Relation Between Ambulatory Electrocardiographic Monitoring and Myocardial Perfusion Imaging to Detect Coronary Artery Disease and Myocardial Ischemia: An ACIP Ancillary Study
Author + information
- John J. Mahmarian, MD, FACCA,*,
- Richard M. Steingart, MD, FACCB,
- Sandra FormanC,
- Barry L. Sharaf, MD, FACCD,
- Mary Ellen CoglianeseB,
- D. Douglas Miller, MD, FACCE,
- Carl J. Pepine, MD, FACCF,
- A. David Goldberg, MD, FACCG,
- Marilyn F. Bloom, RNA,
- Sheila ByersE,
- Laurel DvorakG,
- Craig M. Pratt, MD, FACCA,1,2,
- Asymptomatic Cardiac Ischemia Pilot (ACIP) Investigators
- ↵*Dr. John J. Mahmarian, Baylor College of Medicine, 6550 Fannin, SM-1246, Houston, Texas 77030-2716.
Abstract
Objectives. This study sought to explore the relation between markers of ischemia detected by ambulatory electrocardiographic (AECG) monitoring and stress myocardial perfusion single-photon emission computed tomography (SPECT).
Background. Stress myocardial SPECT and AECG monitoring are both utilized in evaluating patients with coronary artery disease. However, information is limited regarding the relation between the presence and extent of ischemia as detected by these two modalities.
Methods. This was an ancillary study of the Asymptomatic Cardiac Ischemia Pilot (ACIP) trial. One hundred six patients with previous coronary angiography underwent AECG monitoring and stress SPECT within a close temporal time period. The frequency and duration of ischemia as assessed by AECG monitoring and the total and ischemic stress-induced myocardial perfusion defect sizes as assessed by SPECT were quantified in separate core laboratories. Multivariate logistic regression and linear regression analysis were used to determine associations between AECG and SPECT abnormalities with regard to angiographic, demographic and treadmill exercise variables.
Results. Seventy-four percent of patients with significant (≥50%) coronary artery stenosis had SPECT abnormalities, whereas 61% had ischemia by AECG monitoring. The most important predictors of SPECT abnormalities were severity (p < 0.001) of coronary artery stenosis, followed by total exercise duration (p = 0.016) and patient age (p = 0.04). The only predictor of AECG abnormalities was the presence of ST segment depression on the initial exercise treadmill test (p = 0.021). Only a 50% concordance for normalcy or abnormalcy was observed between the SPECT and AECG results, and no relation was observed between the frequency or duration of AECG ischemia and the quantified total or ischemic myocardial perfusion defect size as assessed by SPECT.
Conclusions. Ischemia as detected by AECG monitoring does not correlate with the presence and extent of ischemia as quantified by stress SPECT. Because these techniques appear to detect different pathophysiologic manifestations of ischemia, they may be complementary in more fully defining the functional significance of coronary artery disease and, in particular, which patients are at highest risk for adverse cardiac events.
(J Am Coll Cardiol 1997;29:764–9)
Myocardial perfusion scintigraphy is useful for both diagnosis ([1–12]) and risk stratification ([13–26]) of patients with coronary artery disease. Ambulatory electrocardiographic (AECG) monitoring has also been extensively studied, particularly with regard to its role in detecting myocardial ischemia during daily life and in assessing prognosis ([27–36]). Although both techniques have been utilized in patients with coronary artery disease, information evaluating the relation between the presence and extent of ischemia, as detected by these two modalities, is limited.
The Asymptomatic Cardiac Ischemia Pilot (ACIP) study ([37]) was a National Institutes of Health-sponsored trial designed to assess the feasibility of conducting a major trial of different treatment strategies for reducing myocardial ischemia. Patients were eligible for the ACIP trial if they had documented coronary artery disease (≥50% diameter stenosis) and electrocardiographic (ECG) evidence of ischemia on both treadmill testing and 48-h AECG monitoring. All patients considered for the ACIP trial were evaluated with 48-h AECG monitoring, and a subgroup also underwent stress myocardial single-photon emission computed tomography (SPECT) within a close temporal time period. In this regard, the ACIP trial provided a unique opportunity to explore the relation between markers of ischemia detected by AECG monitoring and stress SPECT.
1 Study design and patient cohort
The ACIP study design has been previously discussed in detail elsewhere ([37]). The present ancillary study identified 160 patients, from 5 of the 10 sites, who underwent both AECG monitoring and SPECT (Fig. 1). Of these 160 patients, 106 also underwent coronary angiography and constitute the cohort for this ancillary study (82 men, 24 women; mean [±SD] age 60 ± 8 years, range 37 to 81).
Population screened for study analysis.
Fifty patients were enrolled in the ACIP trial, and the remaining 56 patients were excluded for various reasons (Table 1). Four patients were excluded from the ACIP trial by the local centers for having only insignificant (<50%) coronary stenosis, but three of these patients were subsequently reported by the angiographic core laboratory to have significant single-vessel coronary artery disease. The majority of patients (68%) had a history of angina within 6 weeks of AECG monitoring. Myocardial SPECT was performed a mean of 46 ± 72 days of AECG monitoring, and most patients (n = 79) had perfusion imaging as the first test. SPECT was combined with either treadmill exercise (n = 92) or pharmacologic stress (n = 14).
Reason for Ineligibility in ACIP Trial
2 Ambulatory electrocardiographic monitoring
AECG monitoring consisted of two 24-h recordings using two-channel cassette devices. Leads monitored were those demonstrating greatest ST segment depression during baseline exercise testing if an exercise test was done. Ischemic ST segment depressionwas defined as reversible horizontal or downsloping ST segment depression ≥1 mm below the isoelectric line and ≥1 mm below the baseline ST segment value or ST segment elevation ≥1 mm above the isoelectric line and ≥1 mm above the baseline ST segment value. An ischemic episodewas defined as ST segment deviation lasting ≥1 min. The AECG tapes were analyzed in blinded manner with regard to clinical information or treatment assignment by the core laboratory.
3 Coronary angiography
All coronary angiograms were analyzed in a core laboratory to determine the extent, location and severity of coronary artery disease. Stenosis severitywas semiquantitatively analyzed using electronic calipers. Significant coronary artery diseasewas defined as ≥50% lumen diameter stenosis in at least one of the three major coronary arteries. To be eligible for the ACIP trial, coronary artery disease had to be documented on an angiogram obtained within the past 3 years, unless the patient had an interim clinical event for which a second angiogram was required.
4 Single-photon emission computed tomography
SPECT imaging was performed by the method previously reported from our laboratory ([2]). At peak exercise or during pharmacologic stress, 3 mCi of thallium-201 (n = 74) or 10 to 12 mCi of technetium-99m sestamibi (n = 32) was injected intravenously and flushed with saline solution. Images were acquired using a large field of view, single-crystal, rotating gamma camera equipped with a high resolution, parallel-hole collimator. Image acquisition was performed over an 180° anterior arc at 6° intervals and for 40 s/image.
SPECT images were quantified and displayed as polar maps by one experienced investigator (J.J.M.) in the core laboratory ([2, 26]). The stress and 4-h delayed thallium-201 or rest technetium-99m sestamibi images were independently computer generated and normalized using a circumferential profile analysis that has been previously described in detail ([2, 26]). The raw data polar maps for each patient were then statistically compared with an appropriate normal data bank to determine total left ventricular perfusion defect size (PDS) and extent of scintigraphic scar and ischemia. Total PDSis the extent of left ventricular hypoperfusion induced by stress, whereas ischemic PDSis that component of the total defect which subsequently improves its perfusion on rest imaging. Myocardial ischemia by SPECTwas defined as the presence of an ischemic perfusion defect. The intraobserver and interobserver reproducibility of our method for quantifying perfusion defects is excellent, with correlation coefficients of 0.98 and 0.97, respectively ([38]). A perfusion scan was considered abnormal if a perfusion defect ≥3% was present.
5 Statistical analysis
Demographic, clinical and angiographic findings at entry were analyzed for associations with AECG monitoring and SPECT findings. The sensitivity for detecting significant (≥50% diameter stenosis) coronary artery disease was based on the presence of a significant (≥3%) perfusion defect (ischemic or nonischemic), as assessed by SPECT, or ≥1-mm ST segment depression lasting ≥1 min, as assessed by AECG monitoring. The p values were calculated using chi-square, Mantel Haenszel or Student ttests as appropriate. Forward stepwise logistic regression using the SAS ([39]) software package was performed to determine variables independently associated with abnormalities on AECG or SPECT. The following variables were considered potential prognostic factors for abnormalities on SPECT: age, gender, stenosis severity, exercise duration, presence of ischemia on the exercise ECG and number of ischemic episodes on AECG. The following variables were considered potential prognostic factors for abnormalities on AECG: age, gender, stenosis severity, exercise duration, presence of ischemia on the exercise ECG and presence of abnormalities on SPECT. Variables entered and remained in the model if the p value for association with the outcome variable was ≤0.05. Linear regression analysis was used to define associations between total and ischemic PDSs and number of episodes of AECG ischemia. A priori, a p value <0.01 was taken to indicate statistical significance for all the ACIP study analyses.
6 Results
6.1 Coronary angiographic findings
Of the 106 patients who underwent coronary angiography, 105 had significant (≥50%) coronary artery stenosis. Sixty-eight percent of patients had multivessel coronary artery disease, and 57% had significant (≥50%) proximal stenosis of the left anterior descending (n = 26), right (n = 25) or circumflex (n = 19) coronary artery. These results are similar to those found in the ACIP randomized patients ([37]). Seventy-five percent of patients had at least one severe (≥70%) coronary stenosis, and 40% of patients had a totally occluded artery. Forty-three percent of patients had evidence of a complex atherosclerotic plaque in one or more of the coronary arteries.
6.2 Exercise test results
In the 92 patients who underwent both exercise treadmill testing and SPECT, the mean exercise time was 7.4 ± 2.4 min, with a mean maximal heart rate of 134 ± 19 beats/min. The mean maximal systolic blood pressure at peak exercise was 178 ± 26 mm Hg. Seventy-one patients (77%) had significant (≥1 mm) ST segment depression, and 34% developed angina during the exercise test. Of the 71 patients with a treadmill ECG for positive ischemia, 52 had abnormalities on SPECT, and 50 had AECG ischemia.
6.3 Scintigraphic results
The mean quantified total and ischemic left ventricular PDSs for the 106 patients studied were 14 ± 14% (median 11%) and 8 ± 9%, respectively. Seventy-eight of the 105 patients (74%) with significant (≥50%) coronary artery disease had abnormalities on SPECT. One patient with insignificant coronary artery disease had normal scan results. Seventy percent of patients with single-vessel, 66% of those with double-vessel and 88% of patients with triple-vessel coronary artery disease had abnormalities on SPECT. Abnormalities on SPECT occurred more frequently in patients with severe (≥70%) versus a lesser degree (<70%) of coronary artery stenosis (84% vs. 42%, respectively, p < 0.001). The most important angiographic predictors of abnormalities on SPECT were extent of coronary artery disease (p = 0.04) and stenosis severity (p < 0.001). By logistic regression analysis, stenosis severity was the most important predictor of scan abnormalities (p = 0.001), followed by shorter treadmill exercise time duration (p = 0.016) and older patient age (p = 0.04).
6.4 Ambulatory electrocardiographic results
Sixty-five patients (61%) had evidence of AECG ischemia over the 48-h monitoring period. Seventeen patients had one episode, 13 had two episodes, 12 had three episodes, 6 had four episodes, and 17 had five or more ischemic episodes. The mean number of ischemic ST segment episodes/day was 2.7 ± 6.8. The one patient with insignificant coronary artery disease had an AECG positive for ischemia. Fifty-eight percent of patients with single-vessel, 63% of patients with double-vessel and 62% of those with triple-vessel coronary artery disease had AECG ischemia. A similar percentage of patients with ≥70% and <70% stenosis had positive AECG results for ischemia (63% vs. 58%, respectively, p = NS). Neither plaque morphology nor extent, location and severity of coronary artery disease predicted ischemia by AECG monitoring. The only angiographic predictor of ischemia was proximal coronary artery stenosis (p = 0.04). By logistic regression analysis, the only variable associated with AECG ischemia was the presence of ST segment depression on the initial exercise treadmill test (p = 0.021). Seventy percent of patients with exercise-induced ST segment depression had an AECG positive for ischemia versus only 43% of patients with an exercise test negative for ischemia (p = 0.02).
6.5 Relation between AECG ischemia and that detected with perfusion imaging
Fifty-eight percent of patients with SPECT abnormalities and 71% of those with normal scan results had ischemia by AECG. Conversely, 69% and 81% of patients with either abnormal or normal AECG results had abnormalities on SPECT, respectively. As shown in Fig. 2, only a 50% concordance was observed between SPECT and the AECG, which minimally improved when the presence of scintigraphic ischemia was compared with that of AECG ischemia. No relation was observed between the SPECT PDS (total or ischemic) and the frequency (Fig. 3) or duration of ischemia as assessed by AECG monitoring.
Comparison of SPECT and AECG results when an abnormal SPECT result was defined as 1) any significant (≥3%) perfusion defect (A),or 2) requiring the presence of an ischemic defect (B). − = normal test result; + = abnormal test result.
Scatterplots comparing the number of episodes of AECG ischemia with the total (top)and ischemic (bottom)perfusion defect size as quantified by SPECT. Linear regression analysis showed a poor correlation between SPECT and AECG ischemia variables (r = −0.018 and r = 0.035, respectively). LV = left ventricle.
7 Discussion
An original findingfrom this investigation is the weak correlation observed between the markers of ischemia traditionally ascribed to AECG monitoring and stress SPECT. A surprising result was the lack of correlation between the number and duration of ischemic episodes detected by AECG and the size of the total or ischemic PDS as quantified by SPECT. Superficially, this lack of correlation may seem paradoxic, but it is not entirely unexpected in light of previously published studies describing what AECG monitoring and SPECT actually measure. In the present study, as in many others, abnormalities on SPECT were related to the extent and severity of coronary artery disease. However, the presence of ischemia during daily life as detected by the AECG was not related to either of these angiographic variables. AECG ischemia is known to have poor predictive accuracy for detecting coronary artery disease as defined by angiography. It would appear that SPECT and AECG monitoring detect different pathophysiologic processes as defined under the broad term “myocardial ischemia.” Because both tests have prognostic value but seem distinctly unrelated, combining these modalities may further describe the functional significance of coronary artery disease as well as enhance risk stratification.
7.1 Myocardial perfusion imaging
The SPECT results observed in this relatively small patient series are consistent with other large published reports ([1–5]). The overall sensitivity of 74% that we report for detecting significant coronary artery disease is only slightly lower than the 85% sensitivity previously published ([1]). As in other studies ([1, 2]), the extent and severity of coronary artery disease best predicted an abnormal scan result. This finding is not surprising because with more extensive coronary artery disease, there is a greater likelihood of having one severe stenosis leading to abnormal rest coronary flow reserve and a perfusion defect. However, because of the diffuse yet patchy distribution of coronary atherosclerosis, some seemingly only moderate (50% to 70%) stenoses may cause severe relative flow limitations, whereas many others of similar angiographic severity may induce minor regional differences and remain undetected. This finding was clearly observed in the present study: Although the majority (84%) of patients with severe coronary stenoses were detected, only 42% of patients with moderate stenoses had SPECT abnormalities. The slightly lower overall sensitivity of SPECT in the present study (74%) may be attributable to the relatively large percentage of patients (25%) with only moderate coronary artery stenosis by angiography, where perfusion defects are less predictably induced than in patients with severe stenosis ([40]).
Our quantitative SPECT results are consistent with previous reports. The mean PDS for our study cohort was 14 ± 14% (range 0% to 57%), which is virtually identical to the 14% PDS reported previously from our group in patients referred for chest pain evaluation ([2]). The wide range of myocardial perfusion defects observed in the present study (0% to 57%) is typical for patients with coronary artery disease and should have enhanced our ability to detect a relation between AECG variables of ischemia and those observed with SPECT.
7.2 Ambulatory electrocardiographic monitoring
The presence of AECG ischemia during daily life has clearly been associated with both severe (death or myocardial infarction) and less severe (revascularization, hospital admission, worsening angina) cardiac events among patients presenting with a broad spectrum of symptomatic and asymptomatic coronary artery disease ([28, 30, 31, 41, 42]). However, the pathophysiologic mechanisms responsible for asymptomatic AECG ischemia are incompletely understood. Among patients with coronary artery disease, ST segment depression during exercise testing, particularly at a low heart rate, is generally acknowledged to enhance the probability of detecting AECG ischemia. Depending on the type of patient studied, ∼25% to 50% of those with ST segment depression during exercise will have AECG ischemia. The probability of having AECG ischemia increases when there is prolonged ST depression after exercise and when ST depression occurs at low exercise work loads ([42, 43]). An increase in heart rate usually precedes AECG ischemia ([44]).
The extent and severity of angiographic coronary artery disease is a highly variable predictor of ischemia as assessed by AECG monitoring ([45–48]), suggesting that coronary stenoses as subjectively defined by coronary angiography are only in part a predictor of ischemia during daily life. Other processes that contribute to the functional and prognostic significance of coronary artery disease are dynamic changes in coronary size at the epicardial, microvascular or collateral level as well as platelet microaggregates and thrombus formation. These processes would not necessarily be evident using “lumenology” derived from coronary angiography but could contribute to the development of ischemia during daily life. The poor association between coronary angiographic findings and ischemia by AEG would be particularly true if coronary endothelial dysfunction contributed to a reduction in coronary blood flow during psychological and environmental stressors present in daily life. Such stressors may not be operative with SPECT imaging. Thus, although AECG and SPECT both measure myocardial ischemia, the reduction in coronary blood flow detected by these techniques appears to occur by means of different mechanisms.
7.3 Study limitations
The present study was a retrospective analysis of patients evaluated for enrollment in the ACIP study who had known coronary artery disease and were at high risk because of the presence of exercise and AECG ischemia. In this regard, our study limited its analyses predominantly to those patients with substantial myocardial ischemia. However, this cohort would seem to be a relevant patient group to study when investigating whether two diagnostic tests detect ischemia in a similar manner. Another limitation is that the AECG and SPECT studies were not performed at the same time or under identical conditions. Many patients during SPECT imaging were still taking anti-ischemic medications, which are known to influence the total PDS ([49]), whereas most AECG monitoring was performed without anti-ischemic drugs, as part of the ACIP protocol. Anti-ischemic drug therapy may have reduced the SPECT PDS in many patients and led to a normal scan result in others, thus underestimating the sensitivity of SPECT. Finally, although the sample size was relatively small and limited to mostly men, this is the largest cohort to be studied with both techniques to date.
7.4 Clinical implications
This study demonstrates a lack of correlation between daily life myocardial ischemia variables as detected by AECG monitoring compared with traditional coronary angiographic variables or the presence and extent of myocardial hypoperfusion as quantified by SPECT. This discordance supports the hypothesis that the presence of AECG ischemia is more dependent on altered coronary vasomotion or plaque instability. The possibility that different, but clinically important, components of risk for ischemia-related adverse outcomes are measured by SPECT and AECG suggests that the results of the two tests may be complementary in more fully defining which patients with coronary artery disease are at highest risk for subsequent cardiac events.
Footnotes
↵1 A complete list of the ACIP investigators and participating centers appears in J Am Coll Cardiol 1995;26:594–605.
↵2 Address for reprints: ACIP Clinical Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Avenue, Baltimore, Maryland 21210.
This study was presented in part at the 46th Annual Scientific Session of the American College of Cardiology, Orlando, Florida, March 1996 and was funded by the National Heart, Lung, and Blood Institute, Cardiac Diseases Branch, Division of Heart and Vascular Disease, National Institutes of Health, Bethesda, Maryland by Research Contracts HV-90-07, HV-90-08, HV-91-05 to HV-91-14. Study medications and placebo were donated by Zeneca Pharmaceuticals Group, Wilmington, Delaware; Hoechst Marion Roussel, Kansas City, Missouri; and Pfizer, New York, New York.
↵fn1 Support for electro cardiographic data collection was provided in part by Applied Cardiac Systems, Laguna Hills, California; Marquette Electronics, Milwaukee, Wisconsin; Mortara Instrument, Milwaukee, Wisconsin; and Quinton Instruments, Seattle, Washington. Some centers had partial support from General Clinical Research Center grants.
- Abbreviations
- ACIP
- Asymptomatic Cardiac Ischemia Pilot
- AECG
- ambulatory electrocardiographic
- ECG
- electrocardiogram, electrocardiographic
- PDS
- perfusion defect size
- SPECT
- single-photon emission computed tomography (tomographic)
- Received July 22, 1996.
- Revision received December 2, 1996.
- Accepted December 4, 1996.
- The American College of Cardiology
