Prognostic Value of DobutamineEchocardiography in Patients withIntermediate Coronary Lesions at AngiographyStefano Ciaroni, M.D., Antoine Bloch, M.D., Jacques Lars Hoffmann, M.D.,Marco Bettoni, M.D., and Dominique Fournet, M.D.

Cardiology Unit, Medical/Surgical Cardiovascular Department, Hopital de la Tour,Meyrin-Geneva, Switzerland

The prognostic value of dobutamine echocardiography (DOBU-ECHO) in patients with intermediatecoronary lesions has not been described in the literature. The aim of this study was to determine theprognostic value of DOBU-ECHO in patients presenting with coronary lesions smaller than 50% atangiography. Ninety-four consecutive patients were analyzed and followed-up for 64 6 7 months(range: 12 to 75 months). All patients presented with coronary lesions between $ 30% and , 50% ofthe luminal diameter of at least one major epicardial vessel. The patient population was divided intotwo groups: Those with a positive DOBU-ECHO (n 5 23) and those with a negative DOBU-ECHO(n 5 71). The number of coronary lesions did not differ between the two groups. The patients with apositive DOBU-ECHO result were more likely than those in the negative group to have a familyhistory of coronary artery disease or suffer from hypertension or a dyslipidemia. During the follow-upperiod, 13 cardiac events occurred (1 cardiac death, 5 myocardial infarctions, 2 unstable anginas,and 5 myocardial revascularizations), 11 (47.8%) of which occurred in patients with positiveDOBU-ECHO. The annual incidence for a cardiac event was 7.9% per year in the positive DOBU-ECHO group and 0.5% per year in the negative DOBU-ECHO group (P , 0.001). This incidenceremained signi�cant for spontaneous cardiac events, such as cardiac death, myocardial infarction,and unstable angina (5.8% per year vs 0.2% per year; P , 0.001). Conclusions. In patients withangiographically con�rmed intermediate coronary lesions, a positive DOBU-ECHO is an additionalrisk factor for the onset of a cardiac event, whereas a negative DOBU-ECHO can be used to de�nepatients with a low cardiac risk. (ECHOCARDIOGRAPHY, Volume 19, No. 7, Part 1, October 2002)

dobutamine echocardiography, coronary angiography, prognosis

Of those patients suffering from angina orwhose symptoms are indicative of coronary ar-tery disease, 4% to 30% will show nonsigni�-cant coronary lesions at angiography accordingto the de�nition criteria.1 Studies analyzingthe cardiac outcome in these patients havebeen based primarily on angiographic data.1

However, whereas coronary angiography isconsidered to be the reference method for as-sessing the severity of coronary atherosclero-sis, it is limited in this assessment since it canonly outline the contours of the arterial lu-men.2,3 At the same time, coronary heart dis-ease remains the primary cause of morbidityand mortality in industrialized countries, and

current forecasts are pessimistic. Coronary ar-tery disease is likely to become even more prev-alent in the future, particularly in those coun-tries lower down the socioeconomic scale thatare currently in the process of developing.Therefore, it is worthwhile to make every effortto improve targeting of those patients with car-diac risk factors, speci�cally through the use ofnoninvasive cardiological investigation tech-niques. To this end, the prognostic value ofstress echocardiography for coronary arterydisease has been investigated extensively.4,5

However, these studies have involved patientpopulations in whom coronary artery diseasewas already suspected or con�rmed clinically.By contrast, the prognostic value of DOBU-ECHO in patients with intermediate coronarylesions at angiography has not been describedin the literature.

The aim of this study was to determine the

Address for correspondence and reprint requests: StefanoCiaroni, M.D., Rue de l’Universite, 1, 1205 Geneva, Swit-zerland. Fax: 41-22-3208435

Reprinted with permission fromECHOCARDIOGRAPHY, Volume 19, No. 7, October 2002

Copyright ©2002 by Blackwell Futura Publishing, Inc.

549ECHOCARDIOGRAPHY: A Jrnl. of CV Ultrasound & Allied Tech.Vol. 19, No. 7, Part 1, 2002

prognostic value of DOBU-ECHO in patientsfound to have intermediate coronary lesions atangiography.

Methods

Population

Between January 1993 and March 2000, 617patients with suspected or con�rmed coronaryartery disease were assessed by DOBU-ECHOin our cardiology department. From this groupwe selected 94 consecutive patients who hadbeen investigated initially by coronary angiog-raphy for chest pain suggestive of coronaryheart disease but who had a negative cardiachistory of unstable angina, myocardial infarc-tion, or myocardial revascularization. We in-cluded only those patients with a stenosis $30% and , 50% of the luminal diameter of atleast one major epicardial vessel. The patientswere then referred by their physicians to ourechocardiography laboratory for DOBU-ECHObecause of a recurrence of angina symptomswithin 25 6 2 days of the invasive investiga-tion.

The population was divided into two groups.The �rst group was comprised of 23 patientswith a positive DOBU-ECHO result for myo-cardial ischaemia and the second consisted of71 patients with a negative DOBU-ECHO re-sult.

Coronary Angiography

Conventional angiography was performed byan experienced cardiologist, and the degree ofstenosis was analyzed visually. The lesion wasevaluated before and after the intravenous in-jection of nitroglycerine (100 –200 mg).

The diameter of the coronary epicardial le-sion did not vary in any patient during thenitroglycerine infusion. The ejection fractionwas calculated during the ventriculography.

DOBU-ECHO

DOBU-ECHO was performed according to aprotocol described previously6 and included theuse of atropine for cases when the heart ratefailed to accelerate suf�ciently (, 85% of themaximum theoretical heart rate according toage). The result was considered positive formyocardial ischemia in the event of the onset ofa segmental contraction abnormality and/orthe absence of myocardial wall thickening. A16-segment model was used for the analysis ofleft ventricular wall motion. The severity of the

contraction abnormality was calculated fromthe ratio of the total of the scores for eachsegment (1 5 normal, 2 5 hypokinesia, 3 5akinesia, and 4 5 dyskinesia) to the total num-ber of segments analyzed (wall-motion scoreindex). A 12-lead electrocardiogram was re-corded and blood pressure measured automat-ically at rest during the stress echo and for 10minutes after termination of the dobutamineinfusion. The patient’s drug treatment was notstopped before the test.

Data Collection and Follow-Up

The baseline clinical and laboratory datawere obtained from the medical records sup-plied by the patient’s doctor. All patients werefollowed up by their own doctors. The meanfollow-up period was 64 6 7 months (range: 12to 75 months). A cardiac event was de�ned asthe onset of cardiac death, a myocardial infarc-tion, unstable angina pectoris, or revascular-ization either by angioplasty or a bypass pro-cedure. Follow-up was terminated on the dateof the cardiac event and veri�ed by checkingthe patient’s case notes.

Statistical Analysis

Quantitative variables were expressed asmean 6 1 standard deviation and comparedusing an appropriate Student’s t-test and chi-square analysis for the data category. We usedthe Kaplan-Meier method to analyze the curvefor the incidence of cardiac events. The log-rank test was used for the intergroup compar-ison. The signi�cance level was set at P , 0.05.

Results

Population and Clinical Parameters

Patient characteristics are presented in Ta-ble I. Patients with a DOBU-ECHO 1 resultwere more likely than other patients to have afamily history of coronary heart disease and tosuffer from hypertension or dyslipidemia. Nopatient showed a wall-contraction abnormalityof the left ventricle at rest, nor was any differ-ence observed between the two groups in re-spect to systolic pressure at rest or at maxi-mum stress, or the frequency of atropine usefor obtaining maximum stress (5 [22%] of 23 vs19 [27%] of 71; P 5 NS). During the stressperiod, no patient showed a malignant ventric-ular arrhythmia, de�ned as a ventriculartachycardia of more than three complexes orthe repetition of isolated polymorphic ventric-

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ular extrasystoles. In the DOBU-ECHO-posi-tive group, the wall-motion score index at peakstress was 1.06 6 0.3 (range: 1.02–1.14).

Prognosis

During follow-up (Table II), 13 (13.8%) of the94 patients suffered a cardiac event, which wasbroken down as follows: Eleven (47.8%) of 23 inthe DOBU-ECHO-positive group and 2 (2.8%)of 71 in the DOBU-ECHO-negative group. One(4.5%) cardiac death occurred in the DOBU-

ECHO-positive group. Accordingly, the posi-tive predictive value for the onset of a cardiacevent was 44% while the negative predictivevalue was 97%.

Figure 1 shows the incidences for the onset ofa cardiac event in the two groups. The annualincidence for a cardiac event was 7.9% per yearin the DOBU-ECHO-positive group versus0.5% per year in the DOBU-ECHO-negativegroup (P , 0.001). This difference between thegroups remained statistically signi�cant (5.8%per year vs 0.2% per year; P , 0.001) for spon-taneous cardiac events (cardiac death, myocar-dial infarction, and unstable angina).

Drug Treatment During Follow-Up

During follow-up, no differences between thegroups were observed for platelet anti-ag-gregant (DOBU-ECHO-positive: 20 [87%] of 23vs DOBU-ECHO-negative: 61 [86%] of 71) orlipid-lowering treatments (DOBU-ECHO-posi-tive: 19 [83%] of 23 vs DOBU-ECHO-negative:54 [76%] of 71). DOBU-ECHO-positive patientswho did not suffer a cardiac event were morelikely to be taking beta blockers, with or with-out vasodilators, as compared to DOBU-ECHO-negative patients (11 [92%] of 12 vs 12[17%] of 71, P , 0.01). No other difference wasnoted between the two groups regarding use ofangiotensin-II antagonists, angiotensin-con-verting enzyme inhibitors, or diuretics. Amongthe female patients, the incidence of hormonereplacement therapy was identical in bothgroups (DOBU-ECHO-positive: 5 [50%] of 10 vsDOBU-ECHO-negative: 14 [48%] of 29, P 5 NS).

Discussion

To our knowledge, this is the �rst study todemonstrate that coronary lesions smallerthan 50% at angiography are associated withan unfavorable cardiac outcome when DOBU-ECHO reveals a positive response to ischemia.In other words, a positive DOBU-ECHO for

TABLE I

Patient Characteristics

DSEPositiven 5 23

(%)

DSENegativen 5 71

(%)

Age (year) 63 6 4 64 6 3Female/male 10/13 29/42BMI (Kg/m2) 26 6 1.5 25 6 2Typical chest pain 5 (22) 11 (15)Atypical chest pain 18 (78) 60 (85)Family history of CAD* 15 (65) 9 (13)Diabetes mellitus 4 (17) 12 (17)Hypertension* 17 (74) 13 (18)Cigarette smoking 5 (22) 28 (39)Dyslipidemia* 14 (61) 11 (15)ECG at rest:

ST-T abnormal 10 (43) 39 (55)RBBB 3 (13) 15 (21)ST-T depression during stress 1 (4) 4 (6)Chest pain during stress 3 (13) 9 (13)

No of CA narrowed $ 30% and,50% in diameter:One vessel 15 (65) 53 (75)Two vessels 7 (30) 18 (25)Three vessels 1 (5) 0EF at angiography 66 6 2 67 6 3

*P , 0.01. DSE 5 dobutamine stress echocardiography;BMI 5 body mass index; CAD 5 coronary artery disease;ECG 5 electrocardiogram; RBBB 5 right bundle branchblock; EF 5 ejection fraction.

TABLE II

Cardiac Events at Follow-Up

Death (%) MI (%) UAP (%) PTCA (%) CABG (%) Total Events (%)

Total patients (n 5 94) 1 (1) 5 (4.2) 2 (2.1) 3 (3.2) 2 (2.1) 13 (13.8)DSE positive n 5 23 1 (4.3) 5 (17.4) 1 (4.3) 2 (8.7) 2 (8.7) 11 (47.8)*DSE negative n 5 71 0 0 1 (1.4) 1 (1.4) 0 2 (2.8)

DSE 5 dobutamine stress echocardiography; MI 5 myocardial infarction; UAP 5 unstable angina pectoris; PTCA 5percutaneous transluminal coronary angioplasty; CABG 5 coronary artery bypass graft. *P , 0.001.

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myocardial ischemia does not necessarily cor-respond to a false-positive result7 but is anindication of the presence of myocardial isch-emia.

Several factors need to be clari�ed when ex-plaining these results. First, the evaluation ofthe ischemic impact of coronary lesions poses adelicate problem in clinical cardiology practicebecause quantitative angiography only pro-vides a geometrical presentation of the lesionswithout taking into account the actual isch-emic impact.7,8 For example, studies have dem-onstrated clearly that coronary reserve playsan important role in myocardial perfusiondownstream of the intermediate coronary le-sion detected at angiography.9,10 Similarly, in-vestigation of the morphology of a coronarylesion by endocoronary ultrasonography hasshown that angiography can underestimatethe lesion.2 This partly explains the frequentdiscrepancies between the functional status ofthe coronary disease on the one hand and theangiographic presentation of the parietal ath-eromatous lesion on the other, and the conse-quent inability to predict its future progres-sion.3 In addition, nor can the possibility beruled out that certain patients with a positiveDOBU-ECHO also are suffering from impairedmyocardial microcirculation associated withepicardial coronary lesions, which would be are�ection of more extensive ischemic disease.11

Another aspect to consider is the progressionof coronary artery disease,12 which can be illus-trated to a certain extent by patients who haveundergone revascularization by angioplasty ora coronary bypass. In this population, thosesuffering a higher incidence of complicationsare more likely to be hypertensive or presentwith abnormal lipid levels or a family history ofcoronary heart disease. Consequently, despite

optimal management of the in�uenceable riskfactors, the hereditary factor continues to af-fect the onset of spontaneous events.13 The fa-vorable cardiac progression of those patientswith a positive DOBU-ECHO result could beexplained in various ways. First, it is possiblethat the initial coronary lesions progressed andthat a collateral circulation developed in par-allel.14,15 Second, the lipid-lowering antihyper-tensive and platelet anti-aggregant treatmentcould have had a bene�cial effect on the pro-gression of the coronary lesion in terms of sta-bilization or regression. To this can be addedthe bene�t of the beta blocker treatment, whichwas received by a higher proportion of patientswith a positive DOBU-ECHO result. This couldexplain the low rate of cardiac death observedin this group of patients as compared with pre-vious angiographic studies.1,12 Finally, many ofthe patients analyzed presented with a lesionin a single coronary vessel and normal systolicfunction at rest, and could therefore be consid-ered to have a better prognosis in terms ofmortality.

The other interesting point in our study isthat a negative DOBU-ECHO result offershigh negative predictive value concerning theonset of a cardiac event in the presence of in-termediate coronary lesions. In this group, theannual incidence for the onset of a cardiacevent was 0.6% per year with no deaths. Thisgood predictive power is comparable with thatreported in patients investigated by DOBU-ECHO4,5 for clinically suspected coronary ar-tery disease. Thus, DOBU-ECHO allows amore accurate assessment of the future cardiacrisk, in addition to the clinical data and man-agement of in�uencing risk factors, in this pop-ulation of patients with intermediate coronarylesions at angiography.

Study Limitations

A methylergometrine test for eliminating apossible vasospastic reaction during angiogra-phy was not conducted. In our own everydayexperience, this test is not performed routinely,in contrast with the practice reported by otherteams.16 In our own investigation, however, thecoronary lesions were evaluated before and af-ter an intravenous injection of nitroglycerine,and no changes were noted in the diameter ofthe coronary lesion. In any case, a vasospasticreaction of the vessel during DOBU-ECHOcannot be ruled out either, even though thisseems rather unlikely in our population since

Figure 1. Cardiac event curves.

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on the one hand all the contraction abnormal-ities of the left ventricle occurred only duringthe dobutamine infusion and on the other, nocorrelation was apparent between the changein the ST segment on the electrocardiogramand the thoracic symptoms.17

Conclusions

Our study has demonstrated that a positiveDOBU-ECHO result in association with inter-mediate lesions at angiography is an indica-tion of ischemic disease with a risk of cardiaccomplications and, therefore, deserves carefulpatient management. In this situation, an eval-uation of the coronary reserve and/or endocoro-nary ultrasonography are useful complemen-tary investigations in determining the appro-priate drug treatment or invasive technique forstabilizing the atheromatous lesion at an ear-lier stage. Our study also shows that a negativeDOBU-ECHO result can be used to identifythose patients with an intermediate coronarylesion with a low, long-term cardiac risk inrelation to the management of the various riskfactors that can be in�uenced by treatment.

Acknowledgments: We thank Drs. P.C. Fournet, P.H. Ur-ban, and P. Schopfer, who manage the cardiac catheteriza-tion unit at Hopital de la Tour, for their help in implement-ing this study.

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