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Circulation. 1996;94:2455-2464

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*Angina

(Circulation. 1996;94:2455-2464.)
© 1996 American Heart Association, Inc.

Articles

Prolonged Impairment of Regional Contractile Function After Resolution of Exercise-Induced Angina

Evidence of Myocardial Stunning in Patients With Coronary Artery Disease

Giuseppe Ambrosio, MD, PhD; Sandro Betocchi, MD; Leonardo Pace, MD; Maria Angela Losi, MD; Pasquale Perrone-Filardi, MD, PhD; Andrea Soricelli, MD; Federico Piscione, MD; Jean Taube, BS; Fiorenzo Squame, MD; Marco Salvatore, MD; James L. Weiss, MD; Massimo Chiariello, MD

the Divisions of Cardiology (S.B., M.A.L., P.P.-F., F.P., M.C.) and Nuclear Medicine (L.P., A.S., F.S., M.S.), Federico II School of Medicine, Naples, Italy; the Division of Cardiology "R" (G.A.), University of Perugia School of Medicine, Italy; and the Division of Cardiology (G.A., J.T., J.L.W.), Johns Hopkins School of Medicine, Baltimore, Md.

Correspondence to Giuseppe Ambrosio, MD, PhD, Dipartimento di Medicina Clinica, Sezione di Cardiologia "R", Via Eugubina 42, 06122 Perugia, Italy.


*    Abstract
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 *Abstract
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Background Delayed recovery of contractile function in spite of normal perfusion (ie, "stunning") has been described in animal models of exercise-induced myocardial ischemia. Therefore, we investigated whether stunning may result from effort angina in patients.

Methods and Results Patients with coronary artery disease underwent exercise testing combined with quantitative measurements of contractile function for up to 240 minutes after exercise determined by either measurement of regional ejection fraction (99mTc radionuclide angiography; n=17, group A) or computer-assisted measurement of systolic wall thickening (n=14, group B). In the latter group, myocardial perfusion was also evaluated by 99mTc-sestamibi tomographic imaging. Angina induced marked contractile dysfunction. Hemodynamic and ECG changes brought about by ischemia were promptly normalized. Furthermore, no perfusion defects could be detected in group B patients 30 minutes after exercise, yet contractile function remained impaired well after cessation of exercise. Thirty minutes into recovery, regional ejection fraction of previously ischemic areas was still 82.6±4.6% of baseline in group A (P<.05). Similarly, in group B patients, systolic thickening of previously ischemic segments was still significantly impaired 60 minutes after exercise, averaging 33.8±2.8% versus 40.5±2.7% at baseline (P<.05). Contractile impairment was fully reversible, as the functioning of previously ischemic segments normalized between 60 and 120 minutes of recovery.

Conclusions Prolonged yet ultimately reversible impairment of regional myocardial function may occur in patients after exercise-induced angina in the absence of perfusion abnormalities. These findings indicate that myocardial stunning may ensue after effort angina in patients with severe coronary artery disease.


Key Words: stunning, myocardial • angina • exercise • coronary disease


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Ischemic episodes of insufficient duration to induce necrosis may nevertheless result in myocardial stunning, ie, prolonged but reversible impairment of regional contractile function that persists in spite of restoration of tissue perfusion.1 2 Occurrence of stunning has been reported initially in animal models of transient coronary artery occlusion.3 4 5 However, subsequent experimental studies have also established that delayed recovery of regional contractility can occur as a consequence of exercise-induced ischemia after normalization of flow in dogs with coronary artery stenosis.6 7 8 9 10 11 12

The clinical picture of many patients with coronary artery disease is characterized by frequent episodes of angina pectoris induced by increased myocardial oxygen demand. Thus, it is important to establish whether stunning may occur in patients as a result of effort angina. Previous clinical studies13 14 15 16 17 have sought to investigate whether regional function remains impaired after exercise-induced angina. However, this issue is still controversial,18 19 20 21 because some investigators13 15 16 reported persistence of wall motion abnormalities for at least 30 minutes after exercise, whereas others14 17 observed prompt normalization of wall motion on cessation of exercise. Furthermore, the impact of those studies may be reduced by limitations of the experimental design. As has been pointed out,18 22 clear demonstration of stunning requires evidence (1) that the phenomenon is reversible and (2) that contractile dysfunction persists at a time when myocardial perfusion has returned to preischemic values. Previous studies did not address these issues, and therefore it has not been established whether regional wall motion abnormalities that persisted after exercise were actually due to stunning or whether they were secondary to other conditions capable of impairing regional contractility (eg, persistence of flow abnormalities or development of myocyte injury), which may also occur in these patients.

The present study was designed to investigate whether contractile function in patients with coronary artery disease may remain depressed after exercise-induced angina as a manifestation of myocardial stunning. In patients with stable angina, contractile recovery was monitored for 4 hours after exercise stress testing by quantitative analysis of regional function. Regional myocardial perfusion during recovery after exercise was also investigated.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
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Patient Selection
We studied 31 patients (43 to 67 years old) with a history of stable angina pectoris for <=3 months, a positive ECG exercise stress test, and no previous myocardial infarction. All patients had coronary artery disease documented by angiograms obtained either <=3 months before the study or in the week that followed. Patients were excluded if regional wall motion abnormalities were already present at rest, as detected on left ventricular angiography or routine echocardiograms. Patients with atrial fibrillation, irregular heartbeat, or intraventricular conduction defects were also excluded. For the echocardiography arm of the study, exclusion criteria were extended to patients with poor acoustic windows or in whom the endocardium and epicardium could not be visualized on a short-axis view. Calcium antagonists and ß-blocking drugs were discontinued at least 3 days before the study was performed. Nitrates were allowed until the night before the study. The study protocol was approved by the local Ethics Committee. All patients gave informed consent to participate in the study.

Study Protocol
The effects of exercise-induced ischemia on recovery of regional contractile function were assessed in one of two protocols: (1) Radionuclide angiography study (group A; n=17). Global and regional left ventricular function were determined from multiple gated acquisition scans (see below). Data were acquired at baseline, during symptom-limited exercise, and 10, 30, 60, 120, and 240 minutes after exercise. (2) Echocardiography/single photon emission computed tomography (SPECT) study (group B; n=14). A tenet of myocardial stunning is the persistence of contractile impairment after normalization of blood flow. To document this point, we designed a protocol to evaluate tissue perfusion simultaneously with regional contractile function. Because radioactive flow tracers would have interfered with radionuclide angiography, regional function was assessed in these patients by computer-assisted measurements of systolic wall thickening on echocardiography scans (see below). This approach provided the additional advantage that recovery of contractile function after exercise was investigated by means of two quantitative but unrelated techniques. Echocardiography scans were performed at baseline, immediately ({approx}2 minutes) after exercise, and 10, 30, 60, 120, and 240 minutes into recovery. Myocardial perfusion during recovery was evaluated by SPECT after injection of 99mTc-sestamibi 30 minutes after exercise (see below). This time point was selected on the basis of preliminary results of the radionuclide angiography study, which suggested that functional impairment persisted at least 30 minutes into recovery.23 Myocardial perfusion after exercise was compared with SPECT acquisitions obtained after injection of 99mTc-sestamibi at rest. Exercise stress testing and data acquisition for both protocols were performed in Italy. Computer-assisted analysis of echocardiography studies was performed at Johns Hopkins.

Exercise Stress Test
A symptom-limited bicycle stress test was performed with the patient lying supine on an exercise table. Workload was set at 25 W initially, and it was increased by 25 W every 2 minutes. A 12-lead ECG was monitored throughout the stress protocol and for the first 10 minutes of recovery. Precordial leads were placed slightly off standard sites so as not to interfere with regional function measurements. Arterial blood pressure was measured at baseline, every 2 minutes during exercise, and for the first 10 minutes of recovery. In the radionuclide angiography protocol, count acquisition during exercise was started at the onset of symptoms (typical angina, or chest discomfort and leg fatigue associated with >1 mV ST-segment depression). Patients continued to exercise at the same load until >=2.5 million counts were collected. Acquisition during symptoms typically lasted 3 to 4 minutes. In the echocardiography protocol, patients exercised until development of symptoms and then continued for {approx}3 minutes at the same workload to achieve a duration of exercise during symptoms comparable to that of the radionuclide angiography protocol.

Radionuclide Angiography
Erythrocytes were labeled in vivo with 25 mCi of 99mTc. Counts were collected by a small-field-of-view Anger camera (Siemens LEM-ZLC) equipped with a general-purpose, parallel-hole collimator oriented in the 45° left anterior oblique view with a 15° cranial tilt. Images were acquired with a 2x digital zoom in frame mode by ECG gating. For baseline and recovery studies, acquisitions were performed at 50 frames/s (corresponding to 20 ms/frame) with 5% gate tolerance until >=150 000 counts/frame were acquired. Exercise studies consisted of >=2.5 million counts, acquired at 20 frames/cycle. All studies were acquired with the patient lying supine on the exercise table.

To measure global ejection fraction, left ventricular regions of interest were automatically drawn on the end-diastolic and end-systolic frames. From each region of interest, a time-activity curve was built after subtraction of the corresponding background curve. The final time-activity curve was computed by weighted interpolation of the former curves. Ejection fraction was calculated on the unfiltered time-activity curve, as previously reported.24 25 In our laboratory, reproducibility for this technique shows an average difference between two studies of 4.3±3.3 ejection fraction points (mean±SD).

For quantitative measurements of regional ejection fraction, left ventricular end-systolic and end-diastolic contours and a left paraventricular background region were manually traced. A computer algorithm26 was used to identify the center of gravity on the end-diastolic image and to automatically divide the left ventricle into five sectors of equal angle (72°). With use of the same center of gravity (ie, keeping a fixed centroid), the end-systolic contour was likewise automatically divided into five sectors. The sector that included counts from the aortic root and mitral valve was not used in the final analysis. In our laboratory, reproducibility for this technique shows an average difference between two studies of only 1.2±0.8 ejection fraction points (mean±SD). This approach is largely independent of cardiac motion and changes in geometry.27 28 Furthermore, although regions of interest were traced along one plane, counts actually provided a tridimensional assessment of regional changes in cardiac function. The fixed centroid system was used because it more accurately detects changes in regional function than does the "floating" centroid system.29

Echocardiography
Two-dimensional studies were obtained with the use of a phased-array echocardiography unit (HP 77030A) with a 2.5-MHz imaging transducer. Patients were lying in the left-lateral decubitus on the exercise table. The parasternal window was used to obtain short-axis images at the mid–papillary muscle level. Depth, gain, and frame rate were adjusted at baseline to achieve a satisfactory view and then kept constant for each patient throughout all studies. Anatomical markers were used to obtain the same short-axis view in repeated studies in each patient. Images were recorded simultaneously with ECG tracing on 0.5-in magnetic videotapes.

Contractile function was quantitatively evaluated from computer-assisted measurements of systolic wall thickening.30 31 32 33 This method has several advantages for the study of regional function over other echocardiographic or planar ventriculographic approaches, such as wall motion score systems, or measurements of radial shortening or endocardial motion.33 34 35 36 Thickening measurements do not rely on the ability of the operator to visually detect and grade wall motion abnormalities, are independent of axis or reference systems, and are not affected by movements of the heart during the cardiac cycle or as an effect of respiratory movements or postural changes. For thickening analysis, images were played back on a video recorder interfaced to a processing unit consisting of a computer, a digital-analog converter, a frame-grabber, and a high-resolution X,Y monitor. Analysis of the echocardiographic data was performed with the use of a computer-assisted contouring system described previously.30 31 32 33 37 In this system, individual frames of cross-sectional views of the heart are selected and displayed. The computer superimposes two sets of 16 points equally spaced in angle around the image originating from the center of area (ie, midwall centroid), and the operator adjusts these points to fit the endocardial and epicardial margins of the image, respectively. Contouring was performed by an experienced technician who was unaware of the purpose of the study and of any clinical information. The best-fit contour for each of the two sets of points (ie, endocardium and epicardium) was then selected by the computer with a spline-fitting algorithm. With this technique, the contour will intersect each of the 16 points and maximize the radius of curvature. With a radial coordinate reference system, the papillary muscle locations are marked as internal landmarks. Time references for stop-frame analysis were end-diastole, defined as the peak of the ECG R wave, and end systole, defined as the minimal apparent cross-sectional cavity area. Using this technique, we measured epicardial and endocardial length at end systole and then at end diastole along each radius. These equally spaced radii divided the wall of the left ventricle on cross-sectional views in 16 segments. For each of these segments, the computer also measured the end-systolic distance between two radii at the epicardial and endocardial border; end-diastolic distances were similarly calculated. Using the trapezoidal geometry of a segment, we calculated wall thickness for a given segment at systole and at diastole as

Contractile function of each segment was then expressed as percent systolic wall thickening (%Th) by the formula

Three cardiac beats were averaged for each determination. The reproducibility of results with this system to measure myocardial thicknesses has been reported previously.31 37 In particular, the SD of differences for intraobserver variation for myocardial thickness was 0.2 mm; the percentage difference for myocardial thickness between readers was 5%.

Myocardial Imaging
SPECT imaging was performed with 99mTc methoxyisobutyl isonitrile (99mTc-sestamibi; 25 mCi IV) with the use of a single-head tomographic gamma camera (Elscint SP4HR). Thirty-two projections (30 s/projection, word mode, 64x64 matrix) were obtained over a semicircular 180° arc, from the 30° right anterior oblique to the left posterior oblique position. Three-pixel-thick slices were reconstructed along the cardiac short axis, horizontal, and vertical long axis after correcting for flood, center of rotation, and decay. Back-projection with a Butterworth filter (order=5; cutoff=0.5 cm-1) was used. Regional myocardial perfusion was assessed both under resting conditions and during recovery. For the postexercise study, 99mTc-sestamibi was injected 30 minutes after termination of stress testing. To avoid overlap with the timing of echocardiography measurements, SPECT acquisition was then performed 1.5 to 2 hours later. This was possible because of the characteristics of 99mTc-sestamibi, which is rapidly extracted by myocytes and shows minimal tissue redistribution.38 39 40 Resting myocardial perfusion was assessed on SPECT images acquired either 1 to 2 days before the exercise test protocol was performed or within 2 days after the study.

Regional myocardial perfusion was evaluated by two approaches. Qualitative assessment was performed by visual inspection of tomographic images. Images for both studies (ie, rest and 30-minute recovery) were simultaneously displayed for each plane on a high-resolution monitor. Images were then analyzed by two expert nuclear cardiologists unaware of the temporal sequence of the studies and of the results of thickening measurements. For each slice of each section, the presence or absence of visually detected perfusion defects was recorded. Divergent evaluations between observers were resolved by consensus.

To further investigate the important issue of adequacy of tissue perfusion, myocardial uptake of 99mTc-sestamibi was also quantitatively measured in left ventricular regions matched with the site of function measurements. Specifically, for each study, two images (3 mm thick) were reconstructed along the short-axis plane of the left ventricle at the midmyocardial level to match the approximate site of thickening measurements on the short-axis view obtained by two-dimensional echocardiogram and then processed with the use of computer software. Each section was then divided into eight equally spaced sectors. Absolute radioactivity counts were then measured in each sector and normalized to the highest value found in each study, which was taken as 100%. Counts from the two slices were averaged for each sector. For the 30-minute postexercise study, counts measured in the sectors corresponding to the left ventricular segments showing impaired thickening (by echo) were analyzed in comparison with counts measured in the same sectors at rest as well as with counts measured in the remaining sectors pooled together (control regions). In our laboratory, reproducibility for this technique shows an average difference between two studies of only 4.0±3.7% (mean±SD).

Statistical Analysis
Data are expressed as mean±SE. Within each patient group, recovery of contractile function was tested for significance by one-way ANOVA with a design for repeated measures. When the overall analysis showed a significant trend, differences for the various time points versus baseline were tested by use of Dunnett's test to correct for multiple comparisons. A value of P<.05 was considered significant.


*    Results
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 *Results
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Radionuclide Angiography Study (Group A)
Typical angina and ECG signs of ischemia developed in all patients on exercise. Exercise was also associated with the expected increases in heart rate and blood pressure (Table 1Down). Duration of acquisition after onset of angina (an estimate of duration of ischemia) averaged 3.8±0.3 minutes. ST-segment changes resolved quickly (ie, by <=5 minutes) in all patients. Heart rate and blood pressure normalized within 10 minutes of recovery in all patients (Table 1Down).


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  		Table 1. Major Exercise Variables in the Two Groups of Patients

Global ejection fraction tended to decrease during exercise, consistent with the presence of severe coronary artery disease. Global ejection fraction returned to baseline within 10 minutes, and it did not significantly change during the remainder of the study (Fig 1Down). A substantially different picture emerged when recovery of regional ejection fraction was analyzed for the various sectors of the left ventricle. Fig 2Down shows the results obtained in a typical patient. Ejection fraction increased in one sector, indicative of normal response to exercise, whereas two other sectors showed modest changes compared with baseline. A marked decrease of regional ejection fraction was observed in another sector of the left ventricle during symptoms, reflecting the occurrence of exercise-induced ischemia in this area of myocardium. Interestingly, although regional ejection fraction of the normal sector quickly returned to baseline values, cessation of exercise was not accompanied by a prompt recovery of this parameter of contractile function in the sector in which it had been impaired by exercise, as it was still substantially depressed 60 minutes into recovery. Delayed recovery of contractile function of a region of the left ventricle was observed in the great majority of patients studied by radionuclide angiography. Specifically, in 14 of 17 patients, regional ejection fraction of ischemic sectors (ie, those showing >=15% reduction of ejection fraction during exercise) remained depressed at <=90% of baseline value when measured 30 minutes after exercise. In the remaining 3 patients, there also was a >=15% decrease in regional ejection fraction in at least one sector during exercise. However, in those patients, regional ejection fraction normalized by 30 minutes. Fig 3Down and Table 2Down show the results obtained when the data from all 17 patients, ie, including those in whom recovery of function was prompt, were combined. Recovery of regional ejection fraction of the sectors subjected to ischemia was impaired in this group after exercise. Regional ejection fraction remained significantly depressed for at least 30 minutes compared either with baseline values for the same sectors or with time-matched values of the nonischemic sectors that were taken as controls. Regional ejection fraction returned to baseline between 60 and 120 minutes after exercise in all patients but 1, in whom it normalized between 120 and 240 minutes.



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  		Figure 1. Time course of global left ventricular ejection fraction (by radionuclide angiography) in 17 patients with stable angina measured at baseline (Base), during symptom-limited exercise stress test (Ex), and at various time points into recovery after exercise.



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  		Figure 2. Time course of regional left ventricular ejection fraction (by radionuclide angiography) in a typical patient at baseline (Base), during symptom-limited exercise stress test (Ex), and at various time points into recovery after exercise. A left ventricular silhouette is depicted in the upper-right-hand corner to show the sectors into which the left ventricle was divided to measure regional ejection fraction (see "Methods"). Regional ejection fraction data are shown for four of the five sectors (B through E). Sector A, corresponding to the aortic and mitral valves, was not included in the analysis.



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  		Figure 3. Time course of regional left ventricular ejection fraction (by radionuclide angiography) in 17 patients with stable angina measured at baseline (Base), during symptom-limited exercise stress test (Ex), and at various time points into recovery after exercise. For this analysis, the sector showing the greatest decrease during exercise in each patient was identified and considered the ischemic region. Regional ejection fraction data for the ischemic sectors from all patients were then averaged together (bottom). Data for the control sectors represent the average of the remaining three sectors of each patient pooled together (top). *P<.05 vs baseline.


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  		Table 2. Time Course of Changes in Regional Contractile Function With Exercise Stress Test

Echocardiography Study (Group B)
In this group, angina and ECG signs of ischemia also developed in all patients on exercise. On average, these patients were comparable to those in group A in terms of age and hemodynamic changes at peak exercise (Table 1Up). Exercise stress testing induced major changes in regional systolic function. The expected normal contractile response to exercise, characterized by increased systolic wall thickening,6 7 8 was always observed in several regions of the left ventricle in all patients. However, in every patient, we were also able to identify one or more regions of the left ventricle in which systolic thickening measured immediately after exercise was impaired. Regions (consisting of at least two contiguous segments) with systolic thickening <=85% of baseline were considered ischemic. Recovery of contractile function was then analyzed separately for these regions and for the remaining segments, which were considered control regions.

In control segments, systolic wall thickening significantly increased on exercise (Fig 4Down, top; Table 2Up). This effect was transient, as systolic wall thickening returned close to baseline values within 10 minutes of discontinuation of exercise. The effect of exercise-induced ischemia on contractile function of ischemic regions was also pronounced. In these segments, systolic wall thickening decreased on average by >50% (Fig 4Down, bottom; Table 2Up). Thirty minutes after discontinuation of exercise, systolic wall thickening of the previously ischemic segments was <=85% of baseline in all but 1 patient. In the group as a whole, systolic wall thickening was still 83.5±4.9% of baseline 60 minutes into the recovery phase (P<.05; Fig 4Down, bottom; Table 2Up). Normalization of regional contractile function occurred between 60 and 120 minutes in 12 patients and between 120 and 240 minutes after exercise in the remaining 2 patients. A typical example of changes in left ventricular systolic thickening during exercise-induced angina and for the initial 30 minutes of recovery is shown in Fig 5Down.



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  		Figure 4. Time course of systolic wall thickening (by computer-assisted echocardiography) in 14 patients with stable angina measured at baseline (Base), immediately after symptom-limited exercise stress test (Ex), and at various time points into recovery after exercise. For this analysis, segments showing >=15% decrease in thickening with exercise in each patient were identified and considered ischemic segments. Systolic wall thickening data for the ischemic segments from all patients were then averaged together (bottom). Data for the control segments represent the average of the remaining segments of each patient pooled together (top). *P<.05 vs baseline.



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  		Figure 5. Typical echocardiographic images of short-axis view of the left ventricle at end systole taken at rest (A), immediately after exercise stress test (B), and 30 and 240 minutes into recovery (C and D, respectively) in a patient with exercise-induced angina. Note that with stress testing, thickness is reduced during systole (compared with baseline) in the anterior wall (closed arrows), whereas other regions of the left ventricle show normal or enhanced thickness (open arrows). Systolic thickness is still reduced after 30 minutes of recovery, whereas it returns to baseline at 240 minutes. For each time point, percent systolic thickening was calculated by computer-assisted technique after semiautomated contouring of systolic and end-diastolic images (not shown).

Myocardial Perfusion Study (Group B)
No perfusion defects were observed in images obtained 30 minutes after exercise (when contractile function was still significantly impaired). In fact, in each patient, myocardial tissue perfusion was similar to that which was observed in the images taken at rest (Fig 6Down). To further corroborate this important point, we also performed semiquantitative evaluation of tracer uptake by counting radioactivity in short-axis sections that matched the site of wall-thickening measurements. 99mTc-sestamibi data taken 30 minutes into recovery showed 90.0±3.7% uptake in the segments with impaired thickening and 93.7±2.4% in control regions. Neither value was statistically different compared with the values of the rest study, because 99mTc-sestamibi counts at rest averaged 91.3±3.5% (of maximum tracer uptake) in the segments corresponding to the regions that would eventually show impaired thickening and 92.0±2.5% in control regions. Thus, in these patients, impaired regional contractile function persisted at a time when perfusion of the same myocardial regions had returned to baseline.



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  		Figure 6. Top, Single photon emission computed tomography (SPECT) images of left ventricular slices reconstructed along the short axis after injection of 99mTc-sestamibi performed at rest (upper row) and 30 minutes into the recovery phase after exercise stress test (bottom row) in a typical patient in whom function and perfusion were simultaneously assessed. A long-axis view is also shown for comparison (right-hand images). Bottom, Systolic wall thickening measurements (% Wth) in the same patient. {bullet}, Thickening measurements taken at various time points for two adjacent left ventricular segments in the anterior region of the left ventricle (centered around the 12 o'clock position in the short-axis SPECT images). In this patient, impairment of systolic wall thickening was induced in the anterior region by exercise stress test. Note that 30 minutes into recovery, no perfusion defects were present, whereas contractile impairment was still evident 60 minutes into recovery, ie, when myocardial perfusion had already normalized. {circ}, Data from two adjacent segments from the control region. Base indicates baseline; Ex, immediately after symptom-limited exercise stress test.

Relationship With Coronary Anatomy
The majority of patients had multivessel coronary artery disease (Table 3Down). No patients showed exercise-induced dysfunction in myocardial regions subtended by angiographically normal coronary arteries. In the eight patients in whom significant stenosis of the left descending coronary artery was the only lesion, exercise-induced dysfunction was always confined to the septum and/or the anterior wall of the left ventricle. As presented above, impaired regional contractile function seen during exercise in four patients resolved sooner than in the rest, and it was no longer evident 30 minutes after exercise. These patients tended to have fewer or less severe lesions (Table 3Down).


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  		Table 3. Coronary Anatomy of Patients


*    Discussion
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 up arrowMethods
 up arrowResults
 *Discussion
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In the present study, an episode of exercise-induced myocardial ischemia in patients with coronary artery disease induced significant impairment of regional contractile function that persisted long after cessation of exercise. Because alterations of contractility eventually normalized, and because they could be documented in the absence of alterations of myocardial perfusion, our data demonstrate that myocardial stunning can occur in patients with coronary artery disease as a consequence of angina on effort.

Delayed recovery of contractile function after an episode of demand ischemia has been repeatedly demonstrated experimentally by exercising conscious dogs with coronary artery stenosis.6 7 8 9 10 11 This observation suggests that stunning might also be observed as a consequence of exercise in patients with coronary artery disease.12 However, available data do not clearly indicate whether or not stunning may occur in patients with effort angina. Although it is well established that regional function is altered at the peak of exercise-induced ischemia, only a few clinical studies13 14 15 16 17 have sought to investigate whether contractile impairment outlasts the ischemic episode. These studies yielded conflicting results and spurred much controversy.18 19 20 21 22 In patients with stable angina, Robertson et al,13 Kloner et al,15 and Scognamiglio et al16 observed wall motion abnormalities (by echocardiography) that persisted for at least 30 minutes after exercise. Incidence of the phenomenon ranged from 35% of patients in one series13 to 84% to 91% in other studies.15 16 In contrast, in similar patient populations, Schneider et al14 and Marzullo et al17 reported that wall motion abnormalities visualized on radionuclide angiography scans performed during exercise-induced angina promptly disappeared after exercise.

Several reasons may account for these divergent findings. First, regional function in these studies was assessed from qualitative analysis of wall motion. This approach may not lend itself well to detailed investigation of contractile function because it may have lower sensitivity to detect changes in contractility compared with quantitative methods, and it may be influenced by movements of the heart and by the operator's subjective judgment. In particular, visual interpretation of radionuclide scans may fail to detect the phenomenon because of limited spatial resolution and edge definition.27 These limitations may partly explain the negative results with this technique.14 17 More importantly, previous studies included patients with infarction or wall motion abnormalities at rest. This may make it difficult to interpret the occurrence of new wall motion abnormalities or their changes over time. Finally, another factor is the possible effect of antianginal medications, which were not discontinued in previous studies.

In addition to documenting functional abnormalities, demonstration of stunning also requires evidence that the phenomenon is reversible and that contractile impairment is present at a time when myocardial perfusion has returned to preischemic values.18 22 In this respect, previous studies did not investigate whether any functional abnormalities persisting after cessation of exercise did eventually disappear, nor whether they occurred in spite of normal myocardial perfusion. These issues have major implications. In fact, failure to recover in due time suggests that prolonged contractile impairment may stem from development of irreversible myocyte damage caused by the preceding ischemic episodes, whereas evidence of contractile dysfunction in the presence of flow abnormalities simply indicates a condition of persisting or recurrent ischemia. In either case, the very definition of stunning is defied.

The present study was designed to address these issues directly. We selected patients without contractile abnormalities at rest and in whom therapy could be discontinued safely. Regional function was then evaluated by methods that provide quantitative measurements and that are rather insensitive to factors that may affect subjective scoring of wall motion. In this regard, it has been shown that computer-assisted measurement of wall thickening by echocardiography gives results comparable to direct measurement of thickening obtained in dogs by sonomicrometers implanted in the myocardium34 35 and that thickening is more accurate than wall motion for assessing regional left ventricular function.33 34 35 The other method we used, namely, measurement of regional ejection fraction by radionuclide angiography, is also a quantitative technique, and it is relatively unaffected by changes in geometry and by cardiac motion.27 28 Interestingly, in the present study, recovery of regional function after exercise in two groups of patients with similar characteristics was comparable irrespective of the method used to monitor cardiac function. The opportunity to document the phenomenon by two unrelated techniques and in different groups of patients provides additional support to our findings. Our investigation was not limited to demonstrating persistence of contractile impairment, because the protocol was performed for 4 hours, and therefore, we were able to document that function eventually returned to baseline. Finally, in keeping with the definition of stunning, in one group of patients, we simultaneously assessed both contractility and myocardial perfusion. This goal was achieved by injection of 99mTc-sestamibi, which allowed us to document that although function remained depressed for at least 60 minutes after exercise, myocardial perfusion had already returned to baseline by 30 minutes. Sestamibi has a distinct advantage over other flow tracers such as 201Tl in that it is characterized by minimal redistribution within the myocardium,38 39 40 and therefore it allows myocardial perfusion to be assessed at a later time after injection. Nevertheless, as recently reported by Dilsizian et al,41 redistribution may still occur to some extent when data are collected several hours after injection. However, we believe that redistribution may not have significantly affected our perfusion data, because we acquired SPECT data much earlier (with respect to tracer injection) than in the study by Dilsizian et al. Furthermore, our finding of normal perfusion 30 minutes after exercise stress testing is consistent with previous positron emission tomographic studies showing that perfusion abnormalities rapidly resolve during recovery postexercise. Selwyn et al42 showed that 82Rb uptake by previously ischemic regions returned to baseline within 20 minutes after exercise in four of five patients and between 20 to 30 minutes in one patient. Similarly, Camici et al43 also documented that flow in the ischemic region returned to baseline 5 to 14 minutes after exercise.

The data obtained in the present study address criteria previously used to demonstrate that effort angina may induce stunning in the experimental setting. Thus, it may be interesting to compare our findings in patients with reports of stunning after exercise-induced ischemia in dogs with coronary artery stenosis.7 9 10 11 In those studies, dogs exercised for 10 minutes versus {approx}9 minutes (ie, time to angina plus acquisition time during angina; Table 1Up) in our patients. Impairment of systolic wall thickening induced by ischemia on effort was comparable, ranging between 25% and 66% of baseline in dog protocols versus >50% in our patients. Magnitude and time course of the phenomenon were also comparable, because function remained depressed at {approx}80% of baseline for 30 to 60 minutes in dog studies, similar to what we observed in patients.

The results obtained in the present study have certain limitations. Patients were selected according to rigorous exclusion criteria, and therefore our results may not be applicable to the larger population of patients with effort angina. In particular, it should be noted that the majority of patients in our protocol had angiographic evidence of multivessel coronary artery disease and that (by entry criteria) exercise stress testing elicited ECG signs of ischemia in all of them. Thus, it is likely that in patients with these characteristics, ischemia tends to be more severe than in the general population of patients complaining of effort angina. This is an important point, because severity of ischemia would conceivably influence development and persistence of regional dysfunction. In this respect, it should be noted that the few patients in whom recovery of function was already completed 30 minutes after cessation of exercise tended to have fewer or less severe coronary lesions. Another limitation of our clinical study is that it did not allow the investigation of important determinants of exercise-induced stunning, namely, extent and duration of ischemia.8 10 Unlike animal studies, in which the investigator has precise control over the site of placement of the coronary constrictor and of its size, atherosclerotic lesions in patients may variably affect vessel diameter, at different sites and in a different number of vessels. Consequently, extent and severity of ischemia may differ from one patient to another and cannot be controlled by the investigator. In addition, we did not investigate the effects of longer duration of angina because of obvious ethical reasons. As already stated, differences in these determinants among patients or among ischemic episodes in a given patient are likely to influence the magnitude and duration of postexercise impairment of function. Finally, although we documented that transmural regional perfusion 30 minutes into recovery was similar to the resting state, it cannot be excluded that a maldistribution of flow persisted that favored epicardial flow at the expense of subendocardial perfusion. This important point cannot be adequately addressed in humans with current radionuclide or positron-emitting techniques because of limited spatial resolution of tomographic devices. However, experimental data may provide indirect support, because quantitative flow measurements with microspheres performed on tissue specimens of dogs demonstrate that contractile recovery after exercise-induced ischemia lags much behind normalization of subendocardial flow.7 8 In fact, the flow-function relationship is shifted to the right compared with measurements taken either at rest or during ischemia, further indicating that in stunned myocardium, function is depressed for a normal level of subendocardial flow.8

In addition to its pathophysiological implications, demonstration of stunning in patients with stable angina may also have important clinical consequences.18 22 Episodes of effort angina occur frequently in many patients with coronary artery disease. Even if the degree of contractile dysfunction were relatively modest after one ischemic episode, animal studies indicate that repeated episodes of exercise-induced ischemia have a cumulative effect, which makes impairment of contractility more pronounced and longer lasting.9 In addition to systolic function, diastolic function may also remain transiently impaired as a result of exercise-induced ischemia.44 Finally, the possibility should be considered that in some patients, presence of dysfunctional yet viable myocardium might be the consequence of stunning (perhaps induced by unrecognized episodes of silent ischemia) as opposed to true hibernation.45 46 47

In conclusion, our data for the first time document that in patients with stable angina, significant yet reversible impairment of regional left ventricular function may persist well after cessation of exercise in the absence of flow abnormalities. This finding demonstrates that myocardial stunning may occur after relatively brief episodes of ischemia in patients with coronary artery disease.


*    Acknowledgments
 
We wish to thank Lewis C. Becker, MD (Baltimore, Md) for his very helpful comments and suggestions.


*    Footnotes
 
Presented in part at the 64th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 11-14, 1991, and at the 66th Scientific Sessions of the American Heart Association, Atlanta, Ga, November 8-11, 1993, and published in abstract form (Circulation. 1991;84[suppl II]:II-475 and 1993;88[suppl I]:I-444).

Received January 10, 1996; revision received June 4, 1996; accepted June 11, 1996.


*    References
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