From the Divisione di Cardiologia I, Istituto Cardiologico "G.M.
Lancisi," Ancona, Italy; and the Division of Cardiology, Harbor-UCLA
Medical Center, Torrance, Calif.
Correspondence to Romualdo Belardinelli, MD, Ospedale Cardiologico "G.M.Lancisi," Divisione di Cardiologia I, 60100 Ancona, Italy.
Methods and Results—To investigate whether exercise
training can improve thallium uptake and the contractile response to
low-dose dobutamine of dysfunctional
myocardium, 46 patients (42 men, 4 women; mean age, 57±9
years) with chronic coronary artery disease and impaired LV
systolic function (ejection fraction <40%) were randomly
assigned to two groups. The exercise group (n=26) underwent exercise
training at 60% of peak oxygen uptake for 8 weeks. The control group
(n=20) was not exercised. At baseline and after 8 weeks all patients
underwent an exercise test with gas exchange analysis and
stress echocardiography using low-dose
dobutamine (5 to 10 µg/kg per minute) followed by
thallium myocardial scintigraphy. Coronary
angiography was performed in 23 patients at baseline and after 8 weeks.
After 8 weeks, peak oxygen uptake increased significantly only in
trained patients (24%). Significant improvements in the contractile
response to dobutamine and thallium activity were observed
in trained patients (28% and 31%, respectively; trained versus
control: P<.001 for both). In a subgroup of trained
patients, both improvements were correlated with an increase in the
coronary collateral score (P<.005 and
P<.001, respectively).
Conclusions—Moderate exercise training improves both thallium
activity and the contractile response of dysfunctional
myocardium to low doses of dobutamine in
patients with ischemic cardiomyopathy. The
implication of this study is that even a short-term exercise
training may improve quality of life by improvement of LV
systolic function during mild-to-moderate physical activity in
patients with ischemic cardiomyopathy.
The ability of positron emission tomography to identify viable
myocardium in patients with wall motion abnormalities at
rest has been compared with that of dobutamine stress
echocardiography or thallium
scintigraphy.9 Nuclear
cardiology techniques have the unique potential to
distinguish viable tissue on the basis of perfusion, cell-membrane
integrity, and metabolic activity, while
dobutamine echocardiography provides
information on inotropic reserve of dysfunctional segments. The former
are more sensitive, while the latter is more specific in identifying
myocardial viability; the concordance between the two methods ranges
from 68% to 79%.10 11
Low-dose dobutamine stress
echocardiography has been compared with positron
emission tomography in detecting viable postischemic
myocardium, giving excellent
results.11 Low doses of dobutamine
can determine inotropic stimulation with minimal increase in heart rate
and reduced onset of myocardial ischemia as well as
ventricular arrhythmias. By comparing pretraining
and posttraining responses to low-dose dobutamine infusion,
we should be able to obtain differential information about the effects
of moderate exercise training on indexes of left
ventricular systolic performance as well as
postischemic myocardial viability.
In the past, Wyatt et al12 and Spina et
al4 reported increased inotropic response to high
doses of catecholamines after endurance exercise training.
However, it is not clear whether the enhanced
contractility after training can be observed in
patients with ischemic heart disease by using small doses of
dobutamine and whether the identification of dysfunctional
but viable myocardium can predict the improvement in
contractility after moderate exercise training.
The purpose of the present study was to determine whether a 2-month
exercise training program of moderate intensity (60% of
peak oxygen uptake) can improve thallium activity and the contractile
response to low-dose dobutamine of dysfunctional
myocardium in patients with coronary artery disease
and depressed left ventricular function. We
hypothesized that both adaptations are related to a training-induced
improvement of coronary collaterals and that a combination of
these adaptations may improve left ventricular
contractility in response to ß-adrenergic
stimulation.
Exercise Training
Cardiopulmonary Exercise Test
Dobutamine Stress Echocardiography
Regional Left Ventricular Function
After 8 weeks, improvement in the contractile response to
dobutamine, as compared with the initial study, was defined
as a reduction in systolic wall thickening grade by 1 or more
at peak infusion in at least two adjacent segments and/or a
Data Analysis
Left Ventricular Systolic Function
Two independent experienced observers evaluated the
echocardiographic images in a blinded manner from
videotape playback. The observers were also blinded with regard to the
patient's identity and allocation into the training or control group.
The two observers disagreed in 7% of the studies; a third independent
experienced cardiologist resolved differences in interpretation.
Thallium Scintigraphy
Data Analysis
Qualitative Analysis
Segments with a score
Quantitative Analysis
Myocardial segments with reduced thallium uptake on the stress images
were considered viable when thallium activity increased by at least one
grade in the redistribution or reinjection images. If a reduced
thallium activity on the stress images did not change during
redistribution or reinjection, the segment was considered
nonviable.
Thallium images obtained after 8 weeks were read using the same methods
as the baseline study and compared side by side to the corresponding
pretraining images. Improvement in thallium uptake, as compared with
the initial study, was defined as an increase in thallium activity by
one or more grades in any of the three acquisition imaging series.
The serial thallium images were visually analyzed by two
independent observers using consensus readings. A third observer was
asked to resolve the difference when agreement was not achieved. A
consensus decision was obtained in all cases.
Coronary Angiography
Statistical Analysis
After 8 weeks, peak oxygen uptake, ventilatory threshold and peak work
rate were all increased in trained patients (24%, 30%, and 27%,
respectively) (Table 2
Dobutamine Stress Echocardiography
After 8 weeks, in trained patients, of 252 segments with resting
wall motion abnormalities, 178 (71%) demonstrated improved
contractility compared with 55% (141 of 257) with
positive inotropic response on initial evaluation. Of the abnormal
segments with contractile response, 125 were hypokinetic, 48 akinetic,
and 5 dyskinetic. On both initial and final dobutamine
stress echocardiographic studies, all the changes in
systolic wall thickening were observed during the first 5
minutes of infusion. At peak infusion, we did not have any further
response. Of interest, only the trained patients had a 28% improvement
in the systolic wall thickening score index at peak infusion,
indicating an increased inotropic response to low-dose
dobutamine after exercise training. The improvement in
systolic wall thickening score index was related to an
increased number of dysfunctional myocardial segments with an enhanced
inotropic response to dobutamine. As shown in Table 3
Left Ventricular Systolic Function
Left ventricular end-systolic wall stress
decreased on study entry and after 8 weeks in trained patients (study
entry: rest 89±6 g/cm2; peak
dobutamine, 71±5 g/cm2; after
training: rest, 87±6 g/cm2; peak
dobutamine, 70±5 g/cm2). However,
from the relation between pretraining and posttraining
changes in rest-to-peak dobutamine end-systolic
volume index and comparable changes in rest-to-peak
end-systolic wall stress, we found a greater decrease in
end-systolic volume index only in trained patients (pre:
-10±6 mL/m2; post: -23±9
mL/m2; P<.001). Since no
concurrent changes in end-diastolic volume index at
comparable levels of end-systolic wall stress were observed,
the effects of exercise training on left ventricular
contractility were likely unrelated to changes in
either preload or afterload.
Thallium Scintigraphy
After 8 weeks, thallium activity improved in 21 out of 26 trained
patients and only 1 control subject (trained versus control:
P<.001). Of 252 segments with wall thickening abnormalities
at rest, 224 (89%) were considered viable. Thallium activity score
index improved by 31% after exercise training (from 2.6±0.3 to
1.8±0.2; P<.001) but did not change in the control group
(2.5±0.5 versus 2.6±0.8; P=.68; trained versus control:
P<.001).
Relation Between Stress Echocardiography and
Thallium Scintigraphy
Coronary Morphology and Collaterals
After 8 weeks, mean collateral score increased significantly only
in the training group (baseline: 0.75±0.75; after training: 2.5±0.80)
without concomitant changes in the severity of stenotic
lesions. No changes were observed in the control group (baseline:
0.91±0.78; after 8 weeks: 0.82±0.79; training versus control:
P<.001). Of 11 control patients, 9 had no change, 1 had a
reduced score (from 2 to 1), and 1 a greater score (from 0 to 1)
after 8 weeks (Fig 2
Exercise Training and Left Ventricular Systolic
Performance
Under basal conditions, ejection fraction and left
ventricular volumes were unchanged after training (Table 4
Those patients with higher inotropic response to dobutamine
and greater thallium uptake at baseline seemed to benefit most from
exercise training. In fact, in accordance with the results of a recent
study,23 we observed that the improvement in
contractility after training was more marked among
initially hypokinetic or akinetic than dyskinetic myocardial segments.
The clinical and prognostic implication of the relationship between the
presence of dysfunctional but viable myocardium at baseline
and the magnitude of the improvement in LV
contractility after moderate exercise training is not
known at present. A preliminary report showed that patients with
improved contractile response to low-dose dobutamine after
moderate exercise training have a better outcome compared with
sedentary patients with ischemic
cardiomyopathy.24
The majority of myocardial segments with enhanced contractile response
after physical conditioning had also an improvement in thallium uptake.
Since the severity of coronary artery stenoses was
unchanged after training, the improved myocardial perfusion should
reflect structural and/or functional adaptations at the level of small
coronary vessels. Improvements in myocardial
contractility and perfusion may contribute to a higher
stroke volume at submaximal and peak exercise, as previously
demonstrated in patients with ischemic heart disease after
intense exercise training.25 As a matter of fact,
we found a significant posttraining increase in
O2 pulse—a good approximation of stroke
volume—at the same absolute as well as relative exercise intensities.
This increase was essentially due to a higher oxygen uptake, being the
heart rate response unchanged after training. Since the A-V
O2 difference has been demonstrated to remain
stable at submaximal exercise intensities after
training,26 the observed increase in
O2 pulse can be interpreted as reflecting an
increase in stroke volume at submaximal work rate exercise.
Exercise Training and Coronary Collaterals
The development of collaterals was more marked in patients with a
higher score at baseline, indicating that the initial level of
coronary collateral expression is predictive of the final
development. Although a direct relation between collateral development
and severity of coronary stenoses has been recently
described,28 we obtained an improvement in
collaterals without progression of coronary stenoses.
Changes in coronary artery stenoses have been observed
after longer and heavier exercise training
programs.29 It is possible that exercise
training, by inducing intermittent myocardial ischemia, may
provide the stimulus for vascular endothelial growth
resulting in new vessel formation. Functional adaptations of
coronary arteries may be also involved.5
A greater capacity of coronary vessels to vasodilate in
response to vasoactive substances may result in an increase in blood
flow capacity and capillary exchange capacity in the territories of
infarct-related arteries of trained
patients.30 31
Limitations
We used peak systolic pressure rather than end-systolic
pressure for calculation of end-systolic wall stress. Though
the
Some degree of error can be derived from the use of planar technique,
which poorly differentiates between a hypoperfused bed and a normally
perfused underlying or overlying myocardium. However,
planar imaging has been previously validated for measurement of
residual thallium uptake on rest, stress and redistribution
scintigrams, giving uniform consensus. Moreover, the planar data
reported in this study are similar to those from other laboratories
using positron emission tomography.32
Not all patients underwent second coronary angiography.
However, when we compared the clinical characteristics of patients who
repeated coronary angiography with those who did not, we found
no significant differences.
In conclusion, moderate exercise training improves both thallium
activity and the contractile response of dysfunctional
myocardium to low doses of dobutamine in
patients with chronic coronary artery disease and left
ventricular systolic dysfunction without affecting
the basal level of contractility. The results in a
subgroup of patients indicate that the training-induced improvements in
thallium uptake and contractility are correlated with
increased coronary collaterals. The implication of
these results is that even a short-term exercise training regimen may
improve quality of life by improvement in left ventricular
function during mild-to-moderate physical activity in patients with
ischemic cardiomyopathy. More follow-up
studies with larger populations are needed to confirm these preliminary
results and evaluate whether these adaptations may favorably affect the
outcome.
Received July 9, 1997;
revision received September 25, 1997;
accepted October 13, 1997.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Effects of Moderate Exercise Training on Thallium Uptake and Contractile Response to Low-Dose Dobutamine of Dysfunctional Myocardium in Patients With Ischemic Cardiomyopathy
Abstract
Top
Abstract
Introduction
Methods
Results
Discussion
References
Background—There is evidence that
exercise training can induce myocardial and coronary
adaptations in both animals and humans. However, the significance of
these potentially important changes remains to be determined in
patients with ischemic heart disease and left
ventricular (LV) systolic dysfunction.
Key Words: exercise • thallium • contractility • myocardium • ischemia • cardiomyopathy
Introduction
Top
Abstract
Introduction
Methods
Results
Discussion
References
Formal exercise
training in patients with coronary artery disease and a prior
myocardial infarction has established benefits, including improvement
of left ventricular systolic
function.1 2 3 The mechanisms contributing to this
adaptation are not well defined. However, one hypothesis suggests that
ß-adrenergic stimulation enhances contractile
response.4 An alternative explanation is that
coronary vascular changes improve function in chronically
hypoperfused myocardium.5 In fact,
collateral growth in the presence of a critical coronary
stenosis has been demonstrated after exercise training in
animals6 7 and humans.8
While these adaptations may enhance metabolic activity and
contractile reserve of hibernating myocardium, the clinical
and prognostic significance of the potentially favorable effects of
exercise must be confirmed.
Methods
Top
Abstract
Introduction
Methods
Results
Discussion
References
Fifty patients with coronary artery disease and
depressed left ventricular (LV) systolic
function were initially enrolled. Patients were in sinus rhythm and
clinically stable in the last 3 months. All patients gave
informed written consent. The Ethical Committee at the Lancisi hospital
approved the protocol. All patients had had a myocardial infarction 6
or more months before enrollment. Patients were excluded if they had
unstable angina, severe (New York Heart Association functional class
IV) or uncompensated congestive heart failure, high-grade
arrhythmias, significant renal insufficiency (serum
creatinine 
2.2 mg/dL), known contrast allergies, and any
orthopedic or neurological illness that limited their ability to
exercise. Pregnant patients were also excluded. Patients were randomly
assigned to one of two matched groups: an exercise group (n=26) and a
control group (n=24). At baseline and after 8 weeks, all patients
underwent an exercise test with gas exchange analysis, thallium
scintigraphy with a low-dose dobutamine
stress-redistribution-reinjection protocol, and a two-dimensional
echocardiogram during the same dobutamine infusion. Four
control patients were excluded because of inadequate
echocardiographic images. All patients underwent
coronary angiography shortly before enrollment. All patients
were asked to have a second coronary angiography after 8 weeks.
However, refusal to undergo the second coronary arteriogram
after 8 weeks was not an exclusion criterion (Table 1
).
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Table 1. Clinical Characteristics
The exercise group underwent a supervised program of physical
training at 60% of the peak oxygen uptake three times a week for 8
weeks. Each exercise session lasted about 1 hour and
consisted of an initial warming up with calisthenics and stretching
exercises (15 minutes), followed by stationary cycling on an
electromagnetically-braked cycle ergometer (Ergometrics
800S) for 40 minutes. Care was taken to avoid training intensities
above or below the initial target. Periodic adjustments of exercise
intensity were made according to individual progression. All patients
were monitored by means of telemetry. Control patients were recommended
to avoid regular exercise at home and any form of physical activity
with caloric expenditure >80% of peak oxygen uptake measured during
the baseline cardiopulmonary exercise test. A list of
acceptable and unacceptable home physical activities, based on
calculated metabolic equivalents, was provided to each
patient in both groups. Every 2 weeks, clinical condition of each
patient was evaluated by a cardiologist in the hospital.
At baseline and after 8 weeks, all patients performed a
symptom-limited incremental exercise test with gas exchange
analysis. Patients pedaled in an upright position on an
electronically braked cycle ergometer (Sensormedics 800 S). Every
minute, a 12-lead ECG was recorded and blood pressure was measured.
Gas exchange measurements were obtained breath-by-breath using a
metabolic chart (Sensormedics 2900 Z). Ventilatory
threshold was calculated by the V-slope method.13
Peak oxygen uptake was the average oxygen uptake over the last 15
seconds of exercise. The oxygen pulse (oxygen uptake/heart
rate) was calculated at the same absolute as well as relative
submaximal exercise intensities (20, 40, and 60 W and 25%, 50%, and
75% of peak work rate, respectively), and at peak exercise. This
measurement is useful because it equals the product of stroke
volume and arterial-venous (A-V) O2
difference.
Under continuous ECG monitoring, dobutamine was
infused into a peripheral vein in an incremental regimen of
5 µg/kg per minute every 5 minutes to a maximum of 10 µg/kg per
minute. Systolic blood pressure was taken at baseline and every
5 minutes. End points of the study included a significant new wall
motion abnormality, significant ST-segment changes, that is, ST-segment
depression or elevation of 1 mm in two contiguous leads,
significant symptoms or arrhythmias, or completion of the
protocol. Two-dimensional echocardiography from
standard views was continuously recorded using a wide-angle
mechanical scanner (Challenge-ESAOTE).
Regional wall thickening was assessed following the
recommendations of the American Society of
Echocardiography.14 A
15-segment model was used for analysis in order to facilitate
the comparison with myocardial segments analyzed with thallium
scintigraphy. We considered both wall motion and wall
thickening for analysis.15 However,
since endocardial excursion in itself is not a good index of
contraction given the translocation and rotation of the heart during
the cardiac cycle, particular attention was paid to systolic
wall thickening rather than endocardial excursion. Regional
systolic wall thickening was visually graded using a
semiquantitative scoring system wherein 1=normal or hyperkinetic,
2=hypokinetic, 3=akinetic, and 4=dyskinetic. A regional
systolic wall thickening score index (SWTI) was defined as the
sum of each segment score divided by the number of interpreted
segments. Abnormal regional wall motion was defined as a value falling
outside the established 95% confidence limits for each segment for a
normal population database from our laboratory. Change from score 4 at
rest to score 3 with dobutamine was considered as unchanged
wall thickening, while change from score 3 at rest to score 2 or 1
during infusion and/or from 2 at rest to 1 was considered improved wall
thickening. A positive contractile response to dobutamine
was defined as an improvement in systolic wall thickening in at
least 2 adjacent segments and a 20% reduction in wall thickening
score index. 20%
reduction in wall thickening score.
Each study was recorded on a super-VHS videotape (Panasonic
AG 7700) both conventionally and in slow motion cineloop format by
using the internal memory mode of the scanner to aid wall motion
analysis. Images were then entered into a personal computer
(Macintosh Quadra 660 AV) to obtain simultaneous
side-by-side displaying of rest and stress images for any individual
study as well as any set of images taken at similar infusion times
during initial and follow-up studies. Left ventricular
end-diastolic (onset of the ECG QRS) and
end-systolic (the videotape frame just prior to the mitral
valve opening) images were identified on the videotape
recording in which all or nearly all of the endocardium and
epicardium could be visualized on a single stop-frame image. The
endocardium of the end-diastolic image and the endocardium
of the end-systolic image were visually identified and manually
digitized. The left ventricular apex was defined as the
point on the endocardial contour furthest from the midpoint of the
mitral valve plane and the left ventricular long axis as a
line connecting the mitral plane midpoint and the apex.
Measurements of left ventricular
end-diastolic volume (EDV) and left ventricular
end-systolic volume (ESV) were obtained from the apical view
using a modified single-plane Simpson's rule from which left
ventricular ejection fraction was automatically calculated
as (EDV-ESV)/EDV · 100. Left ventricular
end-systolic wall stress (
es) was calculated, as described
by Grossman et al16 as
es(g/cm2)=P · r/2 hours · (1+h/2r),
where P is systolic blood pressure, r is end-systolic
radius (end-systolic diameter/2) and h is posterior wall
thickness at end systole. To calculate end-systolic wall
stress, measurements were obtained from the parasternal short axis
view. The end-diastolic diameter was considered the
distance between the left ventricular endocardial border of
interventricular septum and the posterior endocardium at
the onset of the QRS complex of the simultaneously
recorded ECG. The end-systolic diameter was the distance
between the endocardial border of interventricular septum
and the posterior wall endocardium measured at the end of T wave on ECG
recording. To control for the confounding effect of
afterload, the rest-to-peak dobutamine changes
in end-systolic volume index were compared at
similar levels of es changes both before and after
training. Analysis of the systolic blood
pressure–end-systolic volume index17 and
the es–end-systolic volume index relationships were
performed at rest and peak dobutamine infusion both on
study entry and follow-up to assess 1) the response of left
ventricular contractile performance to small doses
of dobutamine and 2) the effect of exercise training on
this response.
At the end of dobutamine infusion, 3 mCi of thallium
was injected into an antecubital vein. Planar
201Tl imaging was performed in the fasting state
(Apex Elscint). Images were acquired using a parallel-hole collimator.
Image acquisition started within 5 minutes in the anterior 45° left
anterior oblique and 70° left anterior oblique. Redistribution
studies were performed 3 hours after stress imaging. After 24 hours, 1
mCi of thallium was reinjected in patients with scintigraphic evidence
of a fixed defect after the redistribution studies. After reinjection,
a third set of images was reacquired within 15 minutes.
The left ventricle on each view was divided into 5 segments (15
segments in total). Planar images were interpreted qualitatively by
visual analysis with the aid of computer
quantification.18 19
Each segment was visually graded on a five-point scale: 0
(normal uptake), 1 (mild reduction), 2 (evident reduction), 3 (severe
reduction), and 4 (absent uptake). We defined the thallium activity
score index as the sum of thallium score of each myocardial segment
divided by the number of segments analyzed. After automatic
normalization to the maximal activity of stress images, each set of
three planar views were simultaneously displayed. "White
on black" display using a linear gray scale was used. The video
display was automatically arranged by computer program in order to
obtain both uniformity of imaging presentation on different
studies and reproducibility of analysis. 2 on stress images were considered abnormal.
Segments with an initial perfusion abnormality were considered
completely reversible when the score was <2 on delayed scans and
partially reversible when score improved by one grade on delayed
images. Defects with no change in thallium score between initial and
delayed images were considered irreversible. Myocardial segments with
irreversible defects were considered to have enhanced thallium activity
after reinjection as compared to redistribution study if regional score
decreased by one or more.
After background correction, the relative distribution of
201Tl in the myocardium was
quantitatively assessed using circumferential count profiles
analysis.18 19 In each patient, the
myocardial region with the maximum counts on thallium
scintigraphy was used as the normal reference region for
that patient. Circumferential profiles were normalized to the segment
with the highest tracer activity and compared with those of a normal
database from our laboratory. The thallium activity in all other
myocardial segments was expressed as a percentage of thallium activity
measured in the reference region for each stress, redistribution, and
reinjection image. Severity of perfusion abnormalities was assessed by
computing the average percent reduction of the relative myocardial
thallium uptake below the lower limit of normal (mean-2 SD). Thallium
activity <85% of the maximum was considered a perfusion defect, also
considering previous measurements of reproducibility obtained in our
laboratory. A perfusion defect was reversible when relative thallium
activity increased by 10% in the redistribution image. Defects were
completely reversible if thallium activity was 85% relative to the
reference region and partially reversible if relative thallium counts
remained <85% of the maximum activity. Defects were considered
irreversible if thallium activity was unchanged or increased <10% on
redistribution studies. Similar methods were followed for
analysis of images after reinjection. Enhanced thallium
activity after reinjection was defined an increase in relative thallium
counts >10% compared with the redistribution studies, while thallium
activity was considered unchanged if it was unaltered or increased by
<10%.
Coronary angiography was performed by Judkins'
technique.20 Multiple projections
including cranial and caudal-angulated views were obtained (Optimus
M200, Philips, The Netherlands). Coronary cineangiographic
films were analyzed by a computer-assisted edge detection
coronary quantitative system (Digital Cardiac Imaging,
Philips). Images of interest were digitized and then
processed. A stenosis was considered
hemodynamically significant if a 50% reduction in
luminal diameter was detected. After 8 weeks, changes in
coronary stenoses were scored as follows: 0=unchanged
(<10% change); +1=progression (>10% change); -1=regression
(negative difference of >10%). The extent of perfusion by collateral
vessels was scored as follows21: 0=absent (no
collaterals); 1=some (incomplete delayed filling of the infarct-related
artery); 2=well-formed (delayed filling of the infarct-related artery);
and 3=abundant (the infarct-related artery is completely filled as the
injected artery). Two experienced interventional cardiologists
independently interpreted the studies in a blinded manner. Disagreement
between the two readers was resolved by consensus.
The effects of exercise training on the contractile response to
dobutamine, thallium uptake, and coronary
collaterals were analyzed on the basis of patients. Therefore,
we created a score as follows: 0=no change; +1=improvement; and
-1=deterioration. Then, the change in this score as a function of
exercise training versus control was analyzed using a
nonparametric test (Mann-Whitney rank test). Fisher's
exact test was used to determine whether the response of the
systolic wall thickening score index during
dobutamine infusion at baseline predicted improvement in
contractility after exercise training. McNemar's test
was performed to compare sensitivities, specificities and predictive
values between thallium scintigraphy and
dobutamine stress echocardiography.
Correlation coefficients were used to assess relationships between
variables. Statistical significance was assumed for a value of
P<.05. Values are expressed as mean±SD.
Results
Top
Abstract
Introduction
Methods
Results
Discussion
References
All patients completed the protocol. The compliance was excellent
in both groups. All patients in the training group performed the 24
scheduled sessions. Two patients of group T had hypotension during
recovery from cycling, which promptly resolved with supine positioning.
Three patients of group T had sporadic ventricular
premature contractions during the initial sessions (first 2 weeks). No
patient had angina during the training sessions. In the control group,
2 patients reported short episodes of palpitations (twice and three
times in 2 months, respectively), not requiring changes in medications.
One control patient had unstable angina on week 4 and was hospitalized.
No other adverse events were reported. ). Ventilation at
peak exercise also increased after exercise training, while respiratory
exchange ratio was unchanged. No changes were observed in the controls.
The oxygen pulse was significantly higher at the same
absolute exercise intensity after training by an average of 16%
(P<.01). At the same relative exercise intensity,
O2 pulse was also increased (average 23%;
P<.001). The heart rate response to the same relative
intensity was unchanged. No changes in O2 pulse
were observed in the control group.
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Table 2. Changes in Metabolic and
Hemodynamic Variables
On study entry, the exercise group showed a positive response to
dobutamine in 141 of the 257 segments with resting wall
motion abnormalities (55%) (Table 3).
This response occurred more frequently among initially hypokinetic (105
of 145) segments than it did among akinetic (32 of 68) or dyskinetic (4
of 44) segments. The control group had similar proportion of segments
with contractile response (111 of 192).
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Table 3. Echocardiographic and Scintigraphic
Responses to Dobutamine on Study Entry and After 8 Weeks in
the Exercise and Control Groups 
, the
improvement in the contractile response was more evident among
initially akinetic and hypokinetic than dyskinetic segments (+29%,
11%, and 4%, respectively). The inotropic response to
dobutamine was unchanged in the unexercised control
patients. Since the doses of dobutamine used in both
initial and follow-up studies were identical, the observed improvement
in the inotropic response to dobutamine in the training
group seems likely due to exercise training itself.
After 8 weeks, 22 of 26 trained patients and only 1 of 20 control
patients showed improvement in ejection fraction and
end-systolic volume index at peak dobutamine
(trained versus control: P<.001 for both). The ejection
fraction at rest was not significantly different in both groups after 8
weeks (Table 4). As shown in Fig 1, left ventricular
end-systolic volume index at peak dobutamine was
significantly lower after training than before, while the
systolic blood pressure at peak dobutamine
increased after training. This results in a shift of the
end-systolic pressure-volume relationship upward and to the
left. In untrained patients no significant changes in the
pressure-volume relationship occurred (trained versus control:
P<.001).
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Table 4. Left Ventricular Response to
Dobutamine on Study Entry and After 8 Weeks in the Exercise
and Control Groups
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Figure 1. Effect of exercise training on systolic
blood pressure–end-systolic volume index (SBP-ESVI)
relationship. In the exercise group, an increase in SBP was accompanied
by a reduction in ESVI from rest to peak dobutamine. The
pressure-volume relationship was shifted upward and to the left
(P<.001). No significant changes in the pressure-volume
relationship were observed in the control group. 
, Baseline; 
, 8
weeks.
At baseline, in the training group, of the 257 myocardial segments
with resting wall thickening abnormalities, 193 (75%) had normal or
only mild to moderate reduction in thallium uptake, and 64 (25%) had
severely reduced or absent thallium activity. A total of 48 of the 257
segments with resting wall motion abnormalities had normal thallium
uptake on the stress images. Of the remaining 145 segments, 22 were
completely reversible on the redistribution images and 106 were
partially reversible; 17 had increased thallium uptake after
reinjection. Of these 145 segments with reversible thallium defects, 77
segments received a score of 2, 60 a score of 3, and 8 a
score of 4 on the stress images. Control subjects showed similar
thallium activity scores (Table 3).
The number of segments considered viable on thallium imaging and
showing improved contractile response to dobutamine
increased significantly only in trained patients (from 131 to 170)
(Table 5). By contrast, the number of
segments considered nonviable on thallium imaging and showing no
contractile response to dobutamine was reduced in the
exercise group (from 61 to 34) but not in the control subjects. In the
exercise group, the concordance between the two tests was 75% on
initial studies and 81% on follow-up; in the control group,
concordance was 76% and 78%, respectively.
View this table:
[in a new window]
Table 5. Relation Between Stress
Echocardiography and Thallium
Scintigraphy on Study Entry and After 8 Weeks in the
Exercise and Control Groups
A total of 23 patients (12 trained and 11 control) repeated
coronary angiography at the end of protocol. On baseline
studies, the greater the collateral score, the greater was the
reduction in systolic wall thickening score
(r=-.86; P<.001) and thallium activity score
(r=-.74; P<.005) in response to
dobutamine infusion. ). None of them had
changes in wall thickening and thallium activity scores (trained versus
control: P<.001). However, of 12 trained patients, all but
1 improved the collateral score, which correlated with improvements in
wall thickening (r=-.76; P<.005) and thallium
activity scores (r=-.88;P<.001) in response to
dobutamine. An example of pretraining and posttraining
thallium uptake, contractile response of dysfunctional
myocardium and coronary collaterals for one
representative patient is shown in Fig 3.
View larger version (20K):
[in a new window]
Figure 2. Collateral score on study entry and after 8 weeks
in the exercise and control patients. Of 12 trained patients, all but 1
improved the collateral score after exercise training. Mean collateral
score increased significantly (from 0.75±0.75 to 2.5±0.8). In
contrast, of 11 control patients, 9 had no changes, 1 had a reduced
score (from 2 to 1), and 1 a greater score (from 0 to 1) after 8
weeks. Mean collateral score was unchanged (trained vs control:
P<.001). , Mean value±SD of collateral score in the
exercise group at baseline and after 8 weeks. , Mean value±SD for
collateral score in the control group at baseline and after 8 weeks.
For details, see text.
View larger version (83K):
[in a new window]
Figure 3. A 49-year-old man with a prior (7 month) anterior
myocardial infarction and depressed left ventricular
systolic function (resting ejection fraction, 28%). A (left),
Baseline coronary angiogram in right anterior oblique (top) and
left lateral (bottom) projections. The right coronary
artery (RCA) is normal. In both images there is no opacification of the
left anterior descending artery (LAD) due to total occlusion of its
first tract. Collaterals were scarcely developed from RCA to LAD. A
(right), After exercise training, evident collaterals developed from
RCA to LAD, partly through the septal branches (top panel). On left
lateral projection (bottom panel), the occlusion of the first tract
of LAD was unchanged from the baseline study. B, Dobutamine
stress echocardiography at baseline (left side: end
diastole, top panel; end systole, bottom panel) and after
training in apical four-chamber view. Images were taken at peak
dobutamine infusion. At baseline, akinesis of apical
anterior and inferior interventricular septum
and apical, mid, and apical lateral segments was observed. After
training, a reduction in end-systolic volume (-26%) (right
side: bottom panel) as well as an improvement in the contractile
response to dobutamine in all the above cited myocardial
segments was observed. C, 201Tl scintigrams from
redistribution studies in the three standard projections
at baseline (left panel) and after exercise training (right panel). On
study entry, a marked reduction of thallium uptake was observed in the
anterolateral, septal, and anterior segments. After training (bottom),
an evident improvement in thallium uptake was observed in the basal and
mid anterolateral segments.
Discussion
Top
Abstract
Introduction
Methods
Results
Discussion
References
The results of the present study indicate that short-term
exercise training of moderate intensity improves thallium uptake and
the contractile response to low-dose dobutamine of
dysfunctional myocardium and significantly increases
exercise tolerance in patients with ischemic
cardiomyopathy. A posttraining increase in the
collateral score, evident only in a subgroup of trained patients, was
correlated with improvements in both thallium uptake and
systolic wall thickening scores, indicating a linkage between
training-induced effects on collateral circulation and both perfusion
and contractility of dysfunctional myocardial segments.
The improvement in the collateral score after 8 weeks of moderate
exercise training was not accompanied by changes in the severity of
coronary artery stenoses, suggesting that mechanisms
other than regression of preexisting coronary artery
obstructions can be involved in explaining this improvement.
The results of the present study are in agreement with those
of previous reports in animals12 22 and humans
with no coronary artery disease4
demonstrating an improvement in myocardial contractile response to
ß-adrenergic stimulation after exercise training. In this
study, however, the enhanced myocardial contractility
was observed after a shorter and milder exercise training
program using a lower ß-adrenergic stimulation. The
improvement in left ventricular systolic function
in response to low-dose dobutamine can be considered
similar to responses to submaximal exercise. Therefore, the implication
is that even a short-term, moderate-intensity exercise training may
improve myocardial contractile function, which is a useful adaptation
during daily physical activity in patients with severe coronary
artery disease and depressed left ventricular function. On
the other hand, the results of the present study cannot be
extrapolated to exercise intensities approaching maximal effort because
this adaptation may be lost. ). This result was not surprising, since even exercise training
regimens of higher intensities failed to improve basal
contractility in patients with ischemic heart
disease.2 3 17 However, we found a greater
reduction in end-systolic volume index in response to
dobutamine at similar changes in end-systolic wall
stress and a shifting of systolic blood
pressure-end-systolic volume index relationship upward and to
the left after exercise conditioning. These changes, in conjunction
with no significant modification of end-diastolic volume
index to the same doses of dobutamine, support the view
that the improved myocardial contractility after
exercise training is unrelated to either afterload or preload.
The present results support the original observation by
Eckstein27 that chronic exercise promotes
coronary collateral development. An interest observation from
the present study is that physical training must not necessarily be
intensive and longer than 2 months to improve
coronary collaterals, and factors such as the type of exercise,
medications or the extension of preexisting collaterals may play a
role.
We used low-dose dobutamine stress
echocardiography in conjunction with thallium
imaging to obtain simultaneous information on
contractility and metabolic activity of
myocardial segments. However, the use of low doses of
dobutamine could lead to underestimation of viability by
both techniques. Panza et al10 showed that the
entity of this phenomenon is very small. In their study, the vast
majority of segments responded at doses 
10 µg/kg per minute, and
only 2.3% (4 segments out of 173) had contractile improvement at
higher doses. Moreover, all methods generally underestimate
viability. es values reported here may be not precise in
absolute terms, we used the same approach for the calculation of
es at baseline and after exercise training. Thus the
degree of error should be minimal.
Acknowledgments
This study was supported in part by a grant from Ospedale
Cardiologico "G.M. Lancisi," Ancona, Italy.
Footnotes
Presented at the 68th Scientific Sessions of the American Heart Association, Anaheim, Calif, November 13 to 16, 1995, and presented in abstract form (Circulation. 1995;92[Suppl I]:I-479).
References
Top
Abstract
Introduction
Methods
Results
Discussion
References
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