Diagnostic value of exercise electrocardiography and angina after coronary artery stenting

CURRICULUM IN CARDIOLOGY

Diagnostic value of exercise electrocardiography and angina after coronary artery stenting Victor Legrand, MD, PhD, Bruno Raskinet, MD, Gertjan Laarman, MD, PhD, Nicolas Danchin, MD, Marie A. Morel, MS, and Patrick W, Serruys, MD, PhD, FACC, on behalf of the Benestent Study Group

Liege, Belgium To determine whether metallic stent implantation within a coronary artery modifies the accuracy of angina or exercise test results in predicting stenosis, we studied 172 patients assigned to stent implantation and 153 patients assigned to balloon angioplasty enrolled in the Benestent trial comparing de novo stenting with conventional balloon angioplasty. Sensitivity and specificity curves were constructed for the prediction of percentage diameter stenosis and minimal lumen diameter. Receiver-operator curves were constructed for comparison of diagnostic accuracy. Identical exercise load and duration were achieved in the two groups, despite a better angiographic result in patients treated with a stent. Similarly, the diagnostic accuracy of clinical symptoms o r exercise test results as a function of the angiographic results were similar in patients with and patients without a stent. The intersection points of the sensitivity and specificity curves for recurrent angina or ST-segment depression were 72% to 77%. The corresponding cut-off points for percentage diameter stenosis were, respectively, 52% and 50% for patients with and without a stent (1.35 and 1.50 mm for minimal lumen diameter). We conclude that the presence of an intracoronary stent does not affect the diagnostic accuracy of recurrent angina or exercise-induced ST depression in predicting residual stenosis. We also conclude that exercise tolerance is similar after balloon angioplasty, with or without stenting, despite a better angiographic outcome in the group receiving a stent, suggesting a minimal threshold beyond which the patient is no longer at risk for ischemia during exercise. (Am Heart J 1997;133:240-8.)

tus at follow-up or a worsening in lesion severity can predict functional status 6 months after successful single-vessel coronary balloon angioplasty. 9 Recently, the Palmaz-Schatz stent has been shown to improve primary angioplasty results and to reduce restenosis. 1°13 However, this metallic foreign body w i t h i n the coronary artery may predispose to thrombosis, affect coronary geometric and rheologic features, and trigger increased proliferation of cellular matrix and new tissue growth. 14"17 In addition, it is not clear whether insertion of a metallic device could also affect the regulation of coronary blood flow and the vasomotor tone of the stented vessel. Therefore it can be hypothesized that clinical status or exercise test results at follow-up may be specifically influenced by intracoronary stenting. Using data collected in a randomized trial comparing single-vessel angioplasty with or without stent implantation, 12 we investigated the relation among coronary artery stenosis, recurrent angina, and exercise test results 3 to 6 months after a successful intervention. Our goal was to determine whether a metallic stent within a coronary artery affects clinical status and exercise performance and modifies the accuracy of angina or exercise test results in the prediction of restenosis.

Angiographic restenosis develops in 15% to 52% of patients in whom dilation is successful. 1-3 Although recurrence of angina or abnormal exercise test results at follow-up have poor predictive value for detection of anatomic restenosis, 4-8 angiographic sta-

METHODS Patient selection and randomization. The original pa-

From the Department of Cardiology, Catheterization Laboratory, Centre Hospitalier Universitaire Sart-Tilman. Received for publication Nov. 14, 1995; accepted May 8, 1996. Reprint requests: Victor Legrand, MD, Department of Cardiology, Catheterization Laboratory, CHU Sart-Tilman, 4000 Liege, Belgium. Copyright © 1997 by Mosby-Year Book, Inc. 0002-8703/97/$5.00 + 0 4/1/76859

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tient group consisted of 516 patients who were enrolled in the multicenter Benestent study. In this randomized trial, patients with stable angina and single coronary intervention of a native coronary artery not supplying an infarcted area were randomly assigned to stent implantation or balloon angioplasty. The study protocol and selection criteria for this trial have been published previously. ~ Of the 516 patients, follow-up angiographic data were obtained in 447 patients (222 patients in the angioplasty group and 225 patients in the stent group) who had a successful procedure, defined as a <50% residual stenosis

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257 pts eligible for PTCA 10 failed PTCA 13 cross-over 1 death 11 refusals

l

222 pts with angiographic F-U 2 MI

241

259 pts eligible for stenting 1t failed stenting 14 cross-over 2 deaths 7 refusals

225 pts with angiographic F-U 2 MI

1 CVA

32 UAP with revascularisation

20 UAP with revascularisation 187 I s eligible for F-U ETT

203 pts eligible for F-U ETT 31 without ETT

34 without ETT

153 I~ts with F-U angio & ETT

172 pts with F-U angio & ETT

Fig. 1. Derivation of final study population from initial 516 patients randomized in Benestent trial.16 Angio, Angiography; CVA, cerebrovascular accident; ETT, exercise test tolerance; F..U, follow-up; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; UAP, unstable angina pectoris.

without in-hospital complications (death, myocardial infarction, cerebrovascular event, bypass grafting, bail-out stenting, or repeat angioplasty). One hundred fifty-three (68.9%) patients assigned to balloon angioplasty and 172 (76.4%) patients assigned to stent implantation underwent a maximal symptom-limited exercise tolerance test 0 to 4 days before follow-up catheterization. Fifty-seven patients were not eligible for an exercise test because of myocardial infarction (n = 4), cerebrovascular accident (n = 1), and unstable angina (n = 52), and an additional 65 patients did not perform an exercise test before angiography (Fig. 1). Patients who received a stent were treated with warfarin for 3 months and aspirin and dipyridamole for 6 months; patients treated by balloon angioplasty received only aspirin and dipyridamole. Other cardiovascular medications were continued if prescribed for reasons other than angina pectoris (e.g., hypertension). Although cardiovascular medication was not standardized, it was similar in the two treatment groups. Angiographic follow-up.All the angiograms obtained at follow-up were analyzed by the Cardiovascular Angiography Analysis System in a central core laboratory (Cardialysis, Rotterdam, The Netherlands). The methods of data

acquisition and analysis were standardized and have been described previously, is Follow-up angiography was performed a mean of 5.77 _+ 1.19 months after dilatation in patients who did not receive a stent and a mean of 5.87 +_ 1.03 months later in those who did receive a stent. Follow-up evaluation and exercise. Each patient was seen for an interview, physical examination, and a symptom-limited exercise test 0 to 4 days before follow-up catheterization. Reports of angina and exercise test results were thus documented before coronary angiography, without knowledge of the coronary anatomic findings. Typical reports of angina were classified according to the Canadian Cardiovascular Society angina classification. The exercise test was performed in supine position on a bicycle ergometer according to a recommended protocol starting with a work load of 50 W, which was increased by 25 W every 2 minutes. In Madrid, the test was performed on a treadmill with the Bruce protocol. Exercise was continued until development of limiting symptoms (angina, dyspnea, fatigue, or claudication), a decrease in systolic blood pressure, severe arrhythmia, or marked and progressive ST-segment displacement. A 12-lead electrocardiogram (ECG) was recorded during exercise and recovery. ST-segment changes

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Table I. Exercise testing and angiographic characteristics

Exercise duration (min) Exercise load (W) Maximum heart rate (beats/min) Maximum blood pressure (mm Hg) RPP <250,000 m m Hg/min ST+ AP+ ST+ or AP+ ST+ and AP+ Diameter stenosis (%) Minimum lumen diameter (mm) >50% diameter stenosis <1.5 m m lumen diameter

Balloon (n = 153)

S t e n t (n = 172)

8.74 _+ 2.98 158 _+ 54 134 _+ 20 189 _+ 31 53 (34.6%) 35 (22.9%) 39 (25.5%) 58 (37.9%) 16 (10.4%) 40.94 _+ 15.2 1.82 _+ 0.53 40 (26.1%) 37 (24.2%)

8.87 _+ 3.36 158 _+ 52 138 _+ 24 186 _+ 31 57 (33.1%) 28 (16.3%) 33 (19.2%) 51 (33.5%) 10 (5.8%) 34.89 _+ 13.7 1.93 _+ 0.52 26 (15.0%) 35 (20.3%)

p Value

<0.02 <0.02

AP+, Recurrent angina; RPP, rate-pressure product; ST+, exercise-induced ST depression.

were measured 80 msec after the J point. The test result was interpreted as positive if any horizontal or downsloping ST-segment displacement registering 0.10 mV or more than the baseline value occurred during or after exercise. No patient was taking digitalis or showed ECG bundle branch block, rendering the ECG uninterpretable. Data analysis for determination of accuracy. Sensitivity and specificity for angina, ST-segment depression during exercise, or both, at various cut-offpoints of continuous angiographic variables (percentage diameter stenosis and minimal lumen diameter) were determined. To compare the diagnostic accuracy of the different variables for each group of patients, receiver-operator characteristic curves were constructed. Continuous variables were expressed as mean -- SD and were compared by the unpaired Student's t test. A p value <0.05 was considered significant. RESULTS Clinical, exercise, and angiographic characteristics of the patients. At follow-up, a second revascularization was required because of recurrent angina in 55 patients in whom no exercise test was performed; this occurrence was more frequent among patients of the angioplasty group (35 [15.8%] patients) t h a n among patients of the stent group (20 [8.9%] patients) (p< 0.05). Similarly, the incidence of revascularization among patients with an exercise test performed was 15.7% (24 of 153 patients) and 8.1% (14 of 172 patients) in the angioplasty group and stent group, respectively (p = 0.05). Exercise performance was similar among patients randomized to angioplasty alone or stent implantation: exercise duration, maximal exercise load, maximal heart rate, and maximal blood pressure were similar i n each treated group. One third of t h e patients in each group showed submaximal exercise performance. Thirty-nine (25.5%) patients had recurrent angina and 35 (22.9%) had a positive exercise

test result in the angioplasty group, as compared with 33 (19.2%) and 28 (16.3%), respectively, in the stent group (p = not significant). The angiographic results, however, favored the stent-treated patients, who had lower residual stenosis (Table I). Value of recurrent angina, positive exercise test result, or both to predict angiographic results at follow-up. Fig. 2 and Table II provide percentage classification of recurrence of angina or positive exercise test result (sensitivity) and percentage classification of absence of angina or exercise-induced ST depression (specificity) as a function of percentage diameter stenosis or minimal lumen diameter. The results of exercise testing (exercise-induced ST-segment depression) were less accurate t h a n recurrence of anginal chest pain during follow-up to predict restenosis. Indeed, the optimal combination of sensitivity and specificity, which corresponds to the point of intersection between the sensitivity and specificity curves, was obtained when considering clinical symptoms (presence of angina) alone or in combination with exercise test results. These cut-off points associated with the highest diagnostic accuracy were similar in patients with and without a stent. They were related, respectively, to residual diameter stenosis at follow-up of 52% and 50% when recurrent angina or a positive exercise test result was considered, and to a residual diameter stenosis of 67% in each group when the presence of angina was considered. The corresponding sensitivities and specificities were 72% to 80%. Sensitivity and specificity curves as a function of minimal l u m e n diameter yielded the same results: points of intersection between the two curves were noted when considering angina at follow-up, with or without exercise-induced ST depression. The greatest accuracy, which lay between 75% and 84%, was

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Stent

Balloon

Value of AP ÷

Value of AP + 100

100

90

90 80

76%y

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Diameter stenosis (%)

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Value of AP + or ST + 180

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Fig. 2. Sensitivity (Sens) (x-axis) and specificity (Spec) (y-axis) for angina (AP+), exercise-induced ST depression (ST+), and recurrent angina or ST depression (AP+ or ST+) as function of various cut-off points for percentage diameter stenosis. Point of intersection of two curves denotes cut-off point with highest diagnostic accuracy.

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Table II. Points of intersection of sensitivity and specificity curves constructed for prediction of percentage diameter stenosis and minimal lumen diameter Percentage diameter stenosis at intersection point

AP+ ST+ AP+ or ST+ AP+ and ST+

Balloon

Stent

Balloon

Stent

67 NI 50 NI

67 NI 52 NI

76 NI 72 NI

80 NI 75 NI

Minimal lumen diameter at intersection point (mm) AP+ ST+ AP+ or ST+ AP+ and ST+

Maximum diagnostic accuracy* (%)

1.25 NI 1.5 NI

0.95 NI 1.35 NI

Maximal diagnostic accuracy* (%) 83 NI 75 NI

84 NI 77 NI

AP+, Recurrent angina; ST+, exercise-induced ST depression. NI, No intersection point between sensitivity and spedficity curves; ST+, exercise-induced ST depression.

*At intersection point, where sensitivity equals specificity.

Table III. Sensitivity, specificity, and positive predictive v a l u e of exercise testing and a n g i n a to predict >50% d i a m e t e r stenosis and <1.5 m m m i n i m a l l u m e n d i a m e t e r Restenosis >50%

Minimal lumen diameter <1.5 mm

Balloon

Stent

Balloon

Stent

(n = 40/153)

(n = 26/172)

(n = 37/153)

(n = 35/172)

40 57 70

46 54 73

43 68 78

37 49 63

83 86 73

89 87 78

84 88 75

89 88 79

46 42 48

43 59 37

46 64 50

46 51 43

Sensitivity (%) ST+ AP+ ST+ or AP+ Specificity (%) ST+ AP+ ST+ or AP+

Predictive value (%) ST+ AP+ ST+ or AP+

AP+, Recurrent angina; ST+, exercise-induced ST depression.

similar in patients with and without a stent and corresponded to a minimal lumen diameter of 1.35 and 1.50 mm for angina or ST depression and of 0.95 and 1.25 for angina alone. Comparison of diagnostic accuracy for patients with or without stent. Fig. 3 shows the receiver-operator

characteristic curves constructed for the comparison of the diagnostic accuracy of residual angina and exercise-induced ST depression, alone or in combination, in each group of patients (with or without stent). None of these comparisons showed any difference between the two groups of patients. Detection of restenosis. Greater than 50% diameter stenosis at follow-up was noted in 40 (26.1%) of the 153 patients without a stent and in 26 (15.0%) of the

173 patients with a stent (p < 0.02). The specificity of persistent angina or exercise-induced ST depression was high among patients with restenosis. Seventy percent and 73% of patients with restenosis had either angina or ST depression on exercise, but the sensitivity of exercise testing alone was only 40% and 46% and that of angina was 57% and 54%. Therefore the predictive value for restenosis is poor, <50% in each group of patients. Similar observations were made for the prediction of a residual minimal lumen diameter of <1.50 mm at follow-up. The sensitivity of recurrent angina was higher in the balloon-treated group (68% vs 49% in the stent-treated group), but this difference was not significant (Table III).

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Receiver Operator Curve

Receiver Operator Curve

Diameter Stenosis

Minimal Luminal Diameter Value of AP +

Value of AP +

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Balloon

---O.--Fig. 3. Receiver-operator characteristic curves for c o m p a r i s o n of diagnostic accuracy of r e c u r r e n t a n g i n a pectoris (AP+), exercise-induced ST depression (ST+), a n d r e c u r r e n t a n g i n a or exercise-induced ST depression (AP+ or ST+) for p e r c e n t a g e d i a m e t e r stenosis a n d m i n i m a l l u m e n d i a m e t e r i n p a t i e n t s w i t h s t e n t (Stent) or w i t h o u t s t e n t (Balloon).

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DISCUSSION Effect of stenting on exercise test performance, The

first observation made in this study is that the presence of an intracoronary stent does not affect the overall performance of exercise at follow-up examination. Although in the stent-treated group the angiographic result was significantly better (percentage stenosis: 35% _+ 14% vs 41% _+_15% in the balloon-treated group) and the proportion of patients with >50% stenosis was lower (15% vs 26% in the balloon-treated group), the maximal exercise load and duration and the maximal heart rate and blood pressure achieved during exercise were similar in the two groups of patients. Because the link between the physiologic consequences of a stenosis in an epicardial artery and its degree of obstruction is determined by a quadratic equation, 19-21 our observation implies that the lumen enlargement achieved by balloon angioplasty yields significant improvement in coronary flow reserve, up to an adequate level for maximal exercise. However, greater lumen enlargement, as obtained by stenting in the current study, is not followed by a significant improvement in exercise tolerance. However, this observation does not mean that maximal coronary flow reserve, as achieved by maximal pharmacologic coronary dilatation, is similar in patients with or without stent implantation. Thus the 0.10 mm difference in the absolute diameter, although associated with a significantly better anglographic appearance, does not result in significant improvement in exercise tolerance. Effect of stenting on the diagnostic value of angina and positive exercise test response, The second observa-

tion made in this study is that stenting does not affect the accuracy of clinical examination and exercise test evaluation. Although the predictive accuracy of angina and exercise testing was poor, as has been previously reported, 4-8 it is remarkable that the points of intersection of the sensitivity and specificity curves were virtually identical in patients with and without a stent (Fig. 2). This finding is corroborated by the comparison of the diagnostic accuracy with the receiver-operator characteristic curves (Fig. 3). The similarity of the two diagnostic accuracy curves for angina, ST depression, or both clearly demonstrates that intracoronary metallic stents are not accountable for angina related to their presence, nor are they responsible for specific ST-segment alterations during exercise. Thus the hypothesis that medial injury, which is often observed after stent implantation, 22 or a direct effect of the metallic stent on the endothelium 23 could alter endothelial function and favor dis-

February 1997 American Heart Journal

tal arteriolar constriction 24is not corroborated by our observations. Clinical status, exercise tolerance, and exercise test results were identical in patients with and without a stent. Conversely, the presence of a metallic stent cannot account for false-positive or false-negative interpretation of angina or exercise response. Detection of restenosis at the site of previous stenting or balloon angioplasty, Anginal symptoms and the re-

sults of exercise testing in follow-up had only a weak relation to restenosis in a population of patients without unstable angina (Table III). This finding confirms previous observations made in similar patient subsets with single-vessel disease treated with angioplasty. 4-s Because the prevalence ofrestenosis, as defined by >50% diameter stenosis, is low in this population, exercise testing and anginal complaints could not discriminate accurately between the presence or absence ofischemia on the basis of Bayes' theorem. 25, 26 In addition, the sensitivity of exercise testing is poor in patients with significant disease in one coronary artery. 27 These findings explain the low predictive value of exercise test and recurrent angina in our population. ST-segment depression on follow-up exercise testing has been reported in patients without restenosis after successful angioplasty for single-vessel disease in relation with the presence of hypokinesis before angioplasty in the territory supplied by the dilated artery 2s and in patients with variant angina. 29 Because the patients involved in this trial had stable angina, 12 it is unlikely that stunned myocardium or coronary spasm play a significant role in the mechanisms of the "false-positive" exercise test responses. Thus the pathophysiologic significance of ST-segment depression in the absence of restenosis is still unclear, although it may be related to functional alterations in small coronary vessels. 29, 30 Estimation of clinically significant narrowing. In this study, exercise test results were characterized by low sensitivity, which explains their low accuracy, as indicated by the absence of a point of intersection between the sensitivity and specificity curves. Recurrent angina was a more sensitive indicator of follow-up angiographic results than exercise-induced ST depression, as observed in previous studies. 6, 9, 27 Indeed, the best accuracy, as assessed by the intersection of the sensitivity and specificity curves, is found when recurrent angina is considered, alone or in combination with exercise test results. This approach yields a reasonable accuracy of 70% to 80%. From an angiographic point of view, the most accurate evidence of ischemia corresponded to coro-

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nary stenosis >52% or >50% and to a minimum lumen diameter <1.35 or <1.50 mm for patients with and without a stent when recurrent angina was considered in combination with the exercise test result. It corresponded to a stenosis >65% and a minimum lumen diameter <1.25 or <0.95 mm, respectively, when recurrent angina alone was considered (Table II). Our findings for angina combined with exercise response are close to those reported by Rensing et al., 9 who found that the angiographic cut-off point that best correlates with functional status a t follow-up after successful single-vessel angioplasty was 46.5% for the diameter stenosis and 1.45 mm for the minimal lumen diameter. The higher diagnostic accuracy of recurrent angina alone for restenosis is associated with a more severe degree of coronary stenosis than its combination with exercise test results. Therefore it is advisable to perform an exercise test to detect restenosis at a lower level of renarrowing (50% stenosis). The results of this test should be considered in combination with the clinical status of the patient to determine the probability of restenosis. Study limitations. The lack of disparity between the exercise test results in the two treatment groups does not reflect the better clinical outcome of patients treated with a stent. Indeed, the presence of clinical symptoms or ischemic signs requiring a second intervention at follow-up were substantially lower in the stent group (34 patients) as compared with the angioplasty group (59 patients) (p < 0.005). 12 Clinical evidence justifying catheterization and revascularization without the need for a n exercise test to substantiate ischemia objectively was more frequent in the angioplasty group (35 patients versus 20 patients, p < 0:05), which primarily explains the discrepancies between the clinical outcome and the exercise data presented in this study. If these patients had undergone an exercise test, they would have tipped the balance in favor of the stent group in terms of functional results and performance. In addition, because of a high probability of an abnormal ECG response during exercise, a higher accuracy of exercise ECG would be expected. Conclusions. Our results demonstrate that intracoronary stent implantation does not affect the accuracy of angina or exercise-induced ST depression at follow-up evaluation in the prediction of restenosis. Specifically, stenting is not associated with false-positive ST-segment depression. This study also reveals that the angiographic improvement in stenosis achieved by stenting at follow-up examination is not accompanied by further improvement in exercise tolerance. This observation suggests that

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the lumen enlargement produced by conventional balloon angioplasty is sufficient to increase coronary flow reserve for maximal exercise. O u r data show that the highest diagnostic accuracy for the prediction of the angiographic result is similar in patients with and without a stent. It is achieved by combination of the anginal status with exercise ECG results and corresponds to almost identical percentage stenosis of 52% and 50% in patients with and without a stent, respectively. Our findings also confirm the poor predictive value of angina or exercise-induced ST depression in the prediction of restenosis after angioplasty for single-vessel disease. REFERENCES

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13.

14.

15.

16.

17.

18.

19. 20.

21.

22.

23. 24.

25.

26.

27.

28.

29.

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February 1997 American Heart Journal

APPENDIX: BENESTENT STUDY GROUP

The following institutions and investigators participated in the Benestent Study. The number of patients enrolled at each center is given in parentheses. University Hospital San Carlos, Madrid, Spain (76): C. Macaya, F. Alfonso, J. Goicolea, R. Hernandez, A. Iniguez. University Hospital Rotterdam-Dijkzigt, Thoraxcenter, Rotterdam, The Netherlands (57): P.W. Serruys, P. de Jaegere, M.A. Morel, P.J. de Feyter, M. van den Brand. Onze Lieve Vrouwe Gasthuis, Amsterdam, The Netherlands (50): F Kiemeneij, G.J. Laarman, R. van der Wieken. Universiti~tsklinikum

Rudolf Virchow / Charlottenburg, Berlin, Germany (39): W. Rutsch. Onze Lieve Vrouwe Ziekenhuis, Aalst, Belgium (38): G. Heyndrickx, B. de Bruyne. Sahlgrenska Hospital, Goteborg, Sweden (36): H. Emanuelsson, P. Albertsson. Clinique Pasteur, Toulouse, France (32): J. Marco, J. Fajadet, S. Doucet, O. Bar. Centre Hospitalier Universitaire Sart-Tilman, Liege, Belgium (32): V. Legrand. Hopital de la Citadelle, Liege, Belgium (19): P. Materne, J. Boland. Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina (19): J. Belardi, J. Berrocal, R. Piraino. Royal Brompton, National Heart and Lung Hospital, London, United Kingdom (12): U. Sigwart, N. Buller, K. Priestley. Centro Cuore, Milano, Italy (11): A. Colombo, L. Maiello. CHUV, Lausanne, Switzerland (11): J.J. Goy, E. Eeckhout. Middelheim Ziekenhuis, Antwerpen, Belgium (10): P. van den Heuvel, F. van den Brande. Gregorio Maranon, Madrid, Spain (10): J. Delcan, E, Garcia. Ziekenhuis de Weezenlanden, Zwolle, The Netherlands (8): H. Suryapranata, J. Hoorntje. St. Antonius Ziekenhuis, Nieuwegein, The Netherlands (8): Th. Plokker, G. Mast. Hospital Maggiore, Trieste, Italy (8): S. Klugmann, E. Della Grazia, A. Salvi. Hopital Cantonal Universitaire, Gen~ve, Switzerland (7): P. Urban, E. Camenzind. Academisch Ziekenhuis Groningen, The Netherlands (6): P. den Heijer, R. van Dijk. Academisch Medisch Centrum, Amsterdam, The Netherlands (6): J. Piek, K. Koch. Christian Albrecht University, Kiel, Germany (6): R. Simon, F. Herrmann. Centre Cardiologique du Nord, Paris, France (5): M.C. Morice, T. Royer. James Hospital, Dublin, Ireland (5): P. Crean. Catharina Ziekenhuis, Eindhoven, The Netherlands (3): H. Bonnier, J. Koolen, F. Bracke. Cliniques Universitaires St. Luc, Universitd Catholique de Louvain, Bruxelles, Belgium (2): W. Wijns. CHUR, Nancy, France (2): N. Danchin, Y. Juilli re. Polyclinique Volney, Rennes, France (2): C. Bourdonnec.