From the Department of Cardiology, Yokohama Minami Kyosai Hospital,
Yokohama, Japan (M.S., M.N., M.A., T.A., N.Y.); the Third Department of
Internal Medicine, Tokyo Medical and Dental University, Tokyo, Japan (T.K.,
F.N.); and the Department of Cardiovascular Diseases, Medical Research
Institute, Tokyo Medical and Dental University, Tokyo, Japan (M.H.).
Correspondence to Mitsuhiro Nishizaki, MD, Department of Cardiology, Yokohama Minami Kyosai Hospital, 500, Mutsuura, Kanazawa-ku, Yokohama, Kanagawa, 236-0031, Japan.
Methods and Results—We assessed the corrected QT (QTc) dispersion
before induction of coronary artery spasm by
intracoronary injection of acetylcholine (baseline) and 30
minutes after administration of isosorbide dinitrate in 50 patients
with vasospastic angina and 50 patients with atypical chest pain. The
baseline QTc dispersion was significantly greater in patients with
vasospastic angina than in patients with atypical chest pain (mean±SD:
69±24 versus 44±19 ms, 95% confidence interval of mean difference
[CI]: 16 to 33 ms; P<0.001). QTc dispersion decreased
significantly, to 48±15 ms (CI: 15 to 26 ms; P<0.001
versus baseline), after administration of isosorbide dinitrate in
patients with vasospastic angina but did not change significantly in
patients with atypical chest pain (mean±SD: 41±17 ms, CI: -3 to 9
ms). During the provocation test, 24 of 50 patients with vasospastic
angina experienced ventricular arrhythmias. The
baseline QTc dispersion was significantly greater in patients with than
without ventricular arrhythmias (mean±SD: 77±23
versus 61±19 ms, CI: 4 to 26 ms; P<0.05).
Conclusions—Patients with vasospastic angina exhibited an
increased baseline QTc dispersion compared with patients with atypical
chest pain, which suggests that inhomogeneity of repolarization and
susceptibility to ventricular arrhythmias are
increased in patients with vasospastic angina, even when
asymptomatic. The association between increased QTc
dispersion and ventricular arrhythmias during the
provocation test suggests that measurement of QT dispersion may help
predict which patients with vasospastic angina are at high risk for
ventricular arrhythmias during ischemia.
Measurement of the variability in the duration of the QT interval among
different leads of a standard 12-lead ECG has been proposed as a
noninvasive method to detect inhomogeneity of ventricular
recovery times and arrhythmogenic potential.8 9 10 11
Prolonged QT dispersion is associated with an increased risk of serious
ventricular arrhythmias in patients with the long
QT syndrome,12 13 14 hypertrophic
cardiomyopathy,15 chronic
heart failure,16 and myocardial
infarction.17 18 19 However, no previous studies
have examined QT dispersion in patients with vasospastic angina and its
relation to susceptibility to arrhythmias.
We recently reported that patients with vasospastic angina exhibit
increased ventricular vulnerability, even during an
asymptomatic phase. This increased vulnerability may
predispose them to the development of malignant ventricular
arrhythmias aggravated by vasospastic
events.20 This study was designed to test the
hypotheses that patients with vasospastic angina exhibit an increase in
QT dispersion and that QT dispersion is related to the susceptibility
to ventricular arrhythmias in these patients.
We also studied 50 patients with atypical chest pain (28 men and 22
women; mean age 57 years, range 45 to 70 years) in whom no spontaneous
chest pain was documented by ambulatory Holter monitoring and/or ECG
and who showed no ischemic ST-segment changes with chest pain
on an exercise test. These patients were referred for evaluation with a
provocation test with acetylcholine and were matched to the patients
with vasospastic angina for age, sex, and body mass index.
Both groups had normal results on physical examination and no history
of cardiac disease, overt diabetes mellitus, chronic obstructive lung
disease, renal disease, or endocrine disorders. None of the patients
had abnormalities on resting 12-lead ECGs, 2-dimensional
echocardiograms, or Doppler echocardiograms. No patient was
receiving antiarrhythmic agents or other types of therapy that can
affect the QT interval.
The study protocol was approved by the ethics committee at our
institution. Written informed consent was obtained from all subjects.
Angiographic Analysis
After the injection of 1.0 mg of isosorbide dinitrate into the left and
right coronary arteries, arteriograms were obtained in several
projections and the organic coronary artery lesion was
evaluated. Coronary arteriography was performed again 30
minutes after the relief of vasospasm to confirm the absence of
significant stenosis.
QT Interval and QT Dispersion of a 12-Lead Surface ECG
QT dispersion, defined as the difference between the maximum and
minimum QT intervals, was determined with previously described
methods.7 8 9 10 11 12 13 14 15 16 17 18 19 Both the QT interval and QT
dispersion were rate-corrected with a modification of Bazett's formula
as follows: QTc interval=QT/square root of the RR
interval.22 Measurements were obtained at
baseline (before intracoronary injection of acetylcholine) and
30 minutes after intracoronary injection of isosorbide
dinitrate (when chest pain and ischemic ST changes were not
observed). Because the effect of acetylcholine disappears within
minutes, we considered an interval of 30 minutes between the relief of
coronary vasospasm and the measurement of QT intervals to be
long enough to allow full recovery of any electrophysiologic properties
that might be affected by acetylcholine.21 23 24
An ECG was monitored continuously to record the incidence of
arrhythmias.
Statistical Analysis
None of the patients with atypical chest pain showed significant
vasospasm (>50%) or ischemic ST-segment changes at baseline
or after intracoronary injection of acetylcholine. The total
coronary vasomotor response to acetylcholine, defined as the
percent decrease in the luminal diameter, ranged from -10% to 50%
(31.1±3.0%) in patients with atypical chest pain.
In patients with vasospastic angina, no chest pain or myocardial
ischemic ECG changes were observed at baseline. A spontaneous
25% vasoconstriction of the right coronary artery was observed
in 4 patients and 25% vasoconstriction of the left anterior descending
artery was observed in 4 patients. One patient showed 50%
vasoconstriction of the right coronary artery but did not
exhibit ischemic ECG changes or chest pain.
The remaining 41 patients had normal coronary arteries at
baseline coronary angiography.
All 50 patients with vasospastic angina developed severe
vasoconstriction and typical ischemic symptoms in response to
acetylcholine. Vasospasm of multiple coronary arteries was
induced in 19 of 50 patients; single coronary artery vasospasm
occurred in the remaining 31 patients. Total occlusion was induced in
22 vessels of 16 patients, subtotal occlusion in 25 vessels of 19
patients, and diffuse constriction in 29 vessels of 25 patients.
The acetylcholine-induced symptoms and ECG changes were completely
relieved by the injection of isosorbide dinitrate; there was no
significant residual stenosis. All patients with vasospastic
angina also exhibited normal coronary arteries, without
stenosis, 30 minutes after administration of isosorbide
dinitrate. There were no major complications relating to the injection
of acetylcholine, either in the catheter laboratory or after
catheterization.
Reproducibility of QT Dispersion Measurements
QTc Intervals and QTc Dispersion on Surface ECGs
The QTc interval was significantly smaller at baseline than that after
the relief of coronary vasospasm in patients with vasospastic
angina (Table 2
Ventricular Arrhythmias in Patients With
Vasospastic Angina
At baseline, QTc dispersion was significantly greater in patients with
than without ventricular arrhythmias (mean±SD:
77±23 ms versus 61±19 ms, MD: 16±26 ms, CI: 4 to 26 ms;
P<0.05) (Figure 3
There were no significant differences in baseline patient
characteristics or the severity of vasospasm between patients with
vasospastic angina with and without ventricular
arrhythmias.No patients with atypical chest pain showed
ventricular arrhythmias during the provocation
test.
QT Dispersion in Patients With Vasospastic Angina
Sudden Death in Patients With Vasospastic Angina
The development of ventricular arrhythmias in
patients with vasospastic angina is thought to be caused not only by
reentry associated with myocardial ischemia during vasospasm
but also by reentry and/or triggered activity associated with
reperfusion after the relief of
spasm.6 7 8 9 10 20 32 33 34
In this study, 24 of 50 patients with vasospastic angina experienced
ventricular arrhythmias, including
ventricular tachycardia. Arrhythmias
were observed during induced ischemia but not immediately after
the relief of spasm by the administration of isosorbide dinitrate
(assumed to be a reperfusion period). This may partly be due to the
very short period of myocardial ischemia induced by the
provocation test. QTc dispersion at baseline was significantly greater
in patients with than without ventricular
arrhythmias. There was no difference in the degree or severity
of coronary vasospasm between patients with and without
ventricular arrhythmias. The greater QTc dispersion
in patients with vasospastic angina who developed
ventricular arrhythmias during induced
ischemia may indicate that the dispersion of
ventricular refractoriness was increased in the
asymptomatic state, due to abnormal
microcirculation35 or autonomic
dysfunction.36 37 These findings suggest that
evaluation of QTc dispersion may provide useful information about
baseline abnormalities of ventricular repolarization and
susceptibility to ventricular arrhythmias caused by
ischemia in patients with vasospastic angina.
We recently reported that the effective refractory period for right
ventricular sites is short and that electrophysiologic
instability is present in patients with vasospastic angina, even
when asymptomatic.20 The results of
the present study support these previous findings. Thus the
measurement of QTc dispersion obtained in the nonmedicated,
asymptomatic state appears to be a simple, noninvasive
method of obtaining information about the susceptibility of patients
with vasospastic angina to ventricular
arrhythmias.
Study Limitations
This study did not directly demonstrate a higher risk of sudden death
in these patients. However, in a previous study from our laboratory,
patients with ventricular arrhythmias during
induced myocardial ischemia had a higher incidence of
ventricular tachycardia induced by programmed
stimulation,20 suggesting that the risk of lethal
cardiac events was increased in these patients.
Conclusions
Received December 11, 1997;
revision received March 12, 1998;
accepted March 21, 1998.
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© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Increased QT Dispersion in Patients With Vasospastic Angina
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—The risk factors for
ventricular arrhythmias in patients with
coronary vasospasm have not been identified. We evaluated QT
dispersion in patients with vasospastic angina and its relation to
susceptibility to ventricular arrhythmias during
myocardial ischemia and reperfusion.
Key Words: angina • vasospasm • intervals • arrhythmia • death, sudden
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Life-threatening
ventricular arrhythmias occur in 5% to 15% of
patients with vasospastic angina.1 2 3 4 5 6 7 These
arrhythmias are associated with an increased incidence of
cardiac events, including sudden death.1 2 3 4 5 6 7
However, the factors that increase the risk for malignant
ventricular arrhythmias have not been identified in
patients with vasospastic angina.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Study Patients
We studied 50 consecutive patients with vasospastic angina (29
men and 21 women; mean age 58 years, range 44 to 71 years) evaluated at
Yokohama Minami Kyosai Hospital. All patients exhibited myocardial
ischemic ST-segment changes, either ST elevation or ST
depression, associated with spontaneous episodes of chest pain on
ambulatory Holter monitoring and/or a 12-lead ECG. After
intracoronary injection of acetylcholine, they were classified
angiographically as having total occlusion, subtotal occlusion (99%
with delay), or diffuse vasoconstriction (>90%) associated with chest
pain and/or myocardial ischemic ST-segment
changes.21
Coronary arteriography was performed by the Judkins
technique in the morning while patients were fasting and unsedated.
Antianginal drugs, except for sublingual nitroglycerin,
were discontinued at least 3 days before the study. Baseline
coronary arteriography was performed in the right anterior
oblique projection for the left coronary artery and in the
left anterior oblique projection for the right coronary
artery. A bipolar electrode catheter was inserted into the right
ventricular apex through the right femoral vein and
connected to a temporary pacemaker. The pacing rate was set at 50 bpm.
Incremental doses of acetylcholine were injected into the left
coronary artery (20, 50, and 100 µg) and the right
coronary artery (20, 50, and 70 µg) until
acetylcholine-induced total, subtotal, or diffuse vasoconstriction was
detected angiographically or until the maximum dose was
given.21
The QT interval and QRS duration were measured in all leads of a
12-lead ECG recorded at a speed of 50 mm/s for 2 consecutive
cycles. The QT interval was measured from the beginning of the QRS
complex to the end of the T wave, which was defined as the return to
the TP baseline (between the end of the T wave and the following P
wave); the U wave was excluded. None of the 100 study subjects had a U
wave superimposed on the terminal portion of the T wave. If the T wave
could not be reliably determined or if it had a very low amplitude, QT
measurements were not obtained, and these leads were excluded from the
analysis. The QT interval was measurable in 9 to 12 leads (mean
11±1 leads) in each subject. The mean QT interval was calculated as
the average of all measurable leads.
Data are expressed as the mean value±SD, mean differences±SD
(MD), and 95% confidence interval of mean difference (CI). The
two-tailed paired Student's t test was used to
analyze changes in the QTc interval, QTc dispersion, and
hemodynamic variables. Between-group comparisons
were made with the two-tailed unpaired Student's t test.
Multiple comparisons of continuous variables were performed by
ANOVA. Fisher's exact probability test or the
2 test was used to evaluate group differences
in categorical variables. A P value <0.05 was
considered to indicate statistical significance. The reproducibility of
the QT dispersion measurements was examined in 50 patients with
vasospastic angina at baseline and after the relief of vasospasm by 2
independent experienced observers who were unaware of the patient's
diagnosis. Agreement between observers was verified with the
Bland-Altman method.25
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Characteristics and Angiographic Results
There were no significant differences in baseline characteristics
between groups (Table 1
).
View this table:
[in a new window]
Table 1. Patient Characteristics
The mean difference between observers in the measurement of
baseline QT dispersion (n=50) was 0±4 ms and 95% CI was between –1
and 1 ms. After the relief of vasospasm, the mean difference between
observers was 0±5 ms and 95% CI was between –1 and 1 ms (Figure 1).
View larger version (22K):
[in a new window]
Figure 1. Reproducibility of measurements of QTc dispersion
at baseline (A) and after the relief of vasospasm (B) in 50 patients
with vasospastic angina by 2 observers using the Bland-Altman method.
There are fewer than 50 points because of data overlap.
The mean heart rate increased significantly after the relief of
coronary vasospasm compared with the baseline value in both
groups (vasospastic angina, mean±SD: 70±14 versus 76±15 bpm, MD:
-6.0±15 bpm, CI: -10 to -2 bpm, P<0.01; atypical chest
pain, mean±SD: 71±14 versus 76±14 bpm, MD: -5±13 bpm, CI: -8 to
-1 bpm, P<0.01). Systemic arterial pressure
did not change significantly after the relief of vasospasm in either
group (vasospastic angina, mean±SD: 125±22 versus 120±20
mm Hg, MD: 5±22 mm Hg, CI: -2 to 10 mm Hg; atypical
chest pain, mean±SD: 124±21 versus 119±20 mm Hg, MD:
5±29 mm Hg, CI: -3 to 13 mm Hg). There was no significant
difference in the mean QRS interval between patients with vasospastic
angina and patients with atypical chest pain. In patients with
vasospastic angina, the QRS interval at baseline was 74±19 ms; after
the relief of coronary vasospasm, it was 74±17 ms (MD: 0±5
ms, CI: -1 to 2 ms). In patients with atypical chest pain, it was
74±16 ms at baseline and after injection of isosorbide dinitrate (MD:
0±5 ms, CI: -1 to 2 ms). ). The baseline QTc
dispersion was significantly greater in patients with vasospastic
angina than in patients with atypical chest pain (mean±SD: 69±24 ms
versus 44±19 ms, MD: 25±30 ms, CI: 16 to 33 ms; P<0.001)
(Figure 2). QTc dispersion decreased
significantly, to 48±15 ms (MD: 21±20 ms, CI: 15 to 26 ms;
P<0.001 versus baseline) after administration of isosorbide
dinitrate in patients with vasospastic angina but did not change
significantly in patients with atypical chest pain (mean±SD: 41±17
ms, MD: 3±22 ms, CI: -3 to 9 ms) (Figure 2).
View this table:
[in a new window]
Table 2. ECG Variables at Baseline and After Isosorbide
Dinitrate in Patients With Vasospastic Angina and in Patients With
Atypical Chest Pain
View larger version (24K):
[in a new window]
Figure 2. QTc dispersion in patients with vasospastic angina
(n=50) and patients with atypical chest pain (n=50). Baseline indicates
before induction of coronary vasospasm; After ISDN, 30 minutes
after relief of vasospasm by intracoronary injection of
isosorbide dinitrate. Bars indicate SD; boxes indicate mean
values.
Ventricular arrhythmias occurred in 24 of 50
patients with vasospastic angina only during the provocation test.
Polymorphic nonsustained ventricular
tachycardias lasting at least 3 consecutive beats were
observed in 5 of 24 patients. The remaining 19 patients had less
serious ventricular arrhythmias, including isolated
premature ventricular contractions, bigemini, and couplets.
All ventricular arrhythmias were observed when the
patients had ischemic symptoms after the administration of
acetylcholine and no ventricular arrhythmias were
observed immediately after intracoronary injection of
isosorbide dinitrate. ). QTc
dispersion did not differ significantly between these subgroups after
the relief of coronary vasospasm (mean±SD: 47±14 versus
48±14 ms, MD: -1±20 ms, CI: -8 to 9 ms) (Figure 3).
View larger version (27K):
[in a new window]
Figure 3. QTc dispersion in patients with vasospastic angina
with (n=24) and without (n=26) ventricular
arrhythmias during induced myocardial ischemia. Bars
indicate SD; boxes indicate mean values. Baseline indicates before
induction of coronary vasospasm; After ISDN, 30 minutes after
relief of vasospasm by intracoronary injection of isosorbide
dinitrate; Ventricular arrhythmias (+) (n=24),
patients with ventricular arrhythmia during the
induction of coronary spasm by acetylcholine; and
Ventricular arrhythmias (-) (n=26), patients
without ventricular arrhythmia.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
In the present study, patients with vasospastic angina
exhibited greater baseline QTc dispersion than patients with atypical
chest pain. Increased QTc dispersion in asymptomatic
patients with vasospastic angina was associated with increased
vulnerability to ventricular arrhythmias related to
ischemic events. These findings suggest that patients with
vasospastic angina have increased dispersion of ventricular
repolarization, which may increase the risk of sudden death caused by
malignant arrhythmias.1 2 3 4 5 6 7 The
present findings support previous reports demonstrating that
subsets of patients with increased QT dispersion are at increased risk
of sudden cardiac death.8 9 10 11 12 13 14 15 16 17 18 19
To the best of our knowledge, this study is the first to evaluate
QT dispersion in patients with vasospastic angina. QT dispersion
reflects the regional variation in ventricular
repolarization, which is an electrophysiologic substrate for the
genesis of arrhythmias. QT dispersion has been proposed as a
marker of arrhythmogenic potential.8 9 10 11 12 13 14 15 16 17 18 19 In this
study, the baseline QTc dispersion was significantly increased in
patients with vasospastic angina without evidence of myocardial
ischemia or angiographically detectable coronary artery
spasm. After the relief of vasospasm by isosorbide dinitrate, QTc
dispersion decreased significantly to the level similar to that in
patients with atypical chest pain. These data suggest that patients
with vasospastic angina have greater inhomogeneity of repolarization,
independent of the presence or absence of ischemic
symptoms.
Fatal ventricular arrhythmias have frequently
been documented in patients with ischemic heart diseases,
including vasospastic angina, exertional angina, and myocardial
infarction.1 2 3 4 5 6 7 Previous studies have shown that
the occurrence of ventricular arrhythmias depends
on the magnitude of the dispersion in the refractory period.
Inhomogeneity and increased dispersion of repolarization may promote
polymorphic ventricular tachycardia and
ventricular fibrillation.20 26 27 28 29 30 31
The relation between the incidence of ventricular
arrhythmias during the ischemic state and the prognosis
of these patients remains to be determined.
QTc dispersion was increased in asymptomatic patients
with vasospastic angina compared with patients with atypical chest
pain, indicating that patients with vasospastic angina had greater
inhomogeneity of ventricular refractoriness, which may
predispose them to life-threatening arrhythmias, even in the
absence of signs of ischemia. The relation between increased QT
dispersion and the incidence of ventricular
arrhythmias during myocardial ischemia in patients with
vasospastic angina suggests that the simple, noninvasive measurement of
QT dispersion may help identify patients at an increased risk of
malignant arrhythmias. The prognostic implications should be
evaluated in prospective follow-up studies.
Footnotes
Presented in part at the 69th Annual Scientific Sessions of the American Heart Association, New Orleans, La, November 10–13, 1996, and previously published in abstract form (Circulation. 1996;94[suppl I]:I-505).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
1.
Hills LD, Braunwald E. Coronary artery
spasm. N Engl J Med. 1978;299:695–702.[Medline]
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