actually lower. Indeed, the occurrence of transient ischemic episodes during daily life is strongly correlated to the workload at which ischemia appears on exercise test, being greater in patients with low ischemic threshold and lower in those with no or high-workload ischemia [Mulcahy et al., 1989; Panza et al., 1991]. Thus, H-ECG has low additional diagnostic value in these patients, although it may reveal ischemia in about 10% of those with negative exercise test [Panza et al., 1991; Lanza et al., 1997]. These latter are usually patients with a high variability of ischemic threshold, likely due to significant vasomotor changes. Furthermore, H-ECG may represent the first diagnostic test in patients who are unable to undergo exercise test.

H-ECG is useful to define number, severity and duration of ischemic episodes during normal daily life, as well as their relationship with activity and daily hours. Thus, H-ECG has shown that episodes of subendocardial ischemia have a typical circardian distribution, with a first peak in the morning hours and a second peak in the afternoon [Rocco et al., 1987; Mulcahy et al., 1988].

H-ECG has also shown that increased myocardial oxygen demand has a predominant role in the induction of ischemia in patients with stable angina [McLenachan et al., 1991; Hinderliter et al., 1991], as heart rate (HR) significantly increases prior to ischemia in the majority of episodes, whereas it shows more limited changes in patients with unstable angina [Patel et al., 1997], and no changes at all in patients with variant angina [Lanza et al., 1996], as expected from the different pathophysiologic mechanisms responsible for these different ischemic syndromes.

Nevertheless, in patients with stable CAD, H-ECG has also shown that: (1) HR at the ischemic threshold (i.e., 1 mm ST depression) is lower during spontaneous ischemic episodes than during ischemia induced by exercise test [Quyyumi et al., 1987; Hoberg et al., 1990; Deanfield et al., 1983], (2) HR at 1 mm ST depression presents wide variability among spontaneous episodes, and (3) HR does not increase prior to ischemia in a significant number of ischemic episodes [Quyyumi et al., 1987; Hoberg et al., 1990; Hinderliter et al., 1991]. These findings suggest that a primary impairment of coronary blood flow, caused by vasomotor changes, also play a significant role in determining the occurrence of ischemia in these patients.

H-ECG is also useful to characterize episodes of ST segment depression in patients with cardiac syndrome X (i.e., anginal pain, positive exercise test, angiographically normal coronary arteries), which is believed to be caused by coronary microvascular disease [Maseri et al., 1991]. Episodes of ST depression in these patients present findings similar to those of stable CAD patients [Lanza et al., 1997; Kaski et al., 1986]. We have also found that H-ECG can detect ST depression episodes in several patients (50%) with angina and normal coronary arteries, but negative exercise test, suggesting that vasomotor microcirculatory changes can be involved in the genesis of symptoms also in this latter group of patients, as in those with classical syndrome X [Mulcahy et al., 1989].

2.2. Silent Ischemia Detection in Patients with Variant Angina

H-ECG has an outstanding role in the diagnosis of Prinzmetal's variant angina, which is caused by occlusive epicardial coronary artery spasm, either in presence or absence of atherosclerotic coronary lesions, and is characterized by angina occurring at rest and associated with ST segment elevation, indicating transmural ischemia, on the ECG [Maseri et al., 1975]. In these patients anginal episodes often occur at night or in the first morning hours and have short duration, so that it is difficult to demonstrate myocardial ischemia on standard ECG. Exercise test, on the other hand, is in most cases negative. H-ECG is in most patients determinant to demonstrate the occurrence of ST segment elevation during angina, or even to detect the occurrence of silent episodes of transmural ischemia, which also in this case constitute the vast majority of all episodes (about 80%). H-ECG has also shown that silent episodes of transmural vasospastic ischemia present typical circadian variation with prevalence in the night [Lanza et al., 1999; Waters et al., 1984] and are often grouped in clusters. Furthermore, analysis of heart rate variability (HRV) prior to ST segment elevation has provided evidence that autonomic changes may be involved in the induction of spasm in these patients [Lanza et al., 1996]. In a study on 64 patients we found that H-ECG was determinant in diagnosing variant angina in 31 (48%) [Maseri et al., 1996], whereas the use of three bipolar chest leads has no or little advantage to detect silent subendocardial ischemia, it can be necessary to detect transmural ischemia, as ST segment elevation specifically occurs in ECG leads directly "exploring" the myocardial ischemic region. A combination of CM5, CM3 (or CM2) and a modified aVF lead appears to be optimal to detect all episodes of transmural ischemia occurring in different myocardial territories [Krucoff, 1988].

H-ECG is important at assessing the effectiveness of vasodilator therapy in the prevention of recurrences of coronary spasm. This is crucial in patients with a history of syncope and/or documentated severe ventricular tachyarrhythmias or bradyarrhythmias during ischemia, who are at high risk of sudden death [Myerburg et al., 1992].

3. Prognostic Implications of Silent Ischemia Detection by H-ECG

A lot of studies have shown that detection of silent ischemia is associated with increased risk of cardiac events in several groups of CAD patients.

3.1. Myocardial Infarction

There have been several reports on the prognostic value of silent ischemia on pre-discharge H-ECG in survivors from acute myocardial infarction [Tzivoni et al., 1988; Gottlieb et al., 1988; Langer et al., 1992; Gill et al., 1996]. Gill et al. [Gill et al., 1996], in a large study on 406 patients, reported that 1-year mortality was 11.6% in patients with transient ischemia, but only 3.9% in those with no ischemic episodes (p=0.009) on 48-hour H-ECG. Similarly, major cardiac events (death or reinfarction) were 23.2% and 9.6% in the two groups, respectively (p=0.001). Silent ischemia on H-ECG had independent prognostic value and appeared particularly useful in the prediction of events in high-risk subgroups of patients, including those excluded from exercise test and those with low left ventricular ejection fraction.

In a recent evaluation of 239 patients with recent myocardial infarction we found that the occurrence of cardiac death or reinfarction at an average follow up of 28 months was 29% in patients with, compared to 8% in those without, silent ischemic episodes (p<0.01). Silent ischemia was the only independent predictor of re-infarction on multivariate analysis (odds ratio 8.7, p=0.006, unpublished data).

3.2. Unstable Angina

Many studies have shown that transient ischemia on H-ECG performed early after hospital admission is amongst the major (and likely the most important) predictor of cardiac events in patients with unstable angina. Gottlieb et al. [Gottlieb et al., 1986] reported that intra-hospital myocardial infarction occurred in 16% of patients with and in 3% of patients without episodes of transient ischemia on H-ECG (p=0.005). They also showed that a total ischemic burden >60 minutes in the 24 hours was more predictive for total coronary events (including revascularization procedures). These data were confirmed by numerous studies [Nademanee et al., 1987; Wilcox et al., 1990; Ardissino et al., 1996].

We performed H-ECG in coronary unit in 102 patients with unstable angina [Rebuzzi et al., 1998]. Episodes of ST depression were found in 33 patients. AMI occurred in 36% of patients with, but in only 4% of those without, ischemia (p<0.001). On multivariate analysis, the detection of transient ischemia on H-ECG was the single most predictive factor of cardiac events.

In a previous study we also showed that assessment of cardiac autonomic function by HRV analysis on H-ECG could help in further stratifying patients with unstable angina. Indeed, among patients who showed ischemic episodes during H-ECG, a low frequency to high frequency (LF/HF) ratio >1.3 (possibly indicating higher adrenergic autonomic state) was associated with a 4-fold increase in the risk of events, compared to those with transient ischemia but LF/HF ratio <1.3 [Lanza et al., 1997].

3.3. Chronic Stable Angina

The prognostic role of H-ECG in patients with a history of stable CAD is more controversial. Among 86 patients with positive exercise test, Rocco et al. [Rocco et al., 1988] reported that all but one cardiac events occurred in the 49 patients with episodes of ST depression on H-ECG. Other studies confirmed these data [Tzivoni et al., 1989; Deedwania and Carbajal, 1990; von Arnim et al., 1996]. In the Total Ischemic Burden Bisoprolol Study (TIBBS) [von Arnim et al., 1996] on 520 patients, the occurrence of major cardiac events (death, myocardial infarction, unstable angina) at a follow-up of 12 months was 4.7% in patients with <2 episodes of transient ischemia, but 12.1% in those with >2 ischemic episodes (p<0.005). Other studies, however questioned the prognostic value of silent ischemia in patients with stable heart disease [Quyyumi et al., 1993; Moss et al., 1993; Mulcahy et al., 1995].

The reasons for these discrepancies are not clear. However, different selection criteria of patients, end points, H-ECG recording and analysis, and therapeutic approaches may have contributed. In our opinion, the detection of transient silent ischemia at H-ECG in patients with stable CAD should likely be considered as a risk factor for future events. However, it should be considered that the detection of ischemia in these patients usually occurs in those with low workload ischemia at exercise test, who already are at higher risk [Weiner et al., 1987; Froelicher et al., 1987]. Thus it is not clear whether silent ischemia on H-ECG may actually add prognostic information compared to those provided by a careful assessment of exercise results, including not only ECG variables, but also clinical (exercise tolerance, symptoms) and hemodynamic (HR, blood pressure) variables.

4. Therapeutic Implication of Silent Ischemia Detection

When assessing the effectiveness of drug therapy on silent ischemia the spontaneous day-to-day variability of ischemic episodes should be taken into account [Nabel et al., 1988]. To this aim, performing H-ECG for at least 48 hours in individual patients could be useful to document the reproducibility of the ischemic pattern.

In patients with variant angina the suppression of episodes of transmural ischemia seems clearly associated with a better outcome [Yasue et al., 1988]. Conversely, it is unknown at present whether suppression of silent episodes of subendocardial ischemia by drug therapy improves prognosis in stable and unstable CAD patients. Some attempts to clarify this point have been done in patients with stable CAD.

In the Atenolol Silent Ischemia Study [Pepine et al., 1994], 306 stable patients with transient ischemia on 48-hour H-ECG were randomized to atenolol or placebo. After 4 weeks, ischemic episodes were present in 61% of patients treated with placebo and in 40% of those treated with atenolol (p=0.002). Total cardiac events at 1-year follow-up occurred less frequently in the group treated with atenolol (11% vs 25%, p<0.001). The absence of ischemia on H-ECG performed after 4 weeks of treatment (with either atenolol or placebo) was associated with a lower occurrence of cardiac events (11.2% vs 26.9%, p=0.001).

The Asymptomatic Cardiac Ischemia Pilot (ACIP) study [Knatterud et al., 1994] was designed to specifically evaluate the feasibility of a trial aimed at assessing the impact of silent ischemia suppression on clinical outcome. In this study, 618 CAD patients who had positive stress test and at least 1 episode of silent ischemia on 48-hour H-ECG were randomised to three strategies of treatment: 1) medical therapy adjusted to suppress angina (angina-guided strategy); 2) medical therapy increased to also suppress silent ischemic episodes (ischemia-guided strategy); 3) coronary revascularization (angioplasty or bypass surgery). At 1-year follow-up, major cardiac events (death or myocardial infarction) occurred in 9.9% of patients in the angina-guided group, in 6.5% of those in the ischemia-guided group and in 2.6% of those in the revascularization group. These differences were significant only for the comparison between groups of revascularization and angina-guided medical therapy (p=0.01) [Rogers et al., 1995]. The ACIP study does not provide evidence that suppression of silent ischemia by drug therapy can be associated with improved prognosis. However, ischemia-guided treatment failed to reach a better control of ischemic episodes in this pilot study, as H-ECG at the 1-year follow-up still showed silent ischemia in 64% of patients in the ischemia-guided group versus 69% of patients in the angina-guided group. Ischemic episodes, on the other hand, were suppressed in 57% of patients assigned to revascularization, but it is not clear whether there was any relationship between suppression of ischemia and improved prognosis [Rogers et al., 1995].

In the Total Ischemic Burden European Trial [Dargie et al., 1996], 537 patients with stable angina and positive exercise test were randomized to atenolol, nifedipine or their combination. The occurrence of ischemia and of cardiac events were similar among the three groups and no relationship was also found between presence of ischemia and cardiac events. Indeed, at 2-year follow-up, major cardiac events occurred in 11% of patients with, and in 9.5% of those without ischemia at H-ECG performed after 6 weeks of treatment.

In the TIBBS study [von Arnim et al., 1996], however, among 283 CAD patients, total cardiac events occurred in 32.3% of patients with, and in 17.5% of patients without, ischemia at follow up (p=0.008). There was no difference in the occurrence of major cardiac events, however (11.3% vs 7.2%, p=0.28).

Overall, these results are controversial and only a well designed future study can answer the question whether suppression of silent ischemia is associated with a better clinical outcome.

References