From the Cardiology Department, University Hospital of Wales, Cardiff,
South Wales (C.A.R., A.Z.L., N.D.M., P.G.A., E.J.); and Cardiology, Royal
Postgraduate Medical School, London, UK (C.A.R., R.J.C.H.).
Correspondence to Dr Christopher A. Rinaldi, Cardiology Department, Medway Hospital, Gillingham, Kent ME7 5NY, United Kingdom. E-mail c.a.rinaldi{at}btinternet.com
Methods and Results—Twenty-four men with chronic stable angina
and normal left ventricular function underwent serial
quantitative exercise stress echocardiography after
3 weeks on each treatment to assess the degree of postexercise stunning
with simultaneous sestamibi single-photon emission computed
tomography perfusion scans at peak stress to quantify the
ischemic burden. Exercise time (P=1), maximum ST
depression (P=0.48), and sestamibi single-photon
emission computed tomography scores (P=0.17) were
unchanged between treatments. Stunning occurred more often with ISMN
than amlodipine (82% versus 48%). The global and segmental stress
echocardiography parameters of stunning
were attenuated in patients while taking amlodipine compared with ISMN.
Shortening fractions and ejection fractions were less impaired 30
minutes after exercise in patients receiving amlodipine (3.5±1.4%
versus 2.5±1.4%, P=0.014, and 59.7±5.4% versus
54.5±8%, P<0.001); similarly, the isovolumic
relaxation period was less prolonged with amlodipine (93±15.5 versus
106.3±14.9 ms, P=0.018).
Conclusions—Despite comparable levels of ischemia,
amlodipine attenuated stunning when compared with ISMN. This beneficial
effect may relate to a prevention of the calcium overload implicated in
the pathogenesis of stunning.
Intracellular calcium plays a key role in myocardial contraction and
relaxation, and alterations in calcium homeostasis are thought to be
involved in the pathogenesis of stunning.9 10 11 12
Animal studies have shown that the administration of calcium
antagonists during ischemia and before reperfusion
can attenuate myocardial stunning.13 14 15 16 17 18 19 20 To
determine whether the calcium antagonist amlodipine could
attenuate exercise-induced myocardial stunning in humans, we performed
a double-blind crossover study in patients with significant
coronary artery disease and chronic stable angina. Quantitative
stress echocardiography was used to assess
postexercise LV dysfunction, and nuclear perfusion imaging was used to
quantify exercise-induced ischemia. Amlodipine was compared
with an equivalent anti-ischemic dose of isosorbide mononitrate
(ISMN), which has no direct effect on myocardial function, in an
attempt to match the ischemic burden on both treatments.
Potential beneficial effects of amlodipine on stunning would therefore
not be attributable to an anti-ischemic action because both
treatments should reduce ischemia equally.
Study Protocol
Exercise-Echocardiogram Protocol
Echocardiography
Echocardiographic Analysis
Myocardial Perfusion Scans
End Points
Statistical Analysis
Primary Efficacy: Echocardiography
Most wall motion abnormalities were present at 15 minutes after
exercise, and the majority of abnormalities had recovered by 45 minutes
after exercise.
Table 2
Mean echocardiographic parameters at 15 and
30 minutes after exercise and the P values for
analysis of preexercise to postexercise changes are summarized
in Table 3
All echo cardiographic data met the assumption of homogeneity of
variances required for using ANOVA.
There was a significant difference between treatments in favor of
amlodipine at 15 and 30 minutes after exercise for SFworst (3.3±1.7%
versus 2.3±1.3% and 3.5±1.5% versus 2.5±1.4%, P=0.014)
and SFwma (2.8±0.8% versus 2.5±0.8% and 3.0±0.7% versus
2.6±0.9%, P=0.008). The differences between SFmean were
also highly significant in the same direction (3.7±0.4% versus
3.1±0.5% and 3.6±0.4% versus 3.2±0.5%, P=0.001), as
were differences in EF after exercise (59.5±4.9% versus 53.1±7.9%
and 59.7±5.4% versus 54.5±8%, P=0.0001).
Nonparametric analysis of IRP revealed the effect
of treatment was also highly significant in favor of amlodipine
(88.5±15.6 versus 106.6±18.9 ms and 93±15.5 versus 106.3±14.9 ms,
P=0.0018).
Figure 4
Secondary Efficacy Parameters
Exercise Test Parameters
Adverse Events
Broadly, this very marked attenuation in stunning could have two
explanations that are not mutually exclusive. The amlodipine may have
reduced the ischemia more than the nitrates, and reduced
stunning was simply due to less causative ischemia, or it may
have an intrinsic antistunning effect. The results of this study and
the results of previous basic and animal work strongly favor the second
explanation. Most importantly, exercise time was the same in the two
situations, whereas the tests of the degree of ischemia both by
myocardial perfusion imaging and ST-segment analysis did not
show any evidence for the reduced ischemia hypothesis, and in
fact there was a slight trend in the opposite direction. Furthermore,
there was no evidence of beneficial changes in
hemodynamics in the amlodipine group (such as reduced
afterload or negative inotropic effect) that could have reduced
ischemia. In our study the favorable
hemodynamic and anti-ischemic effects (defined
and quantified by sestamibi SPECT) of amlodipine and ISMN were matched
by virtue of the crossover design.
Previous experimental work also favors the hypothesis that calcium
antagonists have a direct antistunning effect, possibly
because calcium overload has a pathogenetic mechanism. Calcium
antagonists confer protection from stunning in isolated
hearts with improved recovery of function after global ischemia
and reperfusion.13 14 Nifedipine,
diltiazem, and verapamil reduce stunning in vivo, but it is
unclear whether this is due to favorable hemodynamic
changes that reduce cardiac work or a direct effect on the myocyte by a
reduction in intracellular calcium.17 18 In
conscious dogs instrumented to produce chronic coronary
stenoses, recovery of exercise-induced contractile dysfunction
is shortened (5 versus 30 minutes) in dogs pretreated with
diltiazem,25 although this benefit may have been
due to increased subendocardial flow in the ischemic zone.
Intracoronary injection of calcium antagonists
(thereby avoiding systemic hemodynamic effects) during
coronary angioplasty has shown a protective effect on stunning,
suggesting a direct effect caused by a reduction in intracellular
calcium.26
In a recent study in humans, systolic and diastolic
dysfunction after exercise was attenuated by sublingual
nifedipine but not nitroglycerin
administered at peak exercise,27 and our findings
are in agreement with this. This previous study, however, had several
limitations. It was unblinded and did not use patients as their own
controls. Furthermore, not all patients had definite coronary
disease confirmed by arteriography, and there were favorable changes in
BP after exercise with nifedipine that may have contributed
to its beneficial effect by a reduction in cardiac work, which might
have reduced ischemia and indirectly the degree of stunning.
Similarly, not all patients underwent myocardial perfusion scans and
therefore a significant difference in exercise-induced ischemia
between the groups may have contributed to the reduction in stunning
seen with nifedipine. Our study has controlled for these
factors to a much greater degree and does not have these shortcomings.
Its other main difference is that it is a study of the long-term
therapy of the type that would be given to such patients in real
life.
This finding may have important therapeutic implications, since it is
likely that stunning occurs after episodes of ischemia during
everyday life, which could result in prolonged episodes of LV
dysfunction. It has been postulated that repetitive stunning of the
type shown by us may result in chronic LV
impairment.28 Identification of clinically
available therapeutic strategies that attenuate stunning and therefore
lessen the impact of ischemia on LV function represent
an important step in improving the medical management of patients with
coronary artery disease.
Study Limitations
In conclusion, our data demonstrate a beneficial effect of amlodipine
on postexercise LV dysfunction, and is to our knowledge the first ever
randomized, double-blind study to show a beneficial effect of calcium
antagonists (or any other therapy) on stunning. It is very
unlikely that this benefit was mediated by a mechanism directly related
to its anti-ischemic or hemodynamic effects
because these parameters did not change significantly,
although the exact mechanism remains undetermined.
Received December 15, 1997;
revision received March 30, 1998;
accepted April 21, 1998.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Randomized, Double-Blind Crossover Study to Investigate the Effects of Amlodipine and Isosorbide Mononitrate on the Time Course and Severity of Exercise-Induced Myocardial Stunning
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—Myocardial stunning may
cause prolonged left ventricular dysfunction after
exercise-induced ischemia that can be attenuated by calcium
antagonists in animal models. To assess their effects in
humans, we performed a randomized, double-blind crossover study
comparing the calcium antagonist amlodipine (10 mg once
daily) versus isosorbide mononitrate (ISMN, 50 mg once daily) on
postexercise stunning.
Key Words: stunning, myocardial • calcium channels • echocardiography • exercise
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Myocardial stunning,
or postischemic dysfunction, is the mechanical dysfunction
that persists after ischemia is relieved despite the absence of
irreversible damage.1 2 It is thought to be an
important phenomenon in clinical settings of transient ischemia
and reperfusion including myocardial infarction, unstable angina, and
coronary artery bypass grafting.3 4
Stunning has been shown to occur after ischemia induced by
increased myocardial oxygen demand in animals with partial
coronary stenoses,5 and several
echocardiographic studies in humans have suggested that
stunning occurs after treadmill exercise.6 7
Recently by simultaneously measuring left
ventricular (LV) function and perfusion, reversible
myocardial dysfunction persisting after exercise in patients with
coronary artery disease has been demonstrated to be due to
myocardial stunning.8 Abnormalities of
contraction may persist for up to 1 hour, whereas diastolic
abnormalities may persist for several hours after a single episode of
effort angina. The duration of contractile abnormalities after
exercise-induced ischemia suggests that patients may suffer
important LV dysfunction as the result of myocardial stunning during
daily activities.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient Selection
We studied 24 patients with chronic stable angina, normal
resting LV function as assessed by
echocardiography, and significant coronary
artery disease (
70% stenosis in 2 major epicardial vessels
demonstrated on coronary arteriography <1 month before
randomization). Patient demographics are shown in Table 1
. Patients were excluded if there was a
history of recent myocardial infarction, unstable angina, uncontrolled
hypertension, or concomitant disease that precluded treadmill exercise.
Patients were also excluded if it was not possible to obtain
echocardiograms of sufficient quality to perform quantitative
analysis (1 patient). The study protocol was approved by the
Research Ethics Committee of the University Hospital of Wales, and all
patients gave full written informed consent.
View this table:
[in a new window]
Table 1. Patient
Demographics
After initial evaluation, patients were randomly assigned, in a
double-blind fashion, to receive either oral amlodipine or ISMN for 3
weeks. After a 2-week washout phase, the patient crossed over to the
alternative treatment for a further 3 weeks. The amlodipine regime
comprised 5 mg once daily for 7 days followed by 10 mg once daily for 2
weeks. The ISMN regime comprised 25 mg once daily for 7 days followed
by 50 mg once daily for 2 weeks. With both regimens, adjustment to the
higher dose was subject to adverse events and clinical discretion.
During the study, all patients received metoprolol at a stable dosage
of 50 mg twice daily (although discontinued before exercise testing)
and aspirin 75 mg once daily. All other antianginal medication was
discontinued during the study period.
Exercise Tests
Exercise testing was performed according to the Standard Bruce
Protocol with a Marquette treadmill at the end of each treatment period
4 to 8 hours after the previous dose of study medication. ß-Blockade
was withdrawn before exercise by halving and discontinuing metoprolol
at 48 hours and 24 hours, respectively. Patients were advised to avoid
activities that may precipitate angina for 24 hours before the test and
to use prophylactic glyceryl trinitrate up until 4 hours
before study. Patients were excluded if they had angina or used
prophylactic glyceryl trinitrate within 4 hours
before the test. Three ECG leads (II, V2, and
V5) were continuously monitored during exercise
and recovery. Blood pressure (BP) reading and 12-lead ECG were
performed every 3 minutes during exercise and every 2 minutes in
recovery until resolution of ECG changes and a return of heart rate and
BP to baseline values. Patients exercised until they experienced chest
pain and continued until limited by their symptoms. Exercise was also
discontinued if a drop in systolic BP of 10 mm Hg
or significant arrhythmias occurred with exercise.
Two-dimensional echocardiograms were obtained with the patient
in the left lateral decubitus position with commercially obtainable
equipment (Hewlett-Packard Sonos 1500, model 77025A) with a 2.5-MHz
phased array transducer. All studies were performed by the same
investigator (C.A.R.). To ensure reproducibility, the position of the
patient on the couch was documented at baseline and used for each image
acquisition and the position of the transducer on the patient's chest
was marked. To minimize beat-to-beat variation, all recordings
were made in gently held expiration. Studies were recorded on super
VHS videotape for later off-line analysis. LV contractile
function was assessed in the apical 2-chamber (AP2CH) and apical
4-chamber (AP4CH) views as described in the guidelines from the
American Society of
Echocardiography.21 Pulsed
wave (PW) Doppler tracings of LV diastolic inflow at
the tips of the mitral valve leaflets were recorded at rest with
simultaneous recording of the phonocardiogram (in
the second left intercostal space). Images were recorded at rest,
immediately after exercise, and then at 15-minute intervals for 4 hours
after exercise.
The videotaped images were analyzed by two experienced
observers (C.A.R, A.Z.L.) using an off-line PC-based digitizing program
(Thoraxcenter, Erasmus University, Rotterdam, the
Netherlands).22 Three consecutive beats
(excluding extrasystolic and
postextrasystolic beats) were analyzed for
each time point in the AP2CH and AP4CH views. Endocardial contours were
traced (excluding papillary muscles) at end diastole timed
as the closure of the mitral valve leaflets and at end systole defined
as the point of maximal inward excursion of the endocardial contour.
The centerline method was used to assess regional LV
function23 24 in which the computer superimposes
the end-diastolic and end-systolic endocardial
tracings and calculates a centerline between the two. The deviation
from the centerline of 100 chords around the LV circumference is
calculated after correction for the end-diastolic
circumference and expressed as a percentage shortening fraction (SF).
Each apical view of the LV is divided into 6 segments and the SF of the
chords in each segment is averaged so that a total of 12 values are
obtained (6 AP4CH+6 AP2CH). We calculated SF for all 12 segments
(SFmean), for segments with a wall motion abnormality (SFwma), and in
the segments that developed the most severe wall motion abnormalities
(WMAs) after exercise (SFworst). In preliminary studies we obtained a
10% variability of SF in normal regions; for this study a change in SF
from baseline of >20% was taken as abnormal (ie, WMA). A persistent
WMA abnormality was one defined as present 15 and or 30 minutes
after exercise. LV volumes at end diastole and end systole
were calculated by using the biplane disk method, and global ejection
fraction (EF) (%) was derived by using the formula
Analysis of diastolic indexes were performed
by using a digitizing tablet and tracing PW Doppler LV inflow
signal (5 consecutive beats for each time point). Multiple
diastolic parameters were derived including the
isovolumic relaxation period (IRP), measured as the interval between
aortic valve closure from the phonocardiogram and the onset of the E
wave on the Doppler trace. Other indexes included E wave maximal
velocity, A wave maximal velocity, E/A wave ratio, time velocity
integral of the E wave, deceleration rate, and deceleration time of the
E wave.
Single-photon emission computerized tomography (SPECT) with
99-Technetium sestamibi (sestamibi SPECT) was performed on 3 separate
occasions for each patient. A baseline scan was initially performed on
a separate day at rest with the patients taking no active study
medication to demonstrate resting myocardial perfusion. The two peak
exercise scans were performed at the end of each treatment period. On
each occasion a single peripheral intravenous
injection of 400 MBq sestamibi was given. For the peak stress scans
sestamibi was given at peak exercise and imaging was performed 70
minutes after exercise. Tomographic imaging was performed with an
Elscint SP4 gamma camera and high-resolution low-energy collimator. The
data were quantified with a dedicated PC-based workstation. Two
experienced observers, (P.G.A., E.J.) blinded to the clinical and
echocardiographic data analyzed the SPECT
images. A 4-segment model dividing the ventricle into anterior,
posterior/lateral, inferior, and septal regions was used.
Each segment was given a score from 0 to 3, in which 3=normal
perfusion, 2=mild perfusion defect, 1=moderate perfusion defect, and
0=severe perfusion defect. Peak exercise studies were compared with the
rest study, and a change in a segment score of >1 was considered
abnormal. Total perfusion scores were calculated by adding the sum of
each segmental score.
The primary efficacy analyses were based on a comparison
of the effects of amlodipine and ISMN on the
echocardiographic parameters of LV
dysfunction after exercise. These were SFworst, SFmean, SFwma, EF, and
IRP. Secondary efficacy parameters were time from stunning
to recovery, total sestamibi SPECT scores, maximum ST-segment
depression, and total exercise duration. The safety of amlodipine and
ISMN was assessed from adverse events and intercurrent illnesses during
treatment.
A sample size of 24 patients was calculated to have sufficient
power to give an 80% chance of detecting a significant difference
between treatments at the 95% confidence level. The evaluation of
efficacy was based on the intent-to-treat population with a
subanalysis performed on the efficacy evaluable population. The
echocardiographic parameters and maximum
ST-segment depression were subjected to ANOVA if data met the
homogeneity of variances assumptions; Wilcoxon rank sum tests
were used to analyze data that did not meet those assumptions.
Recovery times for patients who showed stunning were analyzed
with logistic regression. Sestamibi SPECT scores were analyzed
with Wilcoxon rank sum test. Significance values were 10% for
period by treatment interactions and 5% otherwise. Adverse event data
were analyzed with McNemar's test.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
Patient demographic details are shown in Table 1
. The mean age of
patients was 60.25 years (range 47 to 75). All patients had a primary
diagnosis of angina (mean duration 3.54 years). Seventeen (71%)
patients had 3-vessel coronary disease and 7 (29%) had
2-vessel disease. All patients except 1 were of Caucasian origin
(patient 24: Asian origin). The mean weight was 85.35 kg (range 56 to
124 kg). Most patients had at least 1 concomitant condition, most
commonly hypertension and
hypercholesterolemia.
Postexercise stunning was defined as a new wall motion abnormality
(change in SF >20% from baseline) present at 15 and/or 30 minutes
after exercise in myocardial segments that had matched perfusion
defects at peak stress. Overall, fewer patients exhibited stunning
during amlodipine treatment than while receiving ISMN (48% versus
82%, P=0.028). and Figures 1, 2, and 3 demonstrate the systolic and
diastolic echocardiographic
parameters after exercise. The difference between treatment
groups in time to recovery was not statistically significant
(P=0.887). Analysis of percentage change from
preexercise to 15 or 30 minutes after exercise (whenever lower SFworst
occurred) showed that exercise-induced changes were less with
amlodipine than ISMN for all echocardiographic
parameters.
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Table 2. Effects of Exercise-Induced Ischemia on Postexercise
Systolic and Diastolic Echocardiographic Indexes
(Mean±SD)
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Figure 1. Effect of exercise-induced ischemia on
postexercise EF (mean±SE). 
P<0.001 vs
preexercise (ANOVA). Pre indicates preexercise.
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Figure 2. Effect of exercise-induced ischemia on
postexercise IRP (mean±SE). P<0.001,
*P<0.05 vs preexercise (ANOVA). Pre indicates
preexercise.
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Figure 3. Effect of exercise-induced ischemia on
postexercise SFworst (mean±SE). P<0.001,
**P<0.005 vs preexercise (ANOVA). Pre indicates
preexercise..
View this table:
[in a new window]
Table 3. Primary Echocardiographic Efficacy
Variables demonstrates an example of the
beneficial effect of amlodipine on postexercise stunning in a study
patient with 3-vessel disease.
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Figure 4. Changes in SF (mean±SD) after exercise on both
treatments in a patient with 3-vessel disease. SFworst shown for a
segment of the lateral wall subtended by a critically stenosed
circumflex artery. Peak sestamibi SPECT scans demonstrated a moderate
perfusion defect in this area of equal severity on both treatments.
With amlodipine, no significant decrease in SF occurred. With ISMN, SF
was significantly decreased at both 15 and 30 minutes after exercise
(to 35% and 52% of preexercise levels, respectively).
*P<0.01 (ANOVA).
Perfusion Scores
The mean sestamibi scores for each segment and mean total scores
at baseline and at peak stress on both treatments are shown in Table 4. Nonparametric
analysis of total MIBI SPECT scores revealed no significant
difference in the amount of ischemia at peak stress between
amlodipine and ISMN (8.5±2.2 versus 7.9±1.8, P=0.172,
Koch's test). (See Figures 5 and 6.)
View this table:
[in a new window]
Table 4. MIBI SPECT Scores (Mean±SD) at Peak Exercise on
Each
Treatment
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Figure 5. Peak sestamibi SPECT scores (mean±SD) on each
treatment. There was no significant difference in the amount of
ischemia at peak stress. P=0.172 (Koch's
test).
View larger version (92K):
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Figure 6. Echocardiographic analysis
and sestamibi SPECT images. Left, Echocardiographic
analysis of AP4CH views of the left ventricle at rest (top
image) and at 15 minutes after exercise with amlodipine (middle image)
and ISMN (bottom image). End-systolic and
end-diastolic contours are traced, and a centerline is
drawn between them from which regional SF is calculated. A reversible
WMA is seen in the septum after exercise with both treatments, which is
more severe on ISMN than with amlodipine. Right, Horizontal short-axis
SPECT images at rest and at peak stress on each treatment demonstrating
a septal perfusion defect. Severity of the WMA is more severe with ISMN
than with amlodipine despite the equivalent degree of ischemia
at peak stress on MIBI SPECT.
Exercise test results were similar on both treatments. All
exercise parameters including ST-segment depression, chest
pain, BP, and heart rate returned to baseline within 10 minutes of
exercise cessation in all cases. There was no significant difference
for maximum ST-segment depression (1.8±1.3 versus 1.6±.9 mm,
P=0.482, ANOVA). Similarly, total exercise duration
(397±170 versus 404±171 seconds, P=1, Wilcoxon
rank sum test) was unchanged between amlodipine and ISMN. (See Table 5.) There was no difference between blood
pressure measurements between treatments during and after exercise.
View this table:
[in a new window]
Table 5. Exercise Results
(Mean±SD)
Adverse events were more frequent with ISMN than with amlodipine
(46% versus 15%, P=0.008, McNemar's test), with the most
commonly reported adverse event being headache.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The exercise-induced ischemia produced in this study
caused significant regional wall motion abnormalities, reduced global
LV ejection fraction, and lengthening of IRP, which was prolonged but
eventually recovered and thus fulfills the criteria for stunning. These
abnormalities did not occur or were significantly less marked when the
patients were receiving amlodipine compared with ISMN.
There are limitations to the use of endocardial wall excursion as
the sole criterion of abnormal contractile function; neither wall
thickening nor transmyocardial heterogeneity is taken
into account. However, it does provide a quantitative method that is
repeatable and it is likely that only subtle abnormalities of regional
LV function are missed. The use of a semiquantitative scoring system
for myocardial perfusion scintigraphy in SPECT may be
subject to error, but again it is likely that only subtle abnormalities
of myocardial perfusion were missed.
Acknowledgments
This study was supported by a grant from Pfizer Ltd.
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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