J Cardiol 2007 Mar; 49（3）: 109 – 114

Correlation Between Exercise
Electrocardiography Test andCoronary Flow Reserve in Patients
Without Organic Coronary Artery
Stenosis
Minoru MITSUGI, MD
Hironori KANEKO, MD
Takayoshi

YAMAKI, MD

Hiroyuki

KUNII, MD

Yukio MARUYAMA, MD,FJCC

Abstract ─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────────
Objectives. The exercise electrocardiography（ECG）test is frequently positive in patients without organic coronary artery stenosis. Although the reason for this false positive ST depression is not fully understood, one possibility may be related to coronary microvascular abnormality. The present study investigated the relationship between the exercise ECG test and coronary flow reserve（CFR）in patients with angiographically normal coronary arteries, but with positive ECG ST depression.
Methods. This study included 67 patients, 32 with chest pain syndrome, and 35 with vasospasm. The
exercise ECG test was performed without drug administration in all patients, and the CFR was determined
after diagnostic cardiac catheterization.
Results. Although a significant correlation was recognized between ST depression and CFR in patientswith chest pain syndrome（p ＜ 0.05）, there was no correlation in patients with epicardial coronary
vasospasm.
Conclusions. In patients with chest pain syndrome, ST depression detected by the exercise ECG test
may suggest coronary microvascular dysfunction. However, in patients with coronary vasospasm, ST
depression may occur without decreased CFR, suggesting that coronary spasm or other mechanism（s）
relating to ST changes are present during the exercise ECG test, and careful interpretation is needed.
─────────────────────────────────────────────────────────────────────────────────────────────────────────────────────J Cardiol 2007 Mar; 49（3）: 109−114

Key Words
ExerciseElectrocardiography
Coronary vasospasm

INTRODUCTION
The exercise electrocardiography（ECG）test is
the first line test for coronary artery disease1,2）inwhich ST depression of over 0.1 mV has reasonable predictive accuracy for significant coronary
obstructive lesion（s）. However, patients with various cardiovascular diseases frequently show posi-Coronary artery disease flow reserve

tive exercise ECG test but have normal coronary
arteries.3−7）Epicardial coronary vasospasm8,9）andchest pain syndrome10）in particular are frequently
associated with this false positive exercise ST
depression. Recently, coronary flow reserve（CFR）
has been evaluated using a Doppler guidewire
inserted into the coronary artery to assess microvascular maximal dilatory function,11,12）as well as the──────────────────────────────────────────────
福島県立医科大学 第一内科 : 〒 960−1295 福島県福島市光ヶ丘 1
The First Department of Internal Medicine, Fukushima Medical University, Fukushima
Address for correspondence : MARUYAMA Y, MD, FJCC, The First Department of Internal Medicine, Fukushima Medical
University, Hikarigaoka 1, Fukushima, Fukushima 960−1295 ; E-mail:maruyama@fmu.ac.jp
Manuscript received October 31, 2006 ; revised December 14, 2006 ; accepted December 20, 2006

109

110

Mitsugi, Kaneko, Yamaki et alpresence of epicardial coronary artery organic
stenosis.13,14）Accordingly, if CFR decreases corresponding to exercise-induced ECG ST depression
despite the absence of significant coronary stenosis,
the ST depression may be related to a coronary
microvascular dilatory dysfunction. However, few
studies 10） have investigated the relationshipbetween the impairment of CFR and appearance ofa false positive ST depression in various cardiovascular diseases.
To clarify whether such a depression following
exercise is closely related to decreases in CFR, thepresent study investigated the relationship between
CFR and exercise-induced ST depression inpatients with coronary spasm and chest pain syndrome.
SUBJECTS AND METHODS

each coronary artery）to diagnose the degree ofcoronary organic stenosis. Coronary vasospasm
was diagnosed by the acetylcholine provocation
test, in which test total and/or subtotal coronary
artery narrowing including focal and diffuse patterns was observed. A Doppler guidewire（FloWire,
Cardiometrics, Inc）
was advanced into the proximal
left anterior descending coronary artery through a 6
F coronary angiography catheter. The optimal
Doppler signal was obtained by moving theguidewire slightly within the vessel lumen.
Frequency analysis of the Doppler signals was carried out in real time by fast-Fourier transform using
a velocimeter（FloMap, Cardiometrics, Inc）. CFR
was obtained from the ratio of maximal hyperemic
to baseline time-averaged peak velocity at rest after
intracoronary bolus injection of papaverine
15）hydrochloride（10 mg）
over 10 sec.

Subjects
The study population consisted of 35 patientswith epicardial coronary vasospasm（27 men and 8
women, mean age 61.6 ± 9.2 years）. In this study,
patients with coronary vasospasm, diagnosed clinically as well as by the acetylcholine provocation
test, showed no organic stenosis in epicardial coronary arteries. The study also included 32 consecutive patients with atypical chest pain
（18 men and
14 women, mean age 57.1 ± 12.4 years）, but withnormal epicardial coronary arteries and no coronary
spasm on diagnostic cardiac catheterization.
Patients with ST depression at rest were excluded
due to the difficulty of evaluating their exercise
ECG test. All medications except sublingual nitroglycerin were withdrawn before cardiac catheterization. Informed consent was obtained from all
subjects before the study, which was approved by
the ethics committee of Fukushima Medical
University.

Exercise ECG test
All patients underwent treadmill exercise ECG
tests（Stress Test System ML-4500, Fukuda
Denshi）having taken no medication on the day
before cardiac catheterization. The Bruce protocol
was used for the exercise test, and patients wereconsidered positive if over 0.1 mV of a horizontal
and downsloping, or over 0.2 mV of an upsloping
ECG ST depression developed 0.08 sec from the J
point in at least one lead. The level of ST depression was taken from the auto-measured value. The
exercise ECG test was terminated when at least oneof the following end points was reached : chest
symptom, leg fatigue, diagnostic ST depression,
frequent arrhythmias, and target heart rate. The ST
depression with the maximum degree among all 12
leads was selected, and was averaged for eachgroup of patients with chest pain syndrome andcoronary vasospasm.

Study protocol
Standard cardiac catheterization including pressure recording and coronary angiography was performed in all 67 patients using the femoral
approach. After control coronary angiography,
incremental doses of acetylcholine were infused
into the left coronary artery（20, 50, and 100μg）
and subsequently into the right coronary artery（20
and 50μg）during 30 sec. After the acetylcholine
provocation test, multi-directional coronary angiography was performed following intracoronary injection of isosorbide dinitrate（ISDN）（1.25−2.5 mg in

Statistical analysis
All data are expressed as mean values ± SD.
Intergroup comparisons were performed by the
unpaired Student s t-test. Correlation analysis was
performed using Pearson s correlation coefficient.
The proportions of men, smoking, hypertension,
diabetes mellitus, and exercise positive patientswere analyzed by Fisher s exact probability test. A
p value of ＜ 0.05 was considered statistically significant.

J Cardiol 2007 Mar; 49（3）: 109 – 114

Exercise ECG Test and Coronary Flow Reserve

Characteristics of study patients＊

Table 1
Overall（n＝32）

Chest pain syndrome
Exercise positive Exercise negative（n＝17）（n＝15）Overall（n＝35）

Coronary vasospasm
Exercise positive Exercise negative（n＝24）（n＝11）

Age（yr）

57.1±12.4

57.5±12.6

56.7±12.5

61.6±9.3

61.7±8.561.5±11.1

Men/women

18/14

9/8

9/6

27/8

17/7

10/1

Total cholesterol（mg/dl） 201.2±47.7

202.6±41.4

199.7±55.4

196.2±41.7

194.0±45.3

201.1±33.8

Triglyceride（mg/dl）

113.0±76.3

135.8±91.5

87.1±44.3

105.7±57.5

104.4±62.3

108.7±48.1

HDL cholesterol（mg/dl）

56.5±14.955.1±15.0

58.1±15.2

53.4±14.955.3±17.5

50.5±13.4

Smoking§15（46.9）7（41.2）8（53.3）16（45.7）

9（37.5）7（63.6）Hypertension#

12（37.5）

6（35.3）6（40.0）12（34.2）8（33.3）4（36.4）5（15.6）4（23.5）1（6.7）

3（8.6）

2（8.3）

1（9.1）†

Diabetes mellitus

111＞10 cigarettes/day for 10 years. #Blood pressure ＞）：％. ＊p＝NS for all comparisons. §−−Continuous values are mean ± SD.（

＞140 mg/dl or antidiabetic medication.
140/90 mmHg or antihypertensive medication. †Fasting blood glucose −HDL ＝ high-density lipoprotein.

Table 2Overall（n＝32）

Hemodynamic variables

Chest pain syndrome
Exercise positive
Exercise negative（n＝17）（n＝15）Overall（n＝35）

Coronary vasospasm
Exercise positive
Exercise negative（n＝24）（n＝11）

s-AP（mmHg）

150.4±29.6

153.8±29.7

146.7±30.0151.2±23.7152.4±24.4

d-AP（mmHg）

77.5±12.1

78.3±11.9

76.7±12.775.8±10.475.6±11.1

76.4±9.1m-AP（mmHg）

107.1±18.1

107.9±17.8

106.1±19.1

106.2±15.9105.8±17.4

107.1±12.8

s-LVP（mmHg）

150.6±27.2

153.8±28.4146.9±26.2152.4±22.8

153.5±22.2

150.1±25.2

Pcw（mmHg）

8.0±2.79.2±2.96.5±1.79.8±3.5＊9.8±2.0

9.7±5.7

s-PAP（mmHg）

24.2±5.1

26.1±5.822.1±3.225.8±4.626.1±4.725.1±4.7

CI（l/min/m2）

3.62±0.77

3.52±0.52

3.73±1.00

3.41±0.73

3.44±0.79

3.34±0.61EF（％）

65.0±7.364.4±8.4

65.6±6.1

64.2±7.2

65.3±7.3

62.0±6.9#

148.6±23.0

Values are mean±SD.＊p＜0.05 vs overall patients with chest pain syndrome. # p＜0.05 vs exercise negative patients with chest pain
syndrome.
s-AP＝systolic aortic pressure ; d-AP＝diastolic aortic pressure ; m-AP＝mean aortic pressure ; s-LVP＝systolic left ventricularpressure; Pcw＝pulmonary artery wedge pressure ; s-PAP＝systolic pulmonary artery pressure ; CI＝cardiac index; EF＝ejection
fraction.

RESULTS
Patient characteristics are presented in Table 1.
Age, and values of total cholesterol, triglyceride,and high-density lipoprotein cholesterol were notsignificantly different between the two groups, andthe proportions of men, smoking, hypertension, anddiabetes mellitus were also not different. The
results of hemodynamic variables during cardiac
catheterization are shown in Table 2. Pulmonary
wedge pressure in all patients with coronary
vasospasm was significantly higher compared withthat in all patients with chest pain syndrome, andsystolic pulmonary arterial pressure in exercise
positive patients with chest pain syndrome was sigJ Cardiol 2007 Mar; 49（3）: 109 – 114

nificantly higher than that in exercise negative
patients with chest pain syndrome. The results ofthe exercise ECG tests are presented in Table 3.
Positive ST depression in the exercise stress test
was found in 17 with chest pain syndrome and 24
patients with coronary vasospasm.
CFRs of patients with chest pain syndrome andcoronary vasospasm were 3.53 ± 0.75 and 3.61 ±
0.82, respectively, with no significant difference.
The rate of exercise ECG-positive seemed to behigher in patients with epicardial coronary
vasospasm（24/35, 68.6%）compared to that inthose with chest pain syndrome（ 17/32, 53.1%; Tables 1−3）.
The relationship between ST depression and112

Mitsugi, Kaneko, Yamaki et al

Table 3Results of exercise electrocardiography test

Coronary vasospasm
Chest pain syndrome
Exercise positive Exercise negative
Exercise positive Exercise negative
Overall
Overall（n＝17）（n＝24）（n＝15）（n＝35）（n＝11）（n＝32）Rest
HR（beats/min）

71.9±12.873.8±13.3

69.9±12.3

72.1±11.9

70.9±9.574.8±16.2

s-BP（mmHg）

136.9±14.8138.4±15.6135.2±14.2

141.3±19.1

144.3±19.3

135.0±17.8

DP（×102 mmHg/min）

98.7±21.5

101.9±20.7

95.1±22.4

101.9±21.2

102.3±19.6

101.1±25.3

ST depression（mV）

0.16±0.12

0.25±0.09†

0.06±0.03

0.19±0.14

0.26±0.11†

0.05±0.03

HR（beats/min）

146.5±20.1

151.2±15.4

141.2±23.8145.4±18.1

147.0±17.4141.9±19.8

s-BP（mmHg）

200.8±33.9205.5±32.5

195.5±35.8

198.7±22.6

201.4±24.9

193.0±15.9

DP（×102 mmHg/min） 293.5±61.5

310.3±57.1

274.4±62.7

289.4±49.5295.9±48.5275.4±51.1

Maximal exercise

Values are mean±SD.†p<0.01 vs exercise negative patients.
HR＝heart rate ; s-BP＝systolic blood pressure ; DP＝double products.

Fig. 1 Significant positive relationship between ST
depression following exercise test and coronary
flow reserve observed in patients with chest pain
syndrome（n ＝ 32）
It is suggested that false positive ST-segment depression may be induced by coronary microvascular dilatory disturbance.
CFR ＝ coronary flow reserve.

CFR is shown in patients with chest pain syndrome（ n ＝ 32 ; Fig. 1）and those with coronary
vasospasm（n ＝ 35 ; Fig. 2）. A significant correlation was recognized in patients with chest pain syndrome（p ＜ 0.05）, although CFR values between
the exercise positive（n ＝ 17）and negative groups（n ＝ 15）were not significantly different（3.34 ±0.55 vs 3.76 ± 0.89, respectively）. However, there
was no correlation in patients with coronary
vasospasm. Moreover, taking all data into account,
CFR of exercise ECG-positive patients（n ＝ 41）,
did not differ from that of exercise ECG-negative

Fig. 2 Negative relationship observed between exercise-induced ST depression and coronary flow
reserve in patients with coronary vasospasm（n ＝ 35）
The ST depression may not be directly related to
impaired vasodilatory response of coronary microvascular beds.
Abbreviation as in Fig. 1.

patients（n ＝ 26）（3.50 ± 0.77 vs 3.69 ± 0.80, NS）.
DISCUSSION
False positive ECG ST depression has been
observed in angiographically normal epicardialcoronary arteries. Although the mechanism is still
unclear, coronary microvascular disturbance may
be partly associated with the genesis of such false
positive ST depressions. This study showed relationships between CFR and exercise ECG test in
patients with chest pain syndrome and coronary
J Cardiol 2007 Mar; 49（3）: 109 – 114

Exercise ECG Test and Coronary Flow Reservevasospasm, suggesting that coronary microvascular
disturbance may be associated with chest pain syndrome with false positive ST depression.
Exercise-induced ST depression was frequently
found in both patients with chest pain syndromeand coronary vasospasm, who showed normal coronary angiograms（ Table 3）. 8−10） However, wefound the relationship of CFR to exercise-induced
ST depression was different between these two diseases, i.e., exercise-induced ST depression was correlated to CFR in chest pain syndrome, whereas nocorrelation was observed in patients with coronary
vasospasm（Figs. 1, 2）. These results suggest thatthe mechanism of false positive exercise-induced
ST depression in patients with coronary vasospasm
involves other factors such as coronary spasm during and/or following exercise, rather than impairment of coronary microvascular dilatory function.
However, this possibility of epicardial coronary
artery spasm during exercise remains to be verified.
Moreover, some patients with coronary spasm may
suffer not only regulatory impairment of epicardialcoronary artery vasoactivity but also impairment ofsmall vessel dilatory action or microvascularspasm16,17）due to exercise stress despite the absence of reduction in CFR. Hence, the papaverineinduced CFR value measured in this study is only
one marker detecting impairment of small vessel
vasodilatory action, and does not provide full assessment of small vessel regulatory function during
exercise or exercise-induced microvascular spasm.
Further study is necessary to elucidate this issue.
On the other hand, a weak but significant correlation between ST depression following exercise and
CFR in patients with chest pain syndrome wasobserved（ Fig. 1）, although the values of CFR
between exercise positive and negative groups were
not different. These results suggest that ST depression in patients with chest pain syndrome may partly reflect coronary microvascular dysfunction. CFRvalues in patients with chest pain syndrome showing no angiographical coronary stenosis and exercise induced ST depression were significantly

lower than in controls,10）although no relationshipbetween CFR values and exercise induced ST
changes was detected. On the contrary, the impairment of coronary microvascular dilatory action
may not be uniformly and profoundly observed inchest pain syndrome, when taking into account thepresent results. Therefore, as in epicardial coronary
spasm, the assessment of coronary microvascularvasodilatory impairment by only CFR may not beadequate to evaluate the mechanism of exercise
induced ST depression. Also, it is unclear whether
microvascular spasm during exercise occurs or notin patients with chest pain syndrome.16,17）Further
studies are required to clarify these issues.
Study limitations
This study has several limitations. First, the measurement of CFR was done after coronary angiography in which ISDN was administered into eachcoronary artery. Coronary microvascular spasm isrelieved after the ISDN injection.16）Accordingly,
the ISDN injection may affect the CFR value in thisstudy. However, this injection was performed in all
patients. Second, CFR and exercise ECG test were
not done simultaneously, so vasoactivity in eachexamination may not be the same. Third, the relationship between exercise-induced ECG ST depression and the degree of acetylcholine induced epicardial coronary spasm or flow-mediated epicardialcoronary artery dilation after papaverine injection
and was not investigated, so how endothelium
dependent vasodilatory dysfunction, if any, contributes to ST depression in exercise remains
unclear. Further studies are needed.
CONCLUSIONS
In patients with chest pain syndrome, ST depression during the exercise ECG test may partiallyindicate coronary microvascular dysfunction.
However, in patients with coronary vasospasm,
coronary spasm or other contributing factor（s）arelikely to be present during the exercise ECG test, so
a careful approach is needed for the interpretation.

要約
器質的冠動脈狭窄を有さない患者における運動負荷心電図試験と冠血流予備能との関係
三 次
目

実

金子

博智

八巻

尚洋

国井

浩行

丸山

幸夫

的 : 冠動脈に器質的狭窄を有さない患者において，運動負荷心電図試験陽性がしばしば認め

J Cardiol 2007 Mar; 49（3）: 109 – 114

113

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Mitsugi, Kaneko, Yamaki et al

られる．この偽陽性 ST 低下については十分理解されていないが，冠微小循環機能障害に関係している可能性がある．そこで冠動脈に器質的狭窄を有さない患者において，運動負荷試験と冠血流予備能の関係を検討した．
方

法 : 32 例の胸痛症候群および 35 例の冠攣縮性狭心症について検討した．全例で薬剤を投与

せずに運動負荷試験を施行し，その後日，心臓カテーテル検査により冠血流予備能を求めた．
結

果 : 胸痛症候群においては，ST 低下と冠血流予備能の間に有意な負の相関が認められた（p ＜ 0.05）が，冠攣縮性狭心症においては，そのような関係は認められなかった．
結論 : 胸痛症候群においては，運動負荷心電図試験における ST 低下は，一部，冠微小循環障害を反映している可能性がある．しかしながら，冠攣縮性狭心症においては，ST 低下は必ずしも
冠微小循環障害を反映しておらず，運動負荷中に冠攣縮が生じている可能性があり，その解釈には注意が必要である．

J Cardiol 2007 Mar; 49（3）: 109−114

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