J Cardiol 2004 Mar; 43（3）: 109 – 116

New Noninvasive Diagnosis of
Myocardial Ischemia of the Left
Circumflex Coronary Artery Using
Coronary Flow Reserve Measurement by Transthoracic Doppler
Echocardiography : Comparison
With Thallium-201 Single Photon
Emission Computed Tomography
Kohei FUJIMOTO, MD
Hiroyuki WATANABE, MD, FJCC
Takeshi HOZUMI, MD, FJCCRyoOTSUKA, MD

KumikoHIRATA, MD

Hiroyuki YAMAGISHI, MD
MinoruYOSHIYAMA, MD,

FJCC
Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. The usefulness of coronary flow reserve measurement in the left circumflex coronary arteryby transthoracic Doppler echocardiography to detect myocardial ischemia was compared with exercise
thallium-201 single photon emission computed tomography（SPECT）.
Methods. Transthoracic Doppler echocardiography was performed in 110 patients with suspected coronary artery disease. Color Doppler signals of the left circumflex coronary artery flow in the apical fourchamber view were identified, and the velocities at rest and during hyperemia recorded for calculation ofcoronary flow reserve by the pulsed Doppler method. All patients underwent SPECT within 1 week of thetransthoracic Doppler echocardiographic study.
Results. Coronary flow reserve in the left circumflex coronary artery was measured in 79（72%）of 110
patients. SPECT revealed reversible perfusion defect in the left circumflex coronary artery territories in 12
of 69 patients excluding those with multivessel disease. Coronary flow reserve ＜ 2.0 had a sensitivity of
92% and specificity of 96% for reversible perfusion defect detected by SPECT.
Conclusions. Noninvasive coronary flow reserve measurement in the left circumflex coronary artery bytransthoracic Doppler echocardiography can estimate myocardial ischemia in the left ventricular lateralregions.
─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2004 Mar ; 43
（3）
: 109−116

Key Words
Doppler ultrasound coronary flow velocity, coronary flow reserve
Coronary artery disease
Echocardiography, transthoracic

Blood flow──────────────────────────────────────────────
大阪市立大学大学院医学研究科 循環器病態内科学 : 〒 545−8585 大阪市阿倍野区旭町 1−4−3
Department of Internal Medicine and Cardiology, Osaka City University Graduate School of Medicine, Osaka
Address for correspondence : WATANABE H, MD, FJCC, Department of Internal Medicine and Cardiology, Osaka City University
Graduate School of Medicine, Asahimachi 1−4−3, Abeno-ku, Osaka 545−8585
Manuscript received August 28, 2003 ; revised October 27, 2003 ; accepted October 28, 2003

109

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Fujimoto, Watanabe, Hozumi et al

INTRODUCTION
Noninvasive diagnosis of ischemic heart diseaseat relatively low cost has recently become an
important clinical issue. Stress echocardiography is
widely used, but the limitation of this method is thelow sensitivity for the individual coronary arteries ;the sensitivity for detecting coronary artery diseasein the left circumflex coronary artery（LCX）is low
compared with the other coronary arteries1−3）. Moresensitive information on coronary flow abnormality
could be important for the noninvasive diagnosis ofcoronary artery disease.
Coronary flow reserve（ CFR）is an important
physiological index which reflects the severity ofcoronary narrowing. CFR measurement previously
required invasive4,5）, semi-invasive6）or radioactive
exposure methods7,8）, subsequent clinical experience and improvements in transthoracic Doppler
echocardiography（TTDE）have allowed noninvasive examination as the choice for ischemic heartdisease9,10）. However, the potential for identifying
ischemia of the LCX has never been investigated.
The present study evaluated the usefulness of
CFR measurement in the LCX by TTDE comparedwith exercise thallium-201（ 201Tl）single photon
emission computed tomography（SPECT）.
SUBJECTS AND METHODS
Study population
This study included 110 consecutive patients（92
men, mean age 62 ± 10 years）with suspectedischemic heart disease who were scheduled forcoronary angiography. Exclusion criteria were left
ventricular wall motion abnormality, left ventricular hypertrophy, cardiomyopathy, previous cardiac
surgery, atrial fibrillation, and significant valvular
heart disease. All patients continued administrationof anti-ischemic medication（nitrates, beta blockers,
calcium antagonists）
and antiplatelet agents（aspirin
81 mg）on the day of the echocardiographic study.
We obtained informed consent from all participants
to the study protocol, which was approved by theCommittee for the Protection of Human Subjects in
Research at Osaka City University Graduate Schoolof Medicine.
Coronary flow reserve measurement bytransthoracic Doppler echocardiography
We used a commercially available high-resolution ultrasound system（ACUSON Sequoia 512,

Apical four-chamber viewFig. 1 Color Doppler imaging of the left circumflex
coronary artery in the apical four-chamber view
RV ＝ right ventricle ; LV ＝ left ventricle ; LA ＝ left
atrium.

Siemens Medical Solutions USA, Inc.）using a
3V2C probe（ 2− 3 MHz, Doppler frequency
2.0 MHz）. For color flow mapping, the velocity
range was set at ± 12 to ± 30 cm/sec. The color
gain was adjusted to provide optimal images.
Doppler flow signals of the LCX were identified aslinear color signals persisting during diastole on thebase to mid portion of the left ventricular lateralregion in the apical four-chamber view as far as
possible（Fig. 1）. The mid to distal LCX in the left
ventricular lateral region is most likely to be detected in the apical four-chamber view. Doppler spectral tracings of the flow velocities were recorded by
fast Fourier transformation analysis with a sample
volume positioned on the most clearly visualizedcolor signals. Holding the transducer in the same
position as far as possible, the flow velocities wererecorded at rest and during hyperemia induced byintravenous infusion of adenosine triphosphate（0.14 mg/kg/min）for 2 min. Heart rate, blood pressure and electrocardiographic monitoring were continuous throughout the test. All velocity recordings
were continuously recorded on half-inch S-VHS
videotape and stopped frames were also stored digitally on magneto-optical disks（540 MB）for subsequent off-line analysis.
CFR was calculated as the ratio of hyperemic tobasal mean diastolic flow velocities which wereobtained off-line by contouring the spectral
Doppler signals at baseline and at peak hyperemic
J Cardiol 2004 Mar; 43（3）: 109 – 116

Diagnosis of Myocardial Ischemia by Doppler Echocardiography

conditions using analysis software incorporated in
the ultrasound system. Each measurement was
averaged over three consecutive cardiac cycles.
Each study was analyzed by two experienced operators who were unaware of the patient s data.
Normal CFR was defined as ＞
− 2.0 on the basis of
the results of previous studies which had evaluatedflow velocities in the distal left anterior descending
artery5,11）.
Echocardiographic contrast enhancement
Echocardiographic contrast agent（Levovist,
Schering）was administered to obtain spectral
Doppler signals in the event of unsuccessful visualization or unclear recording of the flow spectrum.
On the basis of a previous study12）, the echocardiographic contrast agent was administered intravenously at 300 mg/ml by intravenous infusion of
7 ml at 1 ml/min, using an infusion pump. The infusion rate was adjusted in the range of 2.0 to
0.5 ml/min according to the quality and entity of the
Doppler signal enhancement achieved.
Exercise thallium-201 SPECT
SPECT was performed within 1 week of the
CFR studies. All patients performed symptom-limited exercise on a bicycle ergometer in the sitting
position. Nitrates, beta blockers and calcium channel blockers were withheld on the morning of thetest. Twelve-lead electrocardiography and bloodpressure measurements were obtained at baseline
and every minute during exercise. The initial work
load was 50 W, which was increased by 25 W every
2 min until the end point was reached, marked byexcessive fatigue, dyspnea, dizziness, angina,
hypotension, diagnostic ST segment depression（＞ 1.5 mm horizontal or downsloping or ＞ 2.0 mm
upsloping）or significant arrhythmia. At peak exercise, a dose of 111 MBq of 201Tl was injected intravenously. The initial images were obtained immediately after the termination of exercise, and delayed
images were obtained 4 hr later.
SPECT was performed using a single-headgamma scintillation camera equipped with a low
energy, all-purpose, parallel-hole collimator.
Thirty-two equidistant projections were acquired
over 180 °from the right anterior oblique to left
posterior oblique view at 25 sec/projection.
The lateral including posterior segments on the
SPECT images were considered to be the LCX territories. The SPECT images were analyzed individJ Cardiol 2004 Mar; 43（3）: 109 – 116

111

ually by two experienced nuclear physicians who
had no knowledge of the angiographic or echocardiographic data. Disagreements in interpretation
were resolved by consensus of the two physicians.
The patients were considered to have myocardialischemia if 201Tl SPECT revealed perfusion defects
with redistribution on delayed imaging.
Coronary angiography
Coronary angiography was performed in all
patients by using standard techniques within 1
week of the CFR studies. Angiographic data were
subsequently analyzed by an experienced investigator who had no knowledge of the patient s data.
The severity of coronary stenosis was visually
determined and expressed as the percentage lumen
diameter stenosis. Stenosis was considered significant if there was ＞ 75% diameter stenosis in atleast one projection. Electrical calipers were used
when necessary.
Doppler guide wire study
In a subgroup of 14 randomly selected patients,
coronary flow velocity measurements wereobtained within 10 min after the administration of
intracoronary nitroglycerin after routine diagnostic
angiography simultaneously with Doppler recording of the coronary flow velocity in the LCX territories by TTDE. All patients received an additional
2,000 IU bolus of intravenous heparin. A 0.014inch（0.36 mm）Doppler-tipped angioplasty guidewire（FlowWire, Cardiometrics Inc.）was inserted
into the distal LCX. After satisfactory baseline flow
velocity signals were obtained, hyperemic flow
velocity data were continuously acquired duringcontinous administration of adenosine triphosphate（0.14 mg/kg/min）intravenously. The mean CFR
was calculated as the ratio of hyperemic to basal
mean coronary flow velocities. All studies wererecorded on 0.5-inch S-VHS videotape for subsequent off-line analysis.
Statistical analysis
On the basis of the 201Tl SPECT data for the
LCX territories, the patients were classified into
Group A（abnormal perfusion）and Group B（normal perfusion）. Parametric data were presented as
the mean value ± SD. Categorical variables werecompared using the Fisher exact test.
Echocardiographic and hemodynamic variables
during adenosine infusion in Groups A and B were112

Fujimoto, Watanabe, Hozumi et alevaluated by two-way repeated measures analysis
of variance（ANOVA）; testing for group effect,
adenosine effect, and interaction. The Fisher protected least-significant difference test was used forpost-hoc testing. Mean CFR values for Groups A
and B were compared by the unpaired t-test. p ＜0.05 was considered significant. The sensitivity,
specificity, positive predictive value and negative
predictive value of CFR were calculated in the conventional way, as a predictor of abnormal perfusionon the 201 Tl SPECT image. Interobserver andintraobserver variabilities were assessed for CFR
measurements in eight randomly selected patients.
Interobserver variability was calculated as the SDof the differences between the measurements of
two independent observers unaware of the patient s
data and expressed as a percentage of the averagevalue. Intraobserver variability was calculated as
the SD of the differences between the first and second determinations, 15 min apart, for a single
observer and expressed as a percentage of the average value. Linear regression analysis was used tocompare TTDE with the Doppler guide wire
method for the assessment of CFR, and an analysisof the differences of the measurements between
TTDE and Doppler guide wire was performed
according to the technique of Bland and Altman.

Table 1 Comparison of clinical data in Groups A and B
Group A（n＝12）

Group B
（n＝57）

p value

Age（year）

64±8

60±10

NS

Sex
（M/F）

10/2

53/4

NS

Baseline

129±15126±13NS

Hyperemia

126±16120±15NS

Baseline

73±8

73±10

NS

Hyperemia

70±8

70±11

NS

Baseline

70±14

68±12

NS

Hyperemia

73±13

72±12

NS

SBP
（mmHg）

DBP（mmHg）

HR（beats/min）Continuous values are mean±SD.
Group A : with abnormal perfusion. Group B : with normal
perfusion.
M＝male ; F＝female ; SBP＝systolic blood pressure ; DBP＝
diastolic blood pressure ; HR＝heart rate.

Table 2

Results of two-way repeated measures
analysisGroup（p value）

Adenosine（p value）

Interaction（p value）

SBP

0.53

＜0.01

0.34

DBP

0.19

＜0.01

0.99

RESULTS

HR

0.57

＜0.01

0.67

Adequate spectral Doppler recordings of the
LCX were obtained in 79 of 110 patients（72%）. To
test the accuracy of CFR measurement by TTDE
compared with the results of SPECT in patientswith single-vessel disease, we excluded 10 of the79 patients with multivessel disease according toangiographic findings, because the sensitivity of
SPECT for diagnosis of multivessel disease is
low13,14）. Therefore, the remaining 69 patients comprised the study group. No significant difference inage or sex were found between Groups A and B（Table 1）. The results of the two-way repeatedmeasures ANOVA for group and adenosine effectare summarized in Table 2.

MDV

＜0.01

＜0.01

＜0.01

Thallium-201 SPECT
All patients in this study performed exercise tests
until the end points were reached. Twelve of the 69
patients qualitatively exhibited abnormal perfusionin the LCX territories on 201Tl SPECT and wereclassified as Group A. The remainder of thepatients（n ＝ 57）had no abnormal perfusion in the

MDV＝mean diastolic velocity. Other abbreviations as in Table
1.

LCX territories and were classified as Group B ;normal perfusion（n ＝ 27）in all regions or abnormal perfusion in the other regions（n ＝ 30）. The
peak heart rate and rate-pressure product were similar in Groups A and B for all exercise tests.
Hemodynamic data
No patient developed serious adverse effects,
such as angina, atrioventricular block, nausea,
flushing or palpitations, during the administrationof adenosine triphosphate. Two-way repeated measured ANOVA showed no significant differences orinteraction in terms of heart rate, systolic bloodpressure and diastolic blood pressure between
Groups A and B during administration of adenosine（Tables 1 and 2）.

J Cardiol 2004 Mar; 43（3）: 109 – 116

113

Diagnosis of Myocardial Ischemia by Doppler Echocardiography

Fig. 2 Regression（left）and difference（right）
plots comparing coronary flow reserve measured by thetransthoracic Doppler echocardiography and Doppler guide wire methods
CFR ＝ coronary flow reserve ; TTDE ＝ transthoracic Doppler echocardiography.

Coronary angiography
Coronary angiography demonstrated significant
coronary stenosis in the LCX in 11 patients ofGroup A and in four patients of Group B. There
were discrepancies between coronary angiography
findings, SPECT findings and CFR measurement
by TTDE in one patient of Group A and in four
patients of Group B. In the patient of Group A with
CFR ＜ 2.0, coronary angiography revealed no significant stenosis in the LCX, in which the left ventricular lateral segments were perfused by the rightcoronary artery with significant stenosis. In GroupB, two patients had CFR ＜ 2 that reflected coronary narrowing in a small branch of the postero-lateral coronary artery, and two patients had CFR ＞ 2even with significant stenosis on coronary angiography.
Comparison with Doppler guide wire study
CFR obtained from TTDE was highly correlatedwith that from Doppler guide wire measurements（r ＝ 0.92, y ＝ 1.19x − 0.29, SEE ＝ 0.22 ; Fig. 2）.
The mean difference between these methods was
0.10 ± 0.22 for CFR measurements.
Coronary flow reserve measured by transthoracic Doppler echocardiography versus thallium-201 SPECT
An increase in coronary flow velocity wasobserved in all patients within 1 min of the start ofadenosine infusion. The contour of flow velocity
remained stable throughout the infusion period andreturned to the baseline rapidly after cessation of
adenosine infusion. There was no significant differJ Cardiol 2004 Mar; 43（3）: 109 – 116

Table 3

Coronary flow velocity and reserve in Groups
A and Bp valueGroup AGroup B

Baseline20.2±3.920.0±4.9

NS

Hyperemia

32.6±9.1

56.0±13.9＜0.01

1.6±0.5

2.9±0.6＜0.01

MDV（cm/sec）

CFR

Values are mean±SD.
Explanation of the groups and abbreviations as in Tables 1, 2,
Fig. 2.

ence between Groups A and B in coronary flow
velocity measurements at baseline（ Table 3）.
However, mean diastolic flow velocities increased
significantly during hyperemia in Group B, as compared with those in Group A（p ＜ 0.01 ; Fig. 3）.
Two-way ANOVA showed a significant groupeffect and interaction in mean diastolic flow velocities during hyperemia（Table 2）. Thus, mean CFR
measured by TTDE demonstrated significant differences between Groups A and B（mean CFR 1.6 vs
2.9, respectively ; p ＜ 0.01）.
Only one patient in Group A had mean CFR ＞−
2.0, whereas two patients in Group B had mean
CFR ＜ 2.0（Fig. 4）. Mean CFR ＜ 2.0 predicted areversible perfusion defect in the LCX territories,
with sensitivity of 92%, specificity of 96%, positive
predictive value of 85% and negative predictive
value of 98%.
Observer variability
Interobserver and intraobserver variabilities formeasurement of Doppler velocity recording were114

Fujimoto, Watanabe, Hozumi et al

Group A（CFR＜2 by TTDE）

Baseline

Hyperemia

Group B（CFR＞2 by TTDE）

Baseline

Hyperemia

Fig. 3 Spectral Doppler signals at the baseline（left column）
and during hyperemia（right column）
in a
patient of Group A with abnormal myocardial perfusion in the left circumflex artery territories（upper row）
and in a patient of Group B with normal perfusion in the left circumflex
artery territories（lower row）
Explanation of the groups and abbreviations as in Table 1, Fig. 2.

Fig. 4 Plot showing good correlation between coronary
flow reserve measurements and the results ofthallium-201 single photon emission computed
tomography
There was overall agreement in 66（96%）of 69 patients.
Explanation of the groups and abbreviation as in Table
1, Fig. 2.

5.3% and 4.4%, respectively.
DISCUSSION
The accuracy of CFR measurement on the LCX
by TTDE was compared to the results of 201Tl
SPECT. CFR ＜ 2.0 was found to be associatedwith perfusion abnormality in the LCX territories
by 201Tl SPECT.

Coronary flow reserve measurement in the left
circumflex coronary artery
CFR is an important diagnostic parameter for
functional coronary artery stenosis 5,11,15− 17）.
Previously, the measurement of this parameter
needed the invasive Doppler guide wire or Doppler
catheter4,5）, semi-invasive transesophageal echocardiography6）, or positron emission tomography7,8）.
However, CFR measurement has now become noninvasive, because recent technological advances in
TTDE can obtain this parameter noninvasively9,18）.
In the left anterior descending artery territories,
CFR measurement has been proven to provide data
equivalent to the results of 201 Tl SPECT 10）.
However, the potential in detecting coronary arterydisease in the LCX remained unclear. Thus, weinvestigated whether this technique is suitable fordiagnosis of ischemia in the LCX. We found CFR
measurement by TTDE in the LCX also provides
data equivalent to the result of 201Tl SPECT.
The success in detecting CFR in the LCX
depends on the following factors. First, use of a low
frequency transducer, not a high frequency transJ Cardiol 2004 Mar; 43（3）: 109 – 116

Diagnosis of Myocardial Ischemia by Doppler Echocardiography

ducer, in contrast to left anterior descending arteryflow measurements. The color Doppler signals in
the LCX are located in the far field in the apicalfour-chamber view, so it is often difficult to obtain
good echocardiographic images using a high frequency transducer. Second, echo contrast agent wasadministered intravenously to enhance Doppler signals in patients with low signal to noise ratio.
Without contrast agent, the feasibility of CFR measurement in the LCX will be reduced.
Utility of coronary flow reserve measurement bytransthoracic Doppler echocardiography
Stress echocardiography evaluates myocardialischemia by detecting wall motion abnormalities,
and is used most frequently in the clinical setting as
a noninvasive, simple and relatively low cost test
for angina pectoris. Although this test achieved sufficient accuracy to detect myocardial ischemia inpatients with multivessel disease, the accuracy forischemia in each region is not sufficiently high ;and the sensitivity for ischemia in the LCX territories is the lowest compared with other regions1−3）.
Use of CFR measurement in the LCX by TTDE
with contrast agent could overcome the limitationof stress echocardiography.
要

LimitationsFirst, the number of patients included in thisstudy is small. Actually, there were only 12 patientswith abnormal perfusion in the LCX territories. A
larger number of patients should be included infuture studies. Second, compared with the successrate of CFR measurement by TTDE in the left anterior descending artery, the feasibility of this technique was not sufficiently high even with contrast
agent. In addition to the distance between signals
and the echo probe, artifacts from the lung could
affect coronary flow recordings on the LCX. Moretechnical progress in TTDE is needed. Finally, twopatients of Group B showed normal perfusion in
the LCX territory on 201Tl SPECT, although coronary angiography demonstrated significant stenosis
in the LCX. This may be one of the limitations of
this study. Even with these limitations, the sensitivity and specificity in detection of myocardialischemia in the left ventricular lateral regions issufficiently high for use in daily clinical practice.
CONCLUSIONS
Noninvasive CFR measurement in the LCX by
TTDE can estimate myocardial ischemia in the left
ventricular lateral regions.
約経胸壁ドプラ心エコー図を用いた冠血流予備能による左回旋枝領域の心筋虚血の新しい非侵襲的診断法: タリウム-201 運動負荷心筋シンチグラフィーとの比較
藤本

目

浩平

渡辺

弘之

穂積

健之

大 塚

亮

平田久美子

山岸

広幸

葭 山

稔

吉川

純一

的 : 心筋虚血検出における経胸壁ドプラ心エコー図による左回旋枝での冠血流予備能の有用性をタリウム-201 運動負荷シンチグラフィーと比較することにより検討する．
方法 : 連続した 110 例の冠動脈疾患を疑われた患者を対象とした．経胸壁心エコー図により心尖部四腔像にて左回旋枝血流のカラードプラ信号を検出し，パルスドプラ法により安静時と反応性
充血時の冠血流速度波形を記録し，冠血流予備能を計測した．すべての患者で心筋シンチグラ
フィーが行われた．
結果 : 110 例のうち 79 例（72%）で左回旋枝での冠血流予備能が測定可能であった．心筋シンチ

グラフィーでは，多枝病変患者を除いた 69 例中 12 例で，左回旋枝領域に可逆的な血流欠損が示された．2.0 未満の冠血流予備能の心筋シンチグラフィーによる可逆的な血流欠損に対する感度と特異度は，それぞれ 92%，96% であった．
結論 : 経胸壁心エコー図による冠血流予備能を左回旋枝に適用すれば左室側壁の虚血が推定しうる．

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Fujimoto, Watanabe, Hozumi et al

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