Dobutamine Stress Magnetic Resonance Imaging for Detection ofCoronary Artery DiseaseF. PAUL VAN RUGGE. MD, ERNST E . VAN DER WALL, MD, FACC,* ALBERT DE ROOS, MD,ALBERT V. G . BRUSCHKE, MD, FACC
Leiden, The Netherlands
Objectives. The clinical value of cine magnetic resonanceimaging (MRI) during dobutamine stress for detection of coronaryartery disease was evaluated in 45 patients with chest pain whowere admitted for coronary arterlography .
Background. Development of stress-induced wall motion asyn-ergy is considered an early and reliable sign of myocardialischemia preceding electrocardiographic (ECG) changes and an-gina. As physical exercise during MRI is difficult because ofmotion artifacts and space restriction, dobutamine infusion wasused to induce cardiovascular stress .
Methods. Clue MRI tomograms were obtained in six adjacentshort-axis planes. After baseline acquisition, dobutamine wasadministered to a maximal dose of 20 pglkg per min. Both at restand during peak dobutamine stress, magnetic resonance imageswere displayed in a cinematographic loop to assess regional wallmotion qualitatively . Results of dobutamine MRI were consideredpositive for coronary artery disease if any new or worsening mailmotion abnormality developed. Immediately after MRI at peak
Exercise stress testing is commonly used to demonstratemyocardial ischemia in patients with suspected coronaryartery disease. However, ST segment depression and anginaare rather late manifestations of myocardial ischemia . Theoccurrence of wall motion abnormalities has been consid-ered an early and sensitive marker of myocardial ischemia,preceding the development of ST segment depression andanginal symptoms (1-3) . Therefore, it is invaluable to de-velop reliable imaging methods for assessing accuratelyregional left ventricular function . Magnetic resonance imag-ing (MRI) is a noninvasive tomographic technique thatprovides a three-dimensional data set with high spatialresolution, allowing assessment of left ventricular dimen-sions independently of geometric assumptions (4,5) . Gradi-
From the Departments of Cardiology and Radiology, University HospitalLeiden and *Inleruniversity Cardiology Institute of The Netherlands,Utrecht, The Netherlands . This study was supported in part by Grant 96.076from The Netherlands Heart Foundation, The Hague. The Netherlands.Dobutamine was provided by Eli Lilly Company, Nieuwegein . The Nether-lands .
Manuscript received October 12, 1992 ; revised manuscript receivedDecember 29, 1992, accepted January 7. 1993 .
Address for corresoondence : F. Paul van Rugge. MD. Department ofCardiology. University Hospital Leiden, Building 1 . C5-P, Rijnsburgerweg 10,2333 AA Leiden, The Netherlands .
01993 by the American College cf Cardiology
dobutamine infusion, dobutamine electrocardiography was per-formed outside the magnetic environment . In addition, all patientsperformed symptom-lih.ited exercise electrocardiography.
Results. Significant coronary artery disease (>50% diameterstenosis) was present in 37 patients. During peak dobutaminestress, wall motion asynergy developed or worsened in 30 tients,yielding an overall sensitivity for detectioc of coronary arterydisease of 81% and a specificity of 100% . Corresponding datawere 51% and 63% for dobutamine electrocardiography and 70%and 63% for exercise electrocardiography . The sensitivity ofdobutamine MRI for the detection of coronary artery disease inpatients wilts single-, double- and triple-vessel disease was 75%(15 of 20 patients), 80% (8 of 10) and 100% (7 of 7), respectively .
Conclusion. Dob, .amine MRI is an accurate nonexercise-dependent method for the assessment of myocardial ischemia inpatients with coronary artery disease.
(J Am Coil Cardiol 1993;22 :431-9)
431
ent echo (cine) sequences provide improved temporal reso-lution to identify end-diastole and end-systole in theevaluation of ventricular function (6,7) . Accurate endocar-dial border delineation is facilitated by the inherent contrastbetween the moving blood pool and the relatively stationarymyocardial wall. The value of cine MRI in detecting abnor-malities in regional (8) and global (9) left ventricular functionhas been shown previously . Several studies (10-12) usingtine MRI have reported accurate measurements of leftventricular volumes and ejection fraction that correlatedwell with data obtained by cine ventriculography and two-4imensional echocardiography . Space restriction and motionartifacts preclude performance of physical exercise duringMRI. Consequently, alternatives to dynamic exercise arerequired in the assessment of coronary artery disease withMRI (13) . It has been demonstrated experimentally (14) thatdobutamine is an effective pharmacologic stress agent toinduce wall motion abnormalities. Several studies (15-20)have reported the accuracy of dobutamine stress in combi-nation with two-dimensional echocardiography in detectingcoronary artery disease .
This study was designed to determine the accuracy ofdobutamine stress in conjunction with tine MRI for thediagnosis of coronary artery disease in patients admitted for
0735-10971931$600
432
VAN RUGGE ET AL .DOBUTAMINE ME IMAGING
coronary angiography and the assessment of patient toler-ance of this approach .
Methods
Study patients. We screened 50 consecutive patients whowere admitted for elective coronary arteriography for eval-uation of suspected coronary artery disease . Patients withatrial fibrillation, a pacemaker, claustrophobia, cerebral vas-cular clips, heart failure, unstable angina, known ventriculararrhythmias, hypertrophic cardiomyopathy, valvular heartdisease and uncontrolled hypertension were excluded . Twopatients were excluded because of unacceptable baselineMRI tomograms. Three patients who demonstrated claustro-phobia during baseline MRI acquisition did not receivedobutamine infusion and were also excluded from the study .The remaining 45 patients (36 men and 9 women [mean age61 ± 9 years, range 43 to 74]) underwent dobutamine stressMRI followed by dobutamine electrocardiography, coronaryarteriography and exercise stress testing in random orderwithin 2 weeks. All patients were in sinus rhythm and all hada history of exertional chest pain . Eleven patients had ahistory of previous myocardial infarction (postinfarctiontime >6 months). Beta-adrenergic blocking agents werediscontinued 48 h before both dobutamine and exercisestress tests . Nitrates and calcium antagonists were not takenthe day of the test. The study protocol was approved by thehosp::al Ethics Committee on Human Research and in-formed consent was obtained from each patient .
Cardiac catheterization . Coronary angiography and bi-plaea tine ventriculography were performed according tothe Judkins technique. Multiple views of each coronaryartery were obtained . All angiograms were analyzed by twoindependent observers who were unaware of the clinicaldata. Coronary artery narrowings were expressed as percentdiameter stenosis. Significant coronary artery stenosis wasdefined as >50% lumen narrowing of a major epicardialcoronary artery or major branch vessel .
Dobutantine stress protocol. Before the MRI procedure,an intravenous cannula was inserted into the antecubital veinof the right arm and flushed with heparin to prevent coagu-lation. Dobutamine was administered intravenously by anIVAC syringe pump that was placed outside the magneticenvironment and connected by means of a long line with thecannula, which was primed with dobutamine solution. Afterthe baseline magnetic resonance images were obtained,dobutamine was infused at an initial rate of 5 pg/kg per min,followed by an incremental regimen of 5 pg/kg per min every2 min. The time to reach steady state at peak infusion ratewas 14 ± 2 min after the start of the infusion . Cine MRI wasperformed at baseline and at the maximal infusion rate of20 pg/kg per min. The dobutamine infusion was discontinuedwhen any of the following criteria for termination occurred :1) significant side effects (chest pain, arrhythmia, dyspnea orother intolerable symptoms) ; 2) systolic blood pressure>220 mm Hg or a decrease >20 mm Hg ; 3) diastolic blood
Dobutamlne Infusion
JACC Vol . 22, No. 2August 1993:431-9
40 min
2 4 6 8 10 12
20 minI
I
I10 is 20 Par.0
Baseline
StressMRI
MRI + ECG
Figure 1. Time diagram of the dobutamine infusion protocol, base-line and stress magnetic resonance imaging (MRI) protocol . Imme-diately after stress MRI, an electrocardiogram (ECG) was takenoutside the magnetic environment .
pressure >110 mm Hg ; 4) achievement of the target heartrate (85% of the age-predicted maximal heart rate) ; and 5)maximal infusion rate of 20 µg/kg per min. Intravenousmetoprolol (1 mg/ml) was available to treat side effects .Blood pressure was recorded by an automatic device(Physio-Control) on the left arm every minute during infu-sion.
Clue magnetic resonance imaging. Cine MRI was per-formed at a magnetic field strength of 1 .5 tesla using aGyroscan superconducting magnet (Philips Medical Sys-tems). The electrocardiographic (ECG) signal was recordedsimultaneously and transmitted by telemetry to a remotereceiver (Hewlett-Packard) to trigger the acquisition accord-ing to the R wave . The shortest possible trigger delay was8 ms after the R wave of the ECG. Images triggered by theECG were acquired in the true short-axis plane of the heart,which was derived from coronal and sagittal scout views,followed by double-oblique angulation . Cine MRI was per-formed using a flow-compensated gradient echo sequence(repetition time [TR] 30 ms, echo time [T E] 13 ms, excitationangle 30). Six contiguous slices were taken with a thicknessof 10 mm, starting at the basal level, and each slice wasimaged separately . The acquisition matrix was 128 x 256 andwas interpolated to 256 x 256 for display purposes . The fieldof view was 350 mm and four acquisitions were averaged toimprove signal to noise ratio. The number of sequentialframes per cardiac cycle corresponded to the number of 30°pulses delivered within one RR interval . Accordingly, with aheart rate of 60 beats/min, the RR interval was 1,000 ms andcomposed of 30 time frames (RR interval/TR) because thefinal 100 ms of the diastole could not be imaged . The imagingtime for one total baseline acquisition was 42 ± 4 min . Theincrease in heart rate caused by dobutamine reduced theimaging time during stress to 24 ± 6 min (Fig . 1) .
Electrocardiography during exercise stress and dobu-tamine Infusion. Immediately after completion of the dobu-tamine MRI protocol, the dobutamine infusion was contin-ued and a 12-lead ECG was taken outside the magneticenvironment .
In addition, all patients performed a multistage upright
JACC Vol . 22, No. 2August 1993 :431-9
M
Li Left Anterior Descending distribution
Right Coronary Artery distribution
Left Circumflex distribution
Figure 2. Schematic representation of six adjacent short-axis levelsfrom base (top) to low left ventricular level (bottom) with regions ofcoronary artery distribution ; I = septal ; 2 = anteroseptsl ; 3 =anterior ; 4 = lateral ; 5 = posterolateral; 6 = posterior .
bicycle ergometer test with an initial load of 25 W andincrements of 25 W every 2 min . A 12-lead ECG and bloodpressure were recorded at baseline and thereafter every2 min during exercise . Criteria for termination of the testwere severe angina, limiting dyspnea or fatigue, >20 mm Hgdecrease in systolic blood pressure, >2 mm ST segment shiftor arrhythmias (atrial fibrillation, atrial flutter or other formsof supraventricular tachycardia and ventricular tachycar-dia). Both exercise and dobutamine stress ECGs were con-sidered positive for ischemia when > 1 mm of horizontal ordownsloping ST segment depression 80 ms after the J pointin any lead occurred during three consecutive beats .
Analysis of due magnetic resonance images. Magneticresonance tomograms were analyzed independently by twoobservers who had no knowledge of the patient's history,results of stress electrocardiography or coronary angiogra-phy. Disagreement in interpretation was resolved by consen-sus. Initially, at each level the short-axis images weredisplayed in a cinematographic format to visualize the con-traction pattern through the cardiac cycle . The imagesobtained at 8 ms after the R wave on the ECG wereconsidered to represent end-diastole and the images with thesmallest lumen area gr the thickest wall, or both, wereconsidered to represent end-systole .
For purposes of wall motion analysis, short-axis imageswere divided according to the vascular distribution of themajor epicardial coronary arteries (Fig . 2). The septal,anteroseptal and anterior segments were considered specificfor the left anterior descending coronary artery distributionand the lateral region for the left circumflex coronary arterydistribution, whereas the posterolateral and posterior areas
VAN RLJGGE ET AL.
433DOBUTAMINE MRI IMAGING
were regarded as the territory of the left circumflex or rightcoronary artery depending on dominance of the right coro-nary artery . Wall motion at rest was classified in eachsegment as normal . hypokinetic, akinctic or dyskinetic usingcriteria that rely on both inward endocardial wall motion andsystolic wall thickening . A normal response to dobutamineinfusion was defined as hyperdynamic motion, consisting ofincreased inward endocardial motion with enhanced systolicwall thickening. A response to dobutamine infusion wasconsidered positive for coronary artery disease when one ofthe following criteria were met at any level : 1) in patientswithout wall motion abnormalities at rest, development ofnew wall motion asynergy at any region during dobutaminestress; 2) in patients with wall motion abnormalities at rest,stress-induced worsening of a wall motion abnormality atrest, which was defined as wall motion deteriorating fromhypokinesia to akinesia or dyskinesia, spreading of a wallmotion abnormality at rest to a contiguous segment withinthe distribution of the same coronary artery or developmentof aiiy new wall motion abnormality in a region demonstrat-ing normal baseline contraction .
Statistical analysis. Data are presented as mean value ± ISD. The sensitivity, specificity and predictive accuracy fordobutamine electrocardiography, dobutaminc MIDI and ex-ercise electrocardiography, respectively, are estimated withthe associated 95% confidence intervals .
The hemodynamic alterations during dobutamine andexercise stress were analyzed by two-way analysis of vari-ance with repeated measures . Discrete variables were com-pared by chi-square analysis. A p value < 0.05 was consid-ered statistically significant .
Results
Cardiac catheterization. The artgtographic data are listedin Table 1 . Eight patients had no coronary artery disease .Significant coronary artery disease (>50% diameter steno-sis) was present in 37 patients (82%) : 20 patients withsingle-vessel, 10 with double-vessel and 7 with triple-vesseldisease. No patient had left main coronary artery disease .Eleven patients demonstrated wall motion abnormalities at
rest during biplane ventriculography.Ilemodynamic responses to dobutamine and exercise stress
(Tables 1 and 2). The responses of the hemodynantic vari-ables to dobutamine infusion and exercise stress tecting arepresented in Table 2 . There were: no significant differencesbetween patients without or with coronary artery diseasewith respect to heart rate, systolic blood pressure, diastolicblood pressure and rate-press - : ;i, product for each of thethree conditions (rest, dobutamine stress, exercise stress :p > 0.09). Heart rate, systolic blood pressure and rate-pressure product were significantly different among the threeconditions: heart rate, systolic blood pressure and rate-pressure product increased significantly (p < 0 .001) in allpatients during bath exercise and dobutamine . Moreover,during peak dobutarnine stress, the mean maximal heart rate
'The worst grade of wall motion asynergy is depicted . A = anterior, Ak = akinesia: AS = anteroseptal ; CAD = coronary artery disease ; Dk = dyskinesia;ECG = electrocardiogram : F = female; Hk = hypokinesia ; HR = heart rate (beats/min) ; L = lateral ; LAD = left anterior descending coronary artery ; LCx =left circumflex coronary artery ; M = male; Max = maximal; MR[ = magnetic resonance imaging ; P = posterior ; PL = posterolateral ; Pt = patient ; RCA = rightcoronary artery ; RPP = rate-pressure prod""ct (mm Hg/min) ; S = septal ; SBP = systolic blood pressure (mm Hg) ; WMA = wall motion abnormality ; - _negadvelabsent; + = positive/present .
434 VAN RUGGE ET AL.DOBUTAMINE MRI IMAGING
JACC Vol. 22, No. 2August 1993-431-9
Table I . Clinical Data and Results of Coronary Angiography, Exercise Electrocardiography, Dobutamine Electrocardiography andDobutamine Magnetic Resonance Imaging
Dobutamine MRI
Pt Age (yr)l
Nu. and Type of
Rest
Exercise
Dobutamine Max Max Max
Wall Motion Abnormality
No. Gender
Diseased Vessels
WMA
ECG
ECG HR SHP RPP
+l- Site Type*
Patients Without CAD
I 601M
0 109 170 18,530
2 63/M
U
+ 125 152 19,000
3 491M
0
+ 112 157 17,584
4 67/M
0
+
+ 124 175 21,700
5 531F
0
- 118 164 19,352
6 69/24
0 111 181 20,091
7 61/F
0
+ 116 164 19,024
8 56117
0
+ 96 179 17,184
Patients With CAD
9 65124
I LAD 107 162 17,334
l0 58/M
I LAD
- I15 173 19.895
-II 431M
I LAD
+ 120 166 19,920
+ S Ak12 721M
I LAD 93 145 13.485
+ SIAS Ak13 651F
I LAD
+ 142 144 20,449
+ S/AS Hk14 791M
I LAD
+ 121 174 21,054
+ S/AS Ak15 531M
1 LAD
+
+ 128 181 23,168
+ S Hk16 66/M
I LAD
+ 1I6 169 19,604
+ AS Ak17 551F
I LAD
+
+ 112 182 20,39418 52/M
I LCx
+
+ 105 198 20,790
+ IJPL Ak19 75/M
I LCx
+
+ 128 137 17,536
+ PUP Ak20 52124
I LCx
+ 111 183 20.313
+ L Ak21 721M
I LCx
+
+ 107 167 17,869
+ PLIP Hk22 571M
1 LCx 120 158 18,96023 44/24
1 LCx
+
+ 118 159 18,762
+ P Hk24 701M
I LCx
+
+ 105 198 20,790
+ L Hk25 74124
I LCx
+ 114 138 15,732
+ PUP Ak26 SLIM
1 RCA
+
+ 98 168 16,46427 48/F
I RCA
+
+ 126 172 21,672
+ P Hk28 601M
I RCA
+
+ 120 158 18,960
+ P Dk29 64/M
2 LAD, LCx
+
+
+ 136 143 19.448
+ AIL Ak30 64/24
2 LAD, LCx
+
+ 125 142 17,750
+ PIS ilk31 631F
2 LAD, LCx 119 160 19,040
+ S Hk32 66124
2 LAD, LCx
+
+ 125 179 22,375
+ AS/A/L Ak33 511F
2LAD, LCx
+ 127 149 18,92334 62/M
2LAD, RCA
+ 107 204 21,828
+ AS Hk35 74/M
2LAD, RCA
+
+ 130 157 20,410
+ PIS Hk36 67/M
2 LAD, RCA
+ 109 168 18,312
+ P/S Ilk37 74/F
2LAD, RCA
+ 112 157 17,584
-38 60/24
2 RCA, LCx
+
+
+ 120 207 24,840
+ L/PLIP Ak39 60/24
3
+ 120 202 24,240
+ P/S/AS Hk40 S7iM
3
+
+
+ 103 196 20,188
+ AS/AJL Ak41 501M
3
+
+ 120 180 21 .600
+ A/LIP Hk42 53/24
3
+
+
+ 130 167 21,710
+ LIP/S Ak43 66/24
3
+ I15 183 21,045
+ At/P Ak44 59/24
3
+
+ 115 167 19,205
+ P/LIA Ak45 621M
3
+
+ 107 173 18,511
+ P1S Dk
JACC Vol. 22, No. 2August 1993 :431-9
Table 2. Mean Hemodynamic Alterations During Exercise andDobutamine Stress
$p < .3.001 versus rest and exercise . tp = NS versus rest and exercise.Values are expressed as mean value ± SD .
(116 ± 10 vs. 133 ± 12 beatsimin, p < 0.001), maximalsystolic blood pressure (169 ± 18 vs. 188 ± 20 mm Hg, p <0.001) and maximal rate-pressure product (19,613 ± 2,137vs. 24,833 ± 3,648 mm hg/min, p < 0.001) were lower thanduring exercise . Diastolic blood pressure did not changesignificantly during dobutamine stress or exercise. Threepatients did not achieve I . heart rate >100 beats/min at peakdobutamine stress .
Dobutamme magnetic resonance imaging (Tables I to 4).The results of cine MRI imaging during dobutamine stressarc presented in Table I . The MRI quality during dobu-tamine stress was good in all 45 patients, allowing qualitativewall motion analysis (F." . 3 and 4) . The normal response todobutamine stress was increased reward endocardial wallmotion with enhanced systolic wall thickening (hyperkine-sia). Eleven patients demonstrated wall motion abnormali-ties at rest that either deteriorated further or spread to acontiguous segment during peak dobutamine stress ; all haddocumented myocardial infarction . Nineteen patients with-out wall motion asynergy at rest developed new wall motionabnormalities during dobutamine stress indicating the pres-ence of coronary artery disease . Thus, dobutamine MRIresults were positive in 30 of 37 patients with provedcoronary artery disease, yielding an overall sensitivity of81% (associated 95% confidence interval [CI] 65% to 92%)(Table 3). The zest result was negative in all patients withoutcoronary artery disease (specificity 100%, 95% CI 63% to100%) and the predictive accuracy of the test was 84% (95%
Table 3. Sensitivity, Specificity and Predictive Accuracy ofDobutamine Magnetic Resonance Imaging (MRI), rwbutamineElectrocardiography and Exercise Electrocardiography forDetection of Coronary Artery Disease
*p < O.Oi versus dobutamine electrocardiography . t p = NS versusdobutamine magnetic resonance imaging and dobutamine electrocardio-graphy. Data indicate number of patients and, in parentheses, percentsensitivity, specificity or accuracy .
VAN RUGGE ET AL .DOBUTAMINE MRI IMAGING
Table 4. Sensitivity of Dobutamine Stress Magnetic ResonanceImaging (MRI), Dobutamine Electrocardiography and ExerciseElectrocardiography for Detecting One-, Two- and Three-VesselCoronary Artery Disease
435
Data indicate number of patients and, in parentheses, percent sensitivity .
Cl 71% to 94%) . The sensitivity for detecting coronaryartery disease in patients with single-vessel disease was 75%(15 of 20 patients, 95% CI 51% to 91%), 80% (8 of 10, 95% CI44% to %) for double-vessel disease and 100% (7 of 7, 95%Cl 59% to 100%) for triple-vessel diseasr. (Table 4) .
Electrocardiographic responses to dobutamine and exercisestress (Tables 3 and 4) . During peak dobutamine stress,ischemic ST segment depression was induced in 19 patientswith coronary artery disease and three patients with normalcoronary arteries, yielding a sensitivity and specificity fordetection of coronary artery disease of 51% (95% Cl 34% to68%) and 63% (95% CI 25% to 92%), respectively. Thesensitivity for detecting coronary artery disea in patientswith single-, double- and triple-vessel disease was 45% (95%
Figure 3 . Baseline (upper row) and dobutamine stress (lower row)tine magnetic resonance imaging tomograms at end-diastole (leftca uana) and end-systole (right column) in a patient with significantright coronary artery stenosis . The baseline contraction pattern isnormal with homogeneous systolic wall thickening (upper right
paiel), but at peak dobutamine stress the posterior wall fails todemonstrate systolic wall thickening (lower right panel, arrow) .
Figure 4. Baseline (upper raw) and dobutamine stress (tower row)cine magnetic resonance imaging tomograms at end-diastole (leftcolumn) and end-systole (right column) in a patient with significantleft anterior descending coronary artery stenosis . The baselinecontraction pattern is normal with homogeneous systolic wall thick-ening (upper right panel), but at peak dobutamine stress the an-teroseptal wall fails to demonstrate systolic wall thickening (towerright panel, arrows) .
CI 23% to 69%),50%(95% CI 19% to 8l%) and 71% (95% CI29% to 96%), respectively .
Exercise ECG demonstrated a sensitivity and specificityfor detecting coronary artery disease of 70% (95% CI 53% to84%) and 63% (95% CI 25% to 92%), respectively . Thesensitivity for detecting single-, double- and triple-vesseldisease was 60% (95% CI 36% to 81%), 80% (95% CI 44% to98%) and 86% (95% CI 42% to 100%), respectively .
Stile effects and tolerance to dobutamine stress. Duringdobutamine infusion, all side effects were transient andreversed rapidly after termination of the infusion. No patientrequired administration of metoprolol . Chest pain developedin 9 (20%) of 45 patients with dobutamine stress comparedwith 20 (44%) of 45 patients during exercise stress testing(p < 0.005). Dobutamine-induced chest pain was controlledby reducing the infusion rate, and no patient needed admin-istration of sublingual nitroglycerin . All patients with dobu-tamine-induced chest pain had significant coronary arterydisease and demonstrated ischemic ST segment depressionduring dobutamine electrocardiography immediately afterthe cine MRI. Arrhythmias were seen in 6 (13%) of 45patients, of whom 5 had frequent ventricular prematurecomplexes. One patient demonstrated accelerated idioven-tricular rhythm and this event was considered to be anindication for premature termination of dobutamine infusion ;thereafter the arrhythmia rapidly resolved . Thus, 35 patientstolerated the peak dobutamine infusion rate well . No patient
JACC Vol . 22, No . 2August 1993 :431-9
developed ventricular tachycardia (defined as three or moreconsecutive ventricular premature complexes), hypotensionor dyspnea . I tt ,~ most common noncardiac side effects wereflushing (32%), headache (18%), tingling (7%), nausea (4%),chills (3%) and tremors (3%) .
DiscussionThe present study demonstrates that in patients with
coronary artery disease, dobutamine infusion can induceregional wall motion abnormalities that can be detected bycine MRI. The data also indicate the patient tolerance andsafety of this approach .
Importance of regional wall motion. Assessment of leftventricular function is clinically important for the diagnosisand management of patients with suspected ischemic heartdisease . It has been well established that stress-inducedimpairment of regional left ventricular function is an earlyand reliable sign of coronary artery stenosis (1-3) . In pa-tients with known coronary artery disease, analysis of re-gional left ventricular function plays a prominent role indetermining the therapeutic strategy, evaluating the efficacyof the chosen therapy and assessing prognosis . A decrease inglobal left ventricular ejection fraction frequently indicatessevere and extensive myocardial ischemia . However, in thepresence of less severe ischemia, compensatory hyperfunc-tion in nonischemic myocardium may produce a normalglobal ejection fraction that limits the potential of Lhe ejec-tion fraction to detect regional ischemia (21,22) . Therefore,analysis of regional wall motion would hate importantclinical value to assess the presence, site and severity ofcoronary artery disease .
Diagnostic value of dobutamine stress magnetic resonanceimaging . Our results suggest that dobutamine stress withcine MRI is feasible, safe and accurate for the diagnosis ofcoronary artery disease . Stress-induced wall motion abnor-malities were observed in 30 of 3" patients with angiograph-ically proved coronary artery disease, yielding an overallsensitivity of 81%, with a sensitivity of % for detectingmultivessel disease . The test yielded negative results in eightof eight patients without coronary artery disease, resulting ina specificity of 100%. The value of dobutamine in detectingcoronary artery disease has been assessed in studies usingelectrocardiography (23), radionuclide ventriculography(24), two-dimensional echocardiograpl y (16-20) and planar(25) and tomographic (26) thallium myocardial perfusionscintigraphy. Our data compare favorably with data inprevious reports on myocardial imaging techniques duringdobutamine stress . The high sensitivity in the present studymay be explained by the high spatial and improved temporalresolution of the technique used . In addition, beta-adrenergic blocking agents were discontinued a48 h beforethe test in all patients, resulting in marked hemodynamicchanges during dobutamine infusion associated with a sub-stantial increase in myocardial oxygen demand beyond sup-ply. Sev°ral studies (17,27-29) have emphasized the impor-
JACC Vol. 22, No. 2August 1993 :431-9
tance of an increase in heart rate during dobutamine infusionfor provoking myocardial ischemia . The high sensitivity mayalso be attributed by the maintenance of peak dobutaminestress during image acquisition because stress-induced wallmotion abnormalities may resolve rapidly when the imposedcardiovascular stress is terminated . The reported specificityof 100% might have been affecter! by excluding patients withvalvular, congenital and cardiomyopathic heart disease .
Previous studies on pharmacologic stress magnetic reso-nance imaging . Pharmacologic stress testing during MRI hasbeen reported using dipyridamole as a stress agent . In aselected group of patients with severe coronary artery dis-ease, l3aer et al . (13) performed dipyridamole infusion duringgradient echo MRI. The test result was considered positivefor coronary artery disease if wall motion abnormalitiesoccurred that were absent at rest . The investigators found asensitivity of 78% for detection of coronary artery disease .In a more heterogeneous group of patients, Pennell et al . (30)demonstrated an overall 62% sensitivity of dipyridamoleMRI for detecting coronary artery disease . Although theseinitial results were promising, dipyridamole has severaldrawbacks . It has a long duration of action associated with ahigh incidence of side effects that often require rapid reversalwith aminophylline. Furthermore, the coronary vasodilatingeffects are not consistent in a substantial number of patientsand generation of incremental cardiac stress resemblingexercise is not possible . Additionally, its main action is tocreate a flow maldistribution without causing increasedmyocardial oxygen demand (31) . Experimental studies (14)demonstrated that dipyridamole was more effective thandobutamine in inducing myocardial perfusion abnormalities,whereas dobutamine was superior in causing wall motionabnormalities . In this context, dipyridamole can be seen as aperfusion marker and dobutamine as a functional marker .
Recently, Pennell et al . (32) were the first to report tineMRI during dubutamine stress for the detection of coronaryartery disease by qualitative wall motion analysis . In theirgroup of patients with a high pretest likelihood of coronaryartery disease, dobutamine stress during cine MRI correctlyidentified 20 (91%) of the 22 patients with significant coro-nary artery disease. Although the dobutamine stress proto-col was well tolerated, the investigators observed a highincidence (%%) of chest discomfort .
Comparison with dobutamine stress echocardiographicstudies . Our results are in agreement with previous studiesusing dobutamine stress during echocardiography. Cohen etal . (17), using digital echocardiography during dobutaminestress with doses up to 40 pg/kg per min, obtained asensitivity of 86% and a specificity of 95% for the detectionof coronary artery disease . In a similar study of 103 patientsexamined at peak dobutamine infusion rates of 30 ,ug/kg permin, Sawada et al . (18) reported a sensitivity and specificityof 92% and 79%, respectively . In 141 patients, Marcovitzand Armstrong (19) found a high sensitivity of 96% ofechocardiography during dobutamine stress (30 µg/kg permin) for detecting patients with coronary artery disease .
VAN RUGGE ET At. .
437DuBBUTAMINE MRI IMAGING
However, the reported specificity was only 66%, which wasattributed to the inclusion of patients with wall motionabnormalities at rest not associated with coronary arterydisease . Mazeika et al. (20) studied 50 patients with sus-pected coronary artery disease during dobutamine stress(S20 pg/kg per min) and found an overall sensitivity of 78%and specificity of 93% for the detection of coronary arterydisease .
Comparison with dobutamine thallium-261 perfusion stud-ies. Dobutamine was used in combinatior with planarthallium-201 scintigraphy by Mason et al . (25), who showeda sensitivity of 94% for detecting coronary artery disease .Pennell et al . (26) studied 50 patients with coronary arterydisease and demonstrated that dobutamine thallium perfu-sion tomography was a useful technique for detecting, local-izing and assessing myocardial ischemia, particularly whenexercise potential is limited . They reported a sensitivity of97% for detecting coronary artery disease .
Clinical value and advantages of dobutamine stress . Dob-utamine stress approximates the hemodynamic alterationsduring physical exercise by increasing heart rate, systolicblood pressure and ventricular contractility . A practicaladvantage of dobutamine, which can be easily administeredby a peripheral line, is its short plasma half-life of 2 min,accounting for rapid onset and cessation of action . Conse-quently, if side effects occur, they are short-lived and rarelyrequire reversal with a beta-blocking agent . The increase inheart rate caused by dobutamine shortens imaging time,thereby improving patient tolerance . For purposes of imageanalysis, dobutamine-induced hyperkinesia in nonischemicareas provides natural contrast with ischemic zones thatexhibit stress-induced wall motion abnormalities . The highsensitivity of dobutamine stress in detecting coronary arterydisease, as demonstrated in our study and in studies com-paring dobutamine stress echocardiography with studiesusing dipyridamole as a stress agent (33). may account forthe increased application of dobutamine stress with imagingtechniques that rely on assessment of regional left ventricu-lar function .
Adverse reactions to dobutamine. The present data indi-cate that dobutamine infusion up to 20 µg/kg per min is welltolerated and safe for diagnostic MRI . In all cases, theadverse effects were mild to moderate in intensity andshort-lived. The occurrence of arrhythmias is of concern,but the only major adverse event in our study was oneepisode of accelerated idioventricular rhythm that requiredpremature termination of the infusion . The other arrhyth-mias only lengthened the imaging time because of ECGtriggering difficulties, without considerably degrading theimage quality . This safety profile and tolerance is in agree-ment with previous studies (15-20) . Dobutamine-inducedchest pain rapidly resolved by reducing the infusion rate innine patients . No patient demonstrated hypotension, dys-pneaa or severe arrhythmias during dobutamine infusion .
Limitations. Our study has several limitations . 1) A se-lection bias was introduced because the pretest likelihood of
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coronary artery disease in this group of patients was high .Therefore, further studies are required to establish theclinical value of dobutamine MR1 in a group of patientsreferred for initial diagnostic stress testing . 2) Pharmacologicstress testing is not a physiologic mode to provoke ischemia .However, among several alternative stress methods, dobu-tamine infusion most appropriately reflects dynamic exer-cise. Hemodynamic variables such as heart rate and systolicblood pressure are increased during dobutamine stress re-sembling physical exercise . 3) For purposes of patient ac-ceptability and duration of one examination, we obtainedcine MR images only at baseline and during peak dobu-tamine infusion . In addition, both the acquisition and anal-ysis of cine MR images are time-consuming . Moreover,patients demonstrating claustrophobia during image acquisi-tion are of concern. Therefore, the current approach limitsits introduction into clinical practice . However, recent ad-vances in fast imaging sequences and computer-assistedmeasurements are promising . In this respect, ultrafast MRIduring different levels of stress will be possible, therebymimicking the graded exercise stress test to detect anischemic threshold. 4) We obtained only six adjacent cardiacMR images in the short-axis plane . The total examinationtime within the magnet bote lasted approximately I h. Forreasons of ethics and patient acceptability, our imagingprotocol did not allow acquisition of images in the long-axisplane of the heart. Accordingly, our study does not providea complete set of data on regional wall motion .5) Only qualitative wall motion analysis was performed inthis study. In the future, quantitative wall motion analysisshould be assessed because both endocardial and epicardialinterfaces are well defined by cine MRI, allowing accuratequantification of systolic wall thickening . A modification ofthe centerline method, as described previously for echocar-diography (34), may be a valuable tool for assessing regionalwall thickening on tine MRI . Currently, all studies reportingon dobutamine stress are based solely on qualitative wallmotion analysis . In addition, future studies should address acorrelation of stress-induced wall motion asynergy with thedistribution of diseased coronary arteries . Also, difficultiesarising from cardiac translation and rotation are of concern,but further development of myocardial tagging techniques(35) and three-dimensional display (36) may circumventthese problems in the near future .
Conclusions. Dobutamine stress MRI is a feasible, safeand accurate technique for the noninvasive assessment offunctionally significant coronary artery disease . Dobutamineinfusion is a well tolerated and adequate alternative tophysical exercise for detecting myocardial ischemia as dem-onstrated by stress-induced wall motion abnormalities . CineMRI provide high quality images with three-dimensionalinformation without the need for radiation exposure andcontrast agents . Further development of ultrafast MRI (37)ill shorten imaging time, reduce motion artifacts, circum-vent triggering difficulties arising from arrhythmias andimprove patient tolerance . In conjunction with still-
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improving image quality, three-dimensional display and fur-ther improvement of temporal resolution, this technique maywarrant its applicability to clinical cardiology .
We thank Paul R . M. van Dijkman, MD for critical comment, . on themanuscript . Ad L . M . Bakx, MD and Marianne Bootsma . MD for excellentsupport during the patient examinations and Koos H . Zwinderman, PhD forstatistical advice.
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