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(Circulation. 1995;91:1669-1675.)
© 1995 American Heart Association, Inc.

Articles

Complex Coronary Artery Lesion Morphology Influences Results of Stress Echocardiography

Presented at the 43rd Annual Scientific Session of the American College of Cardiology, Atlanta, Ga, March 14-17, 1994.

Chunzeng Lu, MD; Eugenio Picano, MD; Alessandro Pingitore, MD; Rosa Sicari, MD; Rossana Tongiani, MD; Marco Baratto, MD; Cataldo Palmieri, MD; Mario Marzilli, MD; Antonio L'Abbate, MD

From CNR, Institute of Clinical Physiology, Pisa, Italy.

Correspondence to Eugenio Picano, MD, Istituto di Fisiologia Clinica, CNR, Via Paolo Savi, 8, 56126 Pisa, Italy.

	Abstract

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Background The likelihood of a positive response with dipyridamole stress echocardiography (DSE) is directly related to the extent and severity of angiographically assessed coronary artery disease. Whether coronary lesion morphology—a known predictor of adverse cardiac events—may also modulate stress echo results remains unknown. The objective of our study was to assess the relation between stenosis lesion morphology and stress echocardiographic results.

Methods and Results High-dose (up to 0.84 mg/kg over 10 minutes) DSE and coronary angiographic data of 68 in-hospital patients (39 with stable angina, 29 with angina at rest) with nonoccluding, single-vessel disease at angiography and no previous myocardial infarction were analyzed. DSE was performed in all patients within 3 days of coronary angiography. An angiographic lesion was considered complex when irregular borders and/or intraluminal lucencies suggestive of ulcer and/or thrombus were present. According to angiographic lesion morphology, two groups were identified: group 1, with simple coronary lesions, and group 2, with complex coronary lesions. The two groups were matched for number of patients (n=34 in each group), age (group 1, 59±9 versus group 2, 59±10 years, P=NS), and coronary artery stenosis severity by quantitative coronary angiography (group 1, 60±7% versus group 2, 58±6% diameter reduction, P=NS). The sensitivity of DSE was lower in patients of group 1 when compared with group 2 (53% versus 85%, P<.001). Among positive DSE, the low-dose (0.56 mg/kg over 4 minutes) positivity was less frequent in group 1 than in group 2 patients (17% versus 62%, P<.01). Exercise ECG was completed in 66 patients, and it was positive (>.1 mV ST-segment shift from baseline) in 20 out of 33 group 1 and in 22 out of 33 group 2 patients (61% versus 67%, P=NS). The peak rate-pressure product tended to be higher in group 1 than in group 2 patients (257±52 versus 240±64 mm Hgxbeats per minutex10², P=NS).

Conclusions In patients with single-vessel disease without coronary occlusion or previous myocardial infarction, coronary lesion morphology of the complex type is associated with a higher DSE sensitivity and with a greater prevalence of low-dose, positive responses. Presence of irregular plaque contours, not only plaque geometry, is important in modulating stress responses in the presence of angiographically assessed coronary artery disease.

Key Words: ischemia • stress • echocardiography • exercise • lesion

	Introduction

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A major limitation of the conventional angiographic assessment of noninvasive test results in terms of sensitivity and specificity is the complete disregard of plaque morphology and relying merely on plaque stenosis.^{1 2 3 4 5} This purely anatomic-geometric approach is still the standard one despite explosive growth of evidence demonstrating that coronary arteries are not inert, passive conduits and that a complex angiographic morphology (suggestive of thrombus and/or ulcers) is the marker of a more profound endothelial damage.^{6 7 8} In fact, the variable of plaque morphology is of recognized pathophysiological,⁹ clinical,¹⁰ and prognostic¹¹ relevance but is nevertheless ignored by conventional sensitivity/specificity analysis of test performance. To our knowledge, no information is available on the relation between plaque morphology and ischemic potential as assessed by stress testing and in particular by pharmacological stress echocardiography—a technique increasingly used in the clinical arena for its merits of diagnostic accuracy and excellent cost-effectiveness.¹²

The aim of the present study was to assess the relation between coronary stenosis morphology and dipyridamole stress echocardiography (DSE) results. Accordingly, DSE data were analyzed in two groups of patients with single-vessel, nonoccluded coronary lesions, matched for quantitatively assessed stenosis severity, and with either "simple" or "complex" coronary lesions.^{6 7 8 13} Sixty-six of these 68 patients also completed a diagnostic exercise electrocardiography test (EET).

	Methods

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We initially considered 118 in-hospital patients with DSE and coronary angiography performed within 3 days who had single-vessel (50% diameter stenosis by visual assessment), nonoccluded coronary lesions and no previous myocardial infarction. Of this initial set of 118 patients, 44 were ruled out because of (1) angiographic cinefilms of insufficient quality for quantitative coronary angiographic assessment (n=17), (2) stenosis judged to be critical by visual assessment that was indeed <50% diameter stenosis by quantitative coronary arteriography (n=15), (3) presence of an obvious resting dyssynergy (akinesis or dyskinesis) by either two-dimensional echocardiography or contrast ventriculography (n=11), or (4) segmental wall motion abnormality during DSE that occurred in a territory outside the perfusion bed of the stenotic coronary artery (for example, inferior wall dyssynergy with left anterior descending coronary artery stenosis) and therefore was more likely to be a false-positive result than the indicator of ischemic changes in that territory (n=1). From the remaining 74 patients, on the basis of plaque morphology (complex in 34, simple in 40) and severity, we selected two groups of 34 patients each, matched for stenosis severity and with either simple (group 1) or complex (group 2) lesion morphology. Complex plaques were defined as coronary intraluminal filling defect suggestive of intraluminal thrombus and/or coronary asymmetric narrowing with irregular borders and/or multiple irregularities and/or overhanging edges or with "abrupt proximal face" or a "rough" or "sawtooth" component suggestive of ulcers.^{6 7 8 13} In 66 patients, a diagnostic EET was also completed within 2 days from DET and under identical antianginal therapy, if any.

The demographic, anamnestic, and clinical findings in the two study groups are reported in the Table. Coronary angiography, DSE, and EET were separately and independently performed and analyzed by cardiologists unaware of the results of the other tests.

View this table: [in this window] [in a new window]   Table 1. Clinical Features

Exercise ECG Test
Patients performed a multistage upright cycle ergometer test, with an initial load of 25 W and subsequent increments of 25 W every 2 minutes. A 12-lead ECG and blood pressure determination were obtained at baseline and every minute thereafter. Criteria for interrupting the test were severe chest pain, diagnostic ST-segment shift, fatigue, excessive blood pressure rise (systolic blood pressure >240 mm Hg, diastolic blood pressure >120 mm Hg), limiting dyspnea, or maximal predicted heart rate in the absence of ischemia.

ECG tracings were considered diagnostic for myocardial ischemia when an ST-segment shift of at least 0.10 mV, 0.08 second after the J-point, could be detected. ECG tracings were analyzed visually by an experienced cardiologist who was blind to angiographic and dipyridamole echocardiography test findings. The rate-pressure product (heart ratexsystolic blood pressure) and exercise time (in minutes), assessed either at peak exercise (in negative tests) or at the onset of ischemia (0.10 mV ST-segment depression in positive tests), were also evaluated.¹⁴

Dipyridamole Echocardiography Test
Two-dimensional echocardiographic and 12-lead ECG monitoring were performed in combination with a dipyridamole infusion of 0.56 mg/kg over 4 minutes followed by 4 minutes of no dose and then 0.28 mg/kg in 2 minutes.¹⁴ The cumulative dose was therefore 0.84 mg/kg over 10 minutes. Aminophylline (up to 240 mg over 3 minutes) was readily at hand. During the procedure, the blood pressure and the ECG were recorded each minute. Two-dimensional echocardiograms were obtained continuously during and up to 10 minutes after dipyridamole administration. Commercially available wide-angle, phased-array imaging systems (Hewlett-Packard 1000 and 1500, Toshiba Sonolayer FFA270A, or ESAOTE Biomedica SIM 7000; 2.5- and 3.5-MHz transducers) were used. In the baseline studies as well as during stress, all standard echocardiographic views were obtained when possible. During the test, new areas of abnormal wall motion were identified in multiple views whenever possible. The videotapes were analyzed by the cardiologist-echocardiographist performing the test, who was blind to the clinical and angiographic data. The low level of intraobserver and interobserver variability obtained in our laboratory between experienced readers has been documented previously.¹⁵ A digital acquisition of images of interest was obtained either on line (by ESAOTE Biomedica SIM 7000 or Hewlett-Packard Sonos 1500) or off line by an array processor–based computer for medical image processing (Mipron), and a side-by-side display of images at rest and peak stress in a cineloop mode was obtained. A wall motion score index was derived for rest and peak dipyridamole echocardiograms in each patient. The left ventricle was divided into 11 segments according to a segmentation proposed by the Italian Society of Echocardiography and already adopted in the EPIC multicenter trial on stress echocardiography.¹⁴ The 11 left ventricular segments considered for the analysis were the apex, proximal and distal anterior septum, proximal and distal inferior septum, proximal and distal anterior wall, proximal and distal lateral wall, and proximal and distal inferior wall.

Segmental wall motion was graded as normal: normal motion at rest, with normal/increased wall motion (hyperkinesis) after dipyridamole (score=1); hypokinetic: marked reduction in endocardial motion (score=2); akinetic: virtual absence of inward motion (score=3); or dyskinetic: paradoxical wall motion away from the left ventricular center in systole (score=4). The wall motion score index was derived by summation of individual segment scores divided by the number of interpreted segments. Inadequately visualized segments were not scored. A test result was considered positive when the wall motion score increased by one grade or more at peak stress (for example, a normal segment becoming hypokinetic, akinetic, or dyskinetic). In positive tests, the dipyridamole time, that is, the minutes from the beginning of drug infusion to the development of the stress-induced dyssynergy, was also evaluated. In negative tests, the dipyridamole time was arbitrarily assumed to be 17 minutes (when aminophylline was given).

Angiographic Study
Coronary angiography in multiple views was performed according to the standard Judkins or Sones technique. At least five views (including two orthogonal views) were acquired for the left and at least two orthogonal views for the right coronary arteries, respectively. Additional appropriate projections were obtained in case of superimposition of side branches or foreshortening of the segment of interest. A 5-in. field of view of the image intensifier was used. All angiograms were visually evaluated by two independent observers with an angiogram projection system (CAP/35BII) that allows frame-by-frame analysis selection. Magnification of the segment of interest was used for evaluation of the qualitative angiographic definitions. The observers identified the stenotic segments and scored stenosis morphology as simple or complex according to previously stated criteria. In case of disagreement, a third more experienced observer (M.M.) reviewed the angiogram, and his judgment was binding. The interobserver variability in plaque assignment to either simple or complex morphology was 5%; the intraobserver variability assessed by the same observer on the same set of 20 angiograms was 5%. All stenotic segments were evaluated by an automatic edge detection system (Mipron). A magnification of the region of interest during assessment was possible. A region of interest of 512x512 pixels was manually selected and digitized using a high-quality VIDICON videocamera. The luminal edges were detected on the basis of the weighted sum of the first and second derivative functions of the brightness profile of each scan line perpendicular to the vessel centerline. From these contours, the vessel diameter function was determined by computing the shortest distance between the left and right contour position.

The tip of the angiographic catheter was used as a scaling device, and this allowed the diameters to be obtained as absolute values (expressed in millimeters). The percent diameter stenosis (in the projection in which the stenosis appeared most severe) and the minimum cross-sectional area (a mean of the values obtained in two orthogonal projections, in millimeters squared) were measured for each coronary artery stenosis. The previously assessed intraobserver and interobserver variabilities of the method were 7% and 6%, respectively.¹⁶

Statistical Analysis
Values are expressed as mean±SD. For both the exercise ECG test and the dipyridamole echocardiography test, sensitivity and specificity in detecting angiographically assessed coronary artery disease were calculated according to standard definitions. Differences between the results of the exercise ECG test and the dipyridamole echocardiography test in the different angiographic subsets were compared by using the ² test; a Fisher's exact test was used when appropriate. Comparison between groups for continuous data were made with the Student's t test for unpaired values. A P value <.05 was considered statistically significant.

	Results

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Angiographic Data
By selection, the quantitative angiographic data in the two groups were similar, with comparable percent diameter reduction (group 1, 60±7% versus group 2, 58±6%, P=NS) and minimum cross-sectional area (group 1, 1.1±0.3 versus group 2, 1.2±0.6 mm², P=NS) (Fig 1). An example of a simple-type (group 1) and complex-type (group 2) stenosis morphology is shown in Fig 2 and Fig 3, respectively (upper panel).

View larger version (7K): [in this window] [in a new window]   Figure 1. Bar graphs showing quantitative coronary arteriographic findings of percent diameter reduction (left) and minimum cross-sectional area (right) in patients with simple type (filled bars, group 1) and complex type (open bars, group 2) coronary stenoses.

View larger version (76K): [in this window] [in a new window]   Figure 2. A typical angiographic stress echocardiographic pattern of a patient of group 1. At the top, an example of a tight left anterior descending (LAD) stenosis of the simple type is shown, with a magnification of the stenosis in the right lower corner. At the bottom, the end-systolic frames of the apical four-chamber view show a synergic, symmetric contraction of all imaged myocardial regions (including the septum and apex, perfused by the critically stenosed artery) both at baseline (rest) and after dipyridamole (stress).

View larger version (73K): [in this window] [in a new window]   Figure 3. A typical angiographic stress echocardiographic pattern of a patient of group 2. At the top, an example of a tight left anterior descending (LAD) stenosis of the complex type is shown, with a stenosis magnification in the right lower corner. At the bottom, the end-systolic frames of the apical four-chamber view show a synergic and symmetric contraction of all myocardial regions at baseline (rest) and an obvious dyskinesis of the medium septum and apex (fed by the critically stenosed coronary artery) after dipyridamole (stress).

Exercise Stress Test
No major complications occurred during EET. In two patients, the EET could not be performed and/or completed up to diagnostic end points. In the remaining 66 patients, the EET was positive in 42 and negative in 24. The peak rate-pressure product was 23 000±5800 in patients with a positive test and 28 000±4900 mm Hgxbeats per minute in patients with a negative test (P<.01).

Dipyridamole Stress Echocardiography Results
No major complications or limiting side effects occurred during DSE. In the overall population of 68 patients, 47 (69%) had a positive test. The resting wall motion score was 1±0.04 and rose to 1.3±0.3 at peak stress. The dipyridamole time was 11±5 minutes. Examples of negative and positive DSEs are shown in Fig 2 and Fig 3, respectively.

Correlation of EET With Angiographic Findings
Of the 66 patients with a diagnostic EET, 33 had a complex type and 33 a simple type of coronary stenosis. EET positivity was found in 20 of 33 of patients with simple type (group 1) and 22 of the 33 patients with complex type (group 2) plaques (61% versus 67%, P=NS). The rate-pressure product was higher in patients of group 1 than in patients of group 2 (25 700±5200 versus 24 000±6400 mm Hgxbeats per minute, P=NS) (Table).

Correlation of Dipyridamole Stress Results With Angiographic Findings
Typical examples of angiographic and corresponding stress-echocardiographic response in a group 1 and a group 2 patient are shown in Fig 2 and Fig 3, respectively. The percentage of positive results was lower in group 1 than in group 2 (53% versus 85%, P<.001) (Fig 4). Considering all patients, group 1 exhibited longer dipyridamole time (14±4 versus 9±5 minutes, P<.001; Fig 4) and lower peak wall motion score index (1.2±0.3 versus 1.4±0.3, P<.05), with a similar resting wall motion score index versus group 2 (1±0.04 versus 1±0.1, P=NS); restricting the analysis only to positive patients, the simple type morphology was associated with a trend to a longer dipyridamole time (group 1, 10±4 versus group 2, 8±4 minutes, P=.056), with a less frequent low-dose (0.56 mg/kg) positivity (17% versus 62%, P<.01) and a similar peak wall motion score index (group 1, 1.4±0.4 versus group 2, 1.4±0.3, P=NS).

View larger version (7K): [in this window] [in a new window]   Figure 4. Bar graphs showing resting wall motion score index and stress echocardiographic variables in patients with simple type (filled bars, group 1) and complex type (open bars, group 2) coronary stenoses. Complex type plaques exhibit higher prevalence of positivity (left) and shorter dipyridamole time (right).

	Discussion

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The complex plaque has a stronger ischemic potential during stress than the simple plaque. Coronary arteries are not inert tubes, and, whereas in normal conditions the relaxing factors tend to predominate,^{17 18} an alteration in the endothelium—which is very likely to be more marked on or around the complex atherosclerotic plaque—may contribute to an altered biological response of the complex plaque to endogenous adenosine, accumulated through inhibition of cellular uptake during dipyridamole infusion.¹²

Myocardial and Coronary Effects of Adenosine
Adenosine is produced intracellularly, but it does not exert its effects until it leaves the intracellular environment and interacts with A1 and A2 adenosine receptors on the cell membrane. In the heart, A1-receptors are found on cardiomyocytes and vascular smooth muscle, whereas A2-receptors are found on endothelium and vascular smooth muscle.^{19 20} The effects of adenosine on coronary A2-receptors lead to vasodilation and in turn to increased flow. However, the mechanisms of this effect are complex. Recent work calls for a reexamination of the conventional view that vasodilation represents a direct action of adenosine on coronary smooth muscle. The relaxation of isolated coronary arteries in vitro is at least in part endothelium dependent, with the vascular smooth muscle relaxation (endothelium independent) accounting for a rough 70% of overall relaxation—at least in isolated rings of guinea pig aorta.²¹ In vivo, the share of endothelium-dependent relaxation might even increase, since the A2-receptor–mediated vasodilation of coronary arterioles determines an upstream increase in flow that leads to an increase of shear stress acting on epicardial arteries and to an endothelium-mediated and adenosine receptor–independent vasodilation achieved through endothelium-derived relaxing factor release.²² Experimental data do indeed demonstrate the capability of large epicardial coronary arteries to dilate in response to dipyridamole infusion. Injection of 0.25 mg/kg of dipyridamole in dogs causes almost a 30% increase in the cross-sectional area of large coronary arteries.²³ Few data are available in humans. On the average, in patients with severe stenosis, there is a mild effect on lumen size.²⁴ However, this apparently mild effect can derive from the algebraic sum of two different actions. The fall in poststenotic intraluminal distending pressure due to the Venturi effect may determine a collapse of the lumen for purely passive mechanisms, whereas a direct effect—unopposed in normal arteries—is a coronary relaxation.

Relation of Coronary Stenosis Morphology to Stress Test Response
The angiographic pattern of complex coronary stenosis morphology is associated with more extensive endothelial involvement by disease.^{6 7 8} During dipyridamole or exercise, loss of endothelial integrity (more pronounced in the complex plaque) reduces flow-mediated and endothelium-mediated vasodilation of large epicardial arteries without affecting endothelium-independent dilation of small resistance coronary vessels. Since epicardial vessel diameter is related to the fourth power of the vessel resistance to flow, even a minimally reduced increase in epicardial artery luminal diameter markedly increases transtenotic pressure gradient and therefore the functional severity of stenosis.²⁵

In other words, the downstream dilation achieved by physiologically or pharmacologically induced rise of interstitial adenosine decreases the overall network resistance, thereby increasing flow through upstream segments. This would cause upstream myogenic and flow-induced vasodilation, synergistically acting with adenosine direct receptor-mediated vasodilation. Damage to the endothelium might abolish this response to blood flow. The combined loss of receptor-dependent and flow-mediated vasodilation might easily abolish the vasodilation of large coronary arteries. In this way, the coronary vasodilation due to arteriolar effects, unmatched by epicardial artery dilation, leads to a greater transtenotic pressure loss and to lower perfusion pressure, with greater prevalence of subendocardial ischemia after either exercise or dipyridamole infusion.

Comparison With Previous Studies
Complex coronary stenosis morphology is found in about 70% of patients with unstable angina and in 66% of patients with myocardial infarction and is detectable in about 20% to 30% of patients with chronic stable angina.^{6 7 8} In our study population, there was no higher prevalence of angina at rest in the group with complex type lesions, as it might have been expected. However, one has to take into account the selection criteria of our study: All our patients could withstand stress testing, and therefore unstable angina syndromes referred directly to angiography could not be included in our study population. In most patients, clinical condition allowed therapy withdrawal before testing, indicating that none had refractory angina or preinfarction angina. In addition, the angiographic entry criteria of nonoccluded, single-vessel disease probably tends to exclude unstable more than stable clinical syndromes.

Tousoulis et al¹⁰ evaluated the relation between coronary stenosis morphology and coronary vasomotor effect of serotonin. They found that in patients with stable effort angina as well as in patients with variant angina, the magnitude of the vasoconstrictor response to serotonin at the site of an atheromatous coronary plaque was more closely related to irregular contour rather than to stenosis severity. The study of Tousoulis et al is different from ours in many aspects, since they evaluated coronary reactivity in a direct fashion, through serial quantitative angiographic assessment, whereas we assessed the ischemic potential of the plaque indirectly through provocative testing. Furthermore, they assessed the vasoconstrictive tendency of the coronary plaque, whereas myocardial vulnerability to dipyridamole and exercise-induced ischemia is more an expression of depressed vasodilator capability. Nevertheless, increased angiographic reactivity to vasoconstrictor stimuli and enhanced susceptibility to ischemia after vasodilator stress might be two tightly interrelated aspects of the same pathophysiological defect at the endothelial level of the complex plaque. Damage to the endothelium leads to failure to produce dilatory factors, thus enhancing susceptibility to vasoconstrictor stimuli.

Our findings are also consistent with others independently assessing the prognostic value of angiographic complex type morphology^{6 7 8 9 26 27} and of DSE results, especially after the lower dose,^{5 28 29} in predicting subsequent events. The results of this study point out that stress echo response is related not only to the classic prognostic determinants of extent and severity of coronary artery disease but, for any given stenosis severity, to plaque morphology as well. In positive DSE, dipyridamole time showed a greater discrimination power than peak wall motion score index in separating simple type from complex type plaques. This is in keeping with previous studies showing that the severity of induced ischemia in the time domain—and not in the space domain—is correlated to the physiological and prognostic severity of coronary artery disease, especially in patients with single-vessel disease.^{12 16}

Study Limitations
Nonsystematic sources of error in quantitative coronary arteriography can be methodology related and patient related. Even algorithms used for edge detection in quantitative coronary arteriography can be inaccurate for the correct definition of very irregular contours, which are encountered with complex type plaque.⁵ Changes in vasomotor tone may affect stenosis measurements in the absence of a standardized vasodilation with nitrates.⁵

The assessment of plaque morphology was qualitative and visual. Although analysis of arterial borders with complex computer algorithms has been proposed³⁰ and may allow for a more objective assessment of lesion irregularity or roughness, such techniques do not incorporate an assessment of translucency or filling defects within the borders of the lesion¹³ and have not been extensively applied to date.^{10 11 26}

Besides being based on a visual assessment of plaque morphology, angiography is a very insensitive technique to detect thrombus and complex plaque in comparison with angioscopy³¹ and with intravascular ultrasound.³² Finally, the proposed mechanisms to explain the greater ischemic potential of the complex plaque during dipyridamole stress are largely conjectural, and the true mechanism should be addressed in future studies.

Clinical Implications
We are accustomed to think of the performance of diagnostic tests in terms of sensitivity to the percent stenosis of a coronary artery, but the physiological consequences of a stenosis cannot always be predicted with a simple anatomic-geometric approach.^{1 2 3 4 5} Another possible limitation of the anatomic approach is to consider that all plaques—for any given stenosis severity—are created angiographically equal. This probably is not true. Different plaque morphologies not only imply different susceptibilities to occlusion but probably reflect different degrees of endothelial dysfunction and reactivity to ischemic stimuli. Results of provocative tests are probably dependent both on stenosis hydraulics and on stenosis biology. The results of this study further challenge the hydraulic dogma (that is, disease severity equals stenosis severity) and emphasize the need for a more integrated assessment of angiographic data to truly understand and assess the results of physiological noninvasive testing.³³ Whether the results obtained in this study can be extrapolated to other pharmacological stresses such as dobutamine infusion or to other imaging techniques such as perfusion scintigraphy, whose positivity is related to flow maldistribution rather than to true ischemia, is an issue to be addressed in future studies. Plaque morphology establishes an imperfect but crucial link between the traditional anatomic-geometric view of stenosis and the biology of the plaque—a hidden variable in the traditional sensitivity-and-specificity approach.

	Acknowledgments

 
We are grateful to Claudia Taddei for secretarial help and to Antonio Caselli, PhD, for reviewing the English language.

Received October 5, 1994; accepted October 14, 1994.

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