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J Am Coll Cardiol, 2002; 40:1623-1629
© 2002 by the American College of Cardiology Foundation
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CLINICAL STUDY: CLINICAL APPLICATION OF ECHOCARDIOGRAPHIC FINDINGS

Prognostic significance of the location of wall motion abnormalities during exercise echocardiography

Abdou Elhendy, MD, PhD*, Douglas W. Mahoney, MSc{dagger}, Bijoy K. Khandheria, MD, FACC*, Timothy E. Paterick, MD*, Kelli N. Burger, BSc{dagger} and Patricia A. Pellikka, MD, FACC*,*

* Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
{dagger} Section of Biostatistics, Mayo Clinic, Rochester, MinnesotaUSA

Manuscript received January 23, 2002; revised manuscript received May 16, 2002, accepted June 24, 2002.

* Reprint requests and correspondence: Dr. Patricia A. Pellikka, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905, USA.
pellikka.patricia{at}mayo.edu


   Abstract
Top
 Abstract
Methods
 Results
 Discussion
 References
 
OBJECTIVES: Our aim was to determine whether location of wall motion abnormalities (WMAs) during exercise echocardiography provides independent prognostic value.

BACKGROUND: The effect of the location of WMAs during stress echocardiography on prognostic outcome is unknown.

METHODS: We studied 4,347 patients (mean age, 61 ± 12 years; 2,230 men) with known or suspected coronary artery disease by symptom-limited exercise echocardiography. An abnormal result was defined as resting or exercise-induced WMA. End points were cardiac death and nonfatal myocardial infarction (MI).

RESULTS: There were 133 cardiac events (54 cardiac deaths and 79 nonfatal MIs) during follow-up (median, three years). In a multiple-stepwise multivariate analysis model, clinical and exercise electrocardiography predictors of cardiac events were age, gender, hypertension, typical chest pain, previous MI, smoking, and resting ejection fraction. The percentage of ischemic segments at peak exercise provided additional information to the model (p = 0.0001). The presence of abnormalities in the left anterior descending (LAD) coronary artery distribution had an additional independent effect for the prediction of cardiac events (p = 0.001). Among patients with exercise echocardiographic abnormalities in a single vascular region, those with abnormalities in the left anterior descending coronary artery distribution had a higher event rate than patients with abnormalities elsewhere (3.2% vs. 2.1% at three years and 10.8% vs. 2.1% at five years; p = 0.009).

CONCLUSIONS: Exercise WMAs in the distribution of the LAD coronary artery are associated with an increased risk of cardiac death and nonfatal MI. This risk is independent of the resting ejection fraction and the extent of WMAs during exercise.

Abbreviations and Acronyms
  CAD
  coronary artery disease
  LAD
  left anterior descending
  LCX
  left circumflex artery
  METs
  metabolic equivalents
  MI
  myocardial infarction
  RCA
  right coronary artery
  WMA
  wall motion abnormality

Exercise echocardiography is a valuable clinical tool for the diagnosis of coronary artery disease (CAD) and for the prediction of cardiac events (1–7). Although the cardiac event rate is greater in patients with abnormal results from stress echocardiography than in patients with normal results, revascularizing all patients who have an abnormal test may not be appropriate because cardiac events occur in only a minority of these patients. Therefore, the role of stress echocardiography should not be restricted to categorizing patients into groups with normal and abnormal results. Identification of a high-risk stress echocardiogram is an important additional step in selecting patients for more aggressive intervention in order to reduce the risk of cardiac events.

The extent of exercise wall motion abnormalities (WMAs) is a strong predictor of cardiac death and nonfatal myocardial infarction (MI) (4,5). However, the prognostic value of the location of WMAs is not known. The presence of left anterior descending (LAD) CAD by angiographic diagnosis is among the variables considered in the risk stratification of patients with CAD and the selection of intervention rather than medical treatment, particularly in the presence of a proximal lesion or reduced ejection fraction (8,9). However, little information exists regarding whether functional abnormalities in the distribution of a particular coronary artery may be associated with an increased risk of cardiac events and whether such association is dependent on the extent of functional abnormalities. The aim of this study was to determine whether the location of exercise WMAs affects the risk stratification of patients with known or suspected CAD, in addition to clinical variables and the extent of WMAs with exercise.


   Methods
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 Abstract
 Methods
Results
 Discussion
 References
 
Patients.   We retrospectively studied 6,444 patients who underwent clinically indicated exercise echocardiography at Mayo Clinic (Rochester, Minnesota) from January 1990 through December 1995. Patients were excluded if they had poor imaging quality (322 patients with nondiagnostic studies because of three or more segments inadequately visualized at rest or with stress), refused participation in research (168 patients), or were lost to follow-up (216 patients). Also, 1,319 patients were excluded because of left bundle branch block or previous coronary revascularization because of the possible impact of these conditions on septal wall motion. The final population comprised 4,347 patients. The Mayo Foundation Institutional Review Board approved the study.

Exercise echocardiography protocol
Patients had symptom-limited treadmill exercise testing according to the Bruce protocol (90%), Naughton protocol (5%), or modified Bruce protocol (5%). Standard blood pressure and 12-channel electrocardiographic (ECG) monitoring were performed. Resting two-dimensional echocardiographic images were obtained from the parasternal and apical windows before and immediately after exercise. Studies were recorded on videotape. The standard views were digitized and stored in quad-screen format (10).

Exercise echocardiographic interpretation
Both digitized and videotape-recorded images were used for interpretation of the studies (11). Ejection fraction at rest was measured using a previously validated modification of the method of Quinones et al. (12) or by visual estimation (13). Regional wall motion was assessed semiquantitatively by an experienced echocardiographer, blinded to clinical information. Wall motion at rest and with exercise was scored 1 through 5 according to a 16-segment model (14). Wall motion score index was determined at rest and at exercise as the sum of the segmental scores divided by the number of visualized segments. The difference between the exercise and resting regional wall motion score indexes was reported as {Delta} wall motion score index. The development of new or worsening wall motion in one or more segments was considered indicative of myocardial ischemia. A WMA present at rest and unchanged with exercise was classified as fixed.

Exercise echocardiography results were defined as abnormal if ischemia or fixed WMAs were present (15). Myocardial segments were assigned to a particular coronary artery as follows: the anterior, anteroseptal, apical septal, apical anterior, apical lateral, and midinferoseptal segments were assigned to the LAD coronary artery; the lateral and posterior segments were assigned to the left circumflex artery (LCX); and the apical inferior, midinferior, basal inferior, and basal inferoseptal segments were assigned to the right coronary artery (RCA). The exercise electrocardiogram was considered positive for ischemia if there was horizontal or downsloping ST-segment depression of at least 1 mm at 80 ms after the J point, nondiagnostic if the baseline ST segment was abnormal, and negative for ischemia in the absence of these criteria. Workload was measured by metabolic equivalents (METs).

Follow-up
Follow-up data were obtained from mailed questionnaires and scripted telephone interviews. Events were verified by contacting the patients’ primary physicians and reviewing medical records and death certificates. The end points were "hard cardiac events," defined as nonfatal MI or cardiac death. Sudden unexpected death occurring without another explanation was included as cardiac death. Coronary revascularization procedures during the follow-up period were also noted. Patients who underwent revascularization (i.e., angioplasty or coronary artery bypass surgery) before other events were censored at the time of revascularization.

Statistical analysis
Continuous variables were reported as mean ± SD, and comparisons between groups were based on the Wilcoxon rank-sum test. Categorical variables were summarized as percentages, and group comparisons were based on the chi-square test. Survival free of the end point of interest was estimated by the Kaplan-Meier method. Univariate associations of clinical and exercise echocardiographic variables with the end points were assessed in the Cox proportional hazards model. Variables were selected in a stepwise forward selection manner with entry and retention set at a significance level of 0.05. The results of these analyses were summarized as risk ratios with corresponding 95% confidence intervals. The incremental value of exercise echocardiographic information over clinical and exercise ECG data was assessed in five modeling steps. All univariately significant variables were considered for the model. The first step consisted of fitting a multivariate model of only clinical data. Exercise ECG and hemodynamic variables were added in a stepwise forward selection manner to the clinical model. Rest echocardiographic variables were then added to this model, followed by the standard exercise echocardiographic variables, presence of ischemia, percentage of ischemic segments, {Delta} wall motion score, and exercise wall motion score index. These models did not take into consideration the location of WMAs. In the final step, the location of the WMA was added. The significance of adding additional variables to previous modeling steps was based on the change in model-based likelihood statistics with degrees of freedom equal to the number of additional variables.


   Results
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 Abstract
 Methods
 Results
Discussion
 References
 
The mean age of the patients in the study group was 61 ± 12 years. There were 2,230 (51%) men and 2,117 (49%) women. Of these patients, 423 (10%) had previous MI, 1,903 (44%) had hypertension, 2,291 (53%) had hypercholesterolemia, and 2,139 (49%) were smokers. Reasons for terminating the exercise stress test were fatigue in 2,677 patients (62%), dyspnea in 1,184 patients (27%), angina in 190 patients (4%), arrhythmias in 38 patients (1%), ST-segment changes in 100 patients (2%), and leg distress in 416 patients (10%).

Echocardiographic data.   Resting WMAs were detected in 1,160 patients (27%). Ischemia was detected in 1,138 patients (26%). Of these patients, 592 (52%) also had resting WMAs. The exercise echocardiogram was considered abnormal (rest- or exercise-induced WMAs or both) in 1,706 patients (39%). Exercise WMAs occurred in a single-vessel distribution in 702 patients (16%) and in a multivessel distribution in 1,004 patients (23%). Abnormalities in LAD coronary artery distribution were detected in 1,234 patients (29%), in the left circumflex territory in 650 (15%), and in the RCA distribution in 1,265 (29%). Of those with abnormalities in a single-vessel distribution, abnormalities were located in the territory of the LAD in 355 patients and in the RCA or the LCX in 347 patients.

Coronary revascularization
During follow-up, 276 (6%) patients underwent revascularization (coronary artery bypass grafting in 166 patients and coronary angioplasty in 110 patients) before any cardiac event and were censored. Revascularization was performed early (<3 months) in 121 patients and late (≥3 months) in 155 patients. Patients who underwent revascularization had a greater prevalence of ischemia by echocardiography ([183/276] 66% vs. [955/4071] 23%, p < 0.001), a greater percentage of ischemic segments (24% ± 15% vs. 6% ± 14%, p < 0.001), a greater prevalence of exercise-induced angina ([79/276] 29% vs. [298/4071] 7%, p < 0.001), and a greater frequency of positive electrocardiograms ([139/276] 50% vs. [659/4071] 16%, p < 0.001). Patients who underwent revascularization had a higher prevalence of abnormalities in the LAD distribution ([184/276] 67% vs. [1059/4071] 26%, p < 0.001). In the 702 patients with abnormalities in a single-vessel distribution, 50 patients underwent revascularization. The revascularization rates were not statistically different among patients with abnormalities in the LAD (8%), RCA (6%), or LCX (10%) territories.

Cardiac events
During follow-up (median, three years; maximum, eight years), 133 hard cardiac events occurred: cardiac death in 54 patients and nonfatal MI in 79 patients. These events occurred at a median of two years (range, 1 day to 7.5 years) after exercise echocardiography. Twenty-one of these events (7 cardiac deaths and 14 nonfatal MIs) occurred in patients with abnormalities in a single-vessel distribution. Event-free survival of the 4,347 patients was 99% at one year, 97% at three years, and 95% at five years. Clinical features of patients with and without hard cardiac events are shown in Table 1.


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  		Table 1 Clinical Features of Patients With and Without Hard Cardiac Events*{dagger}

 
Relation between exercise echocardiographic abnormalities and cardiac events
Exercise test and echocardiographic data for patients with and without hard cardiac events are shown in Table 2. Clinical, exercise test, and echocardiographic variables associated with an increased risk of hard cardiac events in the univariate analysis are shown in Table 3. Event-free survival in patients with normal exercise echocardiographic results compared with those with single- or multivessel distribution of disease is shown in Figure 1. Event rates according to the extent and location of exercise echocardiographic abnormalities are shown in Table 4. In patients with multivessel distribution of abnormalities, the event rate was higher when the LAD territory was involved. In patients with abnormalities in a single-vessel distribution, the event rate of cardiac death and nonfatal MI was significantly greater in patients with abnormalities in the LAD distribution than in patients with WMAs in other locations (Fig. 2).


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  		Table 2 Exercise Test and Echocardiographic Data for Patients With and Without Hard Cardiac Events*

 

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  		Table 3 Univariate Association of Clinical, Exercise Test, and Echocardiographic Variables With Risk of Cardiac Death and Nonfatal Myocardial Infarction

 


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  		Figure 1 Kaplan-Meier cardiac event-free survival curves for patients with normal exercise echocardiograms, with single-vessel abnormalities, and with multivessel abnormalities.

 

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  		Table 4 Cumulative Event Rate During Five-Year Follow-Up According to the Presence and Extent of Exercise Echocardiographic Abnormalities

 


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  		Figure 2 Kaplan-Meier cardiac event-free survival curves for the subset of patients with exercise echocardiographic abnormalities suggestive of single-vessel abnormalities. Event-free survival was greater in patients with abnormalities in the distribution of a vessel other than the left anterior descending coronary artery (LAD). LCX = left circumflex coronary artery; RCA = right coronary artery.

 
Predictors of cardiac events in the incremental multivariate analysis models
The results of the five-step incremental model, including the independent predictors at each step, are shown in Table 5. The variable considered in the model of the location of abnormalities was the arterial distribution of the abnormalities. The addition of abnormalities in the LAD distribution provided incremental data over other echocardiographic parameters, including resting ejection fraction, percentage of abnormal segments, and percentage of ischemic segments with exercise (p = 0.0001).


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  		Table 5 Independent Predictors of Cardiac Events Using Five-Step Model

 
When only patients with abnormalities in a single-vessel distribution were considered, the only multivariate predictor of hard cardiac events was a history of previous MI. The location of exercise WMAs was added in the next step. Abnormalities in the LAD coronary artery distribution provided incremental value to the clinical, ECG, and echocardiographic model (global chi-square = 27 vs. chi-square = 38, p = 0.0009).

Effect of ejection fraction
No significant interaction effect existed between LAD abnormalities and resting ejection fraction (p = 0.12), indicating an increased risk for cardiac events across all levels of baseline function of the left ventricle. Also, no difference existed in the association of LAD abnormalities and the type of cardiovascular event (cardiac death vs. MI, p = 0.77).


   Discussion
Top
 Abstract
 Methods
 Results
 Discussion
References
 
We tested the hypothesis that the location of WMAs with exercise echocardiography can be predictive of cardiac death and nonfatal MI, independent of the extent and severity of abnormalities. Exercise echocardiography was performed in 4,347 patients with known or suspected CAD who had follow-up for a median of three years. During follow-up, 133 cardiac deaths and nonfatal MIs occurred. Exercise echocardiographic abnormalities in the LAD coronary artery distribution were predictive of cardiac death and nonfatal MI, independent of the resting ejection fraction and extent of ischemia with exercise.

The independent association between WMAs in the LAD coronary artery distribution and cardiac events in this study is not surprising, as angiographic studies have shown that patients with proximal LAD stenosis have a worse prognosis (16). It might be suspected that this is a result of the larger myocardial territory supplied by the LAD; however, in our study, abnormalities in the LAD territory were incremental to the extent of ischemia in predicting risk. This indicates that, for the same number of segments with exercise WMAs, a patient would have a worse prognosis if these segments were in the LAD territory than if they were remote from the LAD territory.

The clinical implication of these findings is that abnormalities in the LAD distribution should be considered an additional marker of a high-risk exercise echocardiogram, providing incremental value to well-known markers, such as resting ejection fraction, multivessel distribution of abnormalities, and percentage of abnormal and ischemic segments. The association between abnormalities in the LAD distribution and increased risk of cardiac events was not influenced by the type of event or the severity of resting left ventricular dysfunction.

It is possible that the diagnostic usefulness of exercise echocardiography differs in the anterior and posterior circulations; possibly, more false-positive and false-negative results occur in the posterior circulation (17–19). It is the practice of our laboratory to consider worsening of WMAs in a single segment, including the basal inferior wall, as indicative of ischemia. There is controversy in published studies about the differences in the diagnostic performance of stress echocardiography in different vascular territories (20).

Patients with abnormalities suggestive of single-vessel CAD.   Among patients who had abnormalities in a single vascular region during exercise echocardiography, those with WMAs in LAD territory had a higher event rate than patients with WMAs in other locations. Although the initial event rate in patients with the LAD pattern of abnormalities was relatively low (1% at two years), there was a progressive increase in the event rate after the second year (3.2% at three years and 10.8% at five years), whereas patients with abnormalities in the RCA or the LCX continued to have a low event rate at five years of follow-up (2.1%). Exercise WMAs in the LAD coronary artery distribution provided incremental value to clinical and exercise stress test data after adjustment for age, gender, risk factors, symptoms, hemodynamic parameters, and resting ejection fraction. These data indicate that patients with the LAD pattern of abnormalities have an unfavorable late outcome and, therefore, if they were not referred for revascularization, they should be observed carefully. The low event rate in patients with a single-vessel pattern of abnormalities in the RCA or LCX distribution at early follow-up and at intermediate-term follow-up should be considered in the evaluation of patients with such abnormalities. This consideration would be useful in avoiding the risk and cost of invasive diagnostic and interventional procedures in a low-risk population.

Comparison with previous studies
Previous studies of the effect of the location of CAD on outcome have focused mainly on the anatomical abnormalities as delineated by coronary angiography (16,21–23). Evaluation of the prognostic significance of functional abnormalities is essential because the noninvasive evaluation of CAD often provides data for the selection of patients in whom invasive studies may be required. An additional advantage of the current study is that it tested a wider range of patients; angiographic studies include a narrower spectrum of patients who are referred for angiography.

Mancini et al. (21) studied 283 patients with quantitative coronary angiography who had follow-up for a mean of 8.3 years. Myocardial infarction was predicted by the percentage diameter stenosis of the left main and LAD arteries but not the ejection fraction. Califf et al. (22) reported that, in 462 patients with marked CAD, the coronary artery jeopardy score and the percentage diameter stenosis, particularly of the LAD coronary artery, were associated with adverse outcome. Klein et al. (16) performed a follow-up study of 866 medically treated patients with significant CAD. The presence and severity of significant stenoses in the proximal LAD were stronger predictors of prognosis than stenoses elsewhere in the major coronary arteries. In contrast, Cortigiani et al. (24) found that, in patients with single-vessel CAD who had medical follow-up, the involved artery was not predictive of cardiac events.

The guidelines for myocardial revascularization in patients with CAD specify angiographic abnormalities involving the LAD as indications for revascularization in a certain subset of patients, particularly in the presence of a proximal lesion, reduced ejection fraction, or a large ischemic area (8,9). Our study showed that functional abnormalities in the LAD coronary artery distribution are associated with increased risk of cardiac events independent of the severity of resting left ventricular dysfunction and the extent of ischemia with exercise. Despite some evidence from previous studies about the prognostic value of LAD angiographic abnormalities, extrapolation to abnormalities on stress echocardiography has not been validated. With the use of noninvasive imaging for selecting management strategies for patients with known or suspected CAD, proper interpretation of the significance and the outcome associated with various patterns of WMAs is essential to restrict referral for invasive procedures to the high-risk population.

Study limitations
The assignment of myocardial segments to a particular coronary artery is imperfect due to anatomical variation among patients and the presence of abnormalities at overlap segments. Myocardial revascularization after exercise echocardiography may have improved the outcome in some high-risk patients and led to underestimation of the prognostic significance of echocardiographic abnormalities. However, patients with abnormalities in the LAD coronary artery distribution were more frequently referred for revascularization; nevertheless, the risk of these abnormalities was shown despite the possible underestimation of the magnitude of risk associated with such abnormalities by censoring these patients.

Summary and conclusions
Exercise WMAs in the distribution of the LAD coronary artery are associated with an increased risk of cardiac death and nonfatal MI. This risk is independent of the resting ejection fraction and the extent of exercise-induced myocardial ischemia. Therefore, for patients with abnormal exercise echocardiographic results, WMAs in the LAD coronary artery distribution should be considered high-risk factors in addition to the standard measures of the severity of resting and exercise-induced WMAs. In patients with single-vessel distribution of WMAs, those with WMAs in the LAD territory have a higher event rate compared with that of patients with WMAs in other regions.


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 Abstract
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 Discussion
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