Download Magnitude of myocardial dysfunction is greater in painful than in

JACC Vok 25, No. 7
June 1995:1507-12
1507
Magnitude of Myocardial Dysfunction Is Greater in Painful Than in
Painless Myocardial Ischemia: An Exercise Echocardiographic Study
P E T R O S N I H O Y A N N O P O U L O S , MD, FACC, FESC, A N T O N I S M A R S O N I S , MD,
J A Y S H R E E J O S H I , BSc(HoNs), G E O R G E A T H A N A S S O P O U L O S , MD,
C E L I A M. O A K L E Y , MD, F R C P , FACC, F E S C
London, England, United Kingdom
Objectives. This study sought to assess the presence and extent
of inducible myocardial dysfunction during painful and painless
(silent) myocardial ischemia in a homogeneous patient cohort
with coronary artery disease and no previous myocardial
infarction.
Background. The functional significance of painless versus
painful demand-driven ischemia remains controversial, with conflicting results in published reports regarding the amount of
myocardium in jeopardy.
Methods. Exercise echocardiography was performed in 89
patients (mean [+SD] age 59.3 -+ 8.2 years) with significant
coronary artery disease and positive exercise stress test results.
Patients were taking no antianginal medications and were classi l
fled into painless and painful cohorts after the outcome of a
symptom-limited treadmill exercise test. No patients had previous
coronary artery bypass surgery. Images were acquired in digital
format before and immediately after treadmill exercise testing.
Results. Fifty-eight patients had painful and 31 painless myo-
Myocardial ischemia is generally recognized clinically by the
characteristic features described by Heberden (1). However,
painless (silent) myocardial ischemic episodes are also frequently observed in patients with coronary artery disease and
often outnumber painful episodes (2-5). Although detection of
electrocardiographic (ECG) changes during continuous recording is a popular method for identification of transient
ischemic changes, there have been justified concerns about the
interpretation of these changes. Some investigators (6-8)
proposed that there are differences in the amount of myocardium in jeopardy during painless and painful ischemia, painless
episodes generally being shorter and abnormalities of left
ventricular function not as marked as during painful episodes.
However, others (9,10) used radionuclide studies to demonstrate that abnormalities in left ventricular function induced by
exercise were similar whether painless or painful. Only recently
From the Departmentof Medicine,CardiologyUnit, HammersmithHospital, London,England,UnitedKingdom.
ManuscriptreceivedSeptember7, 1994;revisedmanuscriptreceivedFebruary 1, 1995,acceptedFebruary8, 1995.
Address for corresoondence:Dr. PetrosNihoyannopoulos,Departmentof
Medicine, Clinical Cardiology,HammersmithHospital, R.P.M.S., Du Cane
Road, LondonW12 ONN,UnitedKingdom.
©1995by the AmericanCollegeof Cardiology
cardial ischemia. Clinical and demographic characteristics as well
as coronary artery anatomy were similar in both groups. Patients
with painless ischemia achieved better exercise performance with
greater exercise duration (p < 0.001) and higher maximal rateblood pressure product (p < 0.001) than those with painful
ischemia. New wall motion abnormalities were seen in 54 patients
(93%) with painful versus 17 (55%) with painless ischemia (p <
0.001). Total ischemic score was greater in patients with painful
than in those with painless ischemia (15.9 + 3.7 vs. 12 -+ 1.4, p <
0.001, respectively), with a greater number of ischemic myocardial
segments in painful than in painless ischemia (101 [16%] vs. 21
[6%], p < 0.001, respectively).
Conclusions. Patients with painless ischemia frequently have
regional myocardial dysfunction on exertion detected by echocardiography, but painful episodes are accompanied by a greater
magnitude of myocardial dysfunction.
(J Am Coil Cardio11995;25:1507-12)
has it been suggested (11) that the induction of angina is
associated with more functional abnormalities during exercise
testing.
Exercise echocardiography has the advantage of providing
physiologic cardiovascular stress with detailed global and regional myocardial imaging as well as continuous ECG recording and offers higher diagnostic accuracy than exercise electrocardiography alone (12-14). The purpose of this study,
therefore, was to evaluate the extent and severity of regional
wall motion abnormalities occurring during exercise in a
homogeneous group of patients with painless and painful
myocardial ischemia without previous myocardial infarction.
Methods
Study patients. Ninety-five consecutive patients with
known coronary artery disease and a positive exercise stress
test result (>l-mm horizontal or downsloping ST segment
depression) underwent exercise echocardiography. In six patients (6%) the endocardial border could not be defined in all
myocardial segments, and they were excluded from the study.
Patients with previous coronary artery bypass grafting, associated valvular heart disease or myocardial infarction or other
0735-1097/95/$9.50
0735-1097(95)00096-M
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NIHOYANNOPOULOS ET AL.
EXERCISE ECHOCARDIOGRAPHY IN MYOCARDIAL ISCHEM1A
intravascular interventions were not included. The remaining
89 patients (22 women, 67 men; mean [+SD] age 59.3 _+ 8.2
years, range 46 to 74) constituted our study group. All patients
had diagnostic coronary arteriography within 3 weeks of
exercise echocardiography with demonstration of significant
coronary artery disease (>70% diameter narrowing of at least
one coronary artery). All antianginal therapy was discontinued
at least 24 h before the exercise tests.
Exercise electrocardiography. A symptom-limited treadmill exercise stress test was performed according to the modified Bruce protocol in all patients (Marquette Case 15,
Worsley, Manchester, United Kingdom) within 2 weeks of the
original test and under the same circumstances. Patients with
painless ischemia were encouraged to exercise until exhaustion. The 12 ECG leads were first positioned in the usual
manner and then moved according to the transducer location
from which the best echocardiographic image could be obtained (usually by one intercostal space).
Exercise echocardiography. A two-dimensional echocardiographic study usiug commercially available cardiac ultrasound equipment (Toshiba SSH 160A) was first performed
with the patient lying in the left lateral decubitus position.
Echocardiographic images of the left ventricle were acquired
before and immediately after treadmill exercise. These were
recorded simultaneously on 0.75-in. videotape and in digital
format using parasternal long- and short-axis (best midpapillary muscle level) as well as apical four- and two-chamber
projections. Particular attention was paid to image all of the
endocardial surface. Immediately after exercise, patients returned to the left lateral decubitus position, and echocardiographic images were again acquired in similar manner. Before
commencing exercise, patients practiced their return to the
original lateral decubitus position to minimize the lapse of time
between the exercise halt and echocardiographic image
acquisition.
Echocardiographie image analysis. Images were acquired
and digitized on-line before and immediately after exercise
in a quad-screen format (Preview III version 4.050, Nova
MicroSonics). At the same time, using a separate output from
the echocardiographic equipmeut, a continuous recording of
left ventricular function was obtained on videotape. Images
were stored on 5.25-in. floppy disks. Single selected cycles from
the rest and corresponding postexercise images were subsequently replayed side by side in a cine loop format and
analyzed off-line by a different physician, expert in interpreting
stress echocardiographic studies, who was unaware of the
exercise results.
Regional left ventricular wall motion analysis was performed
according to previously published criteria (14). In brief, we
used an ll-segment model, in line with the routine practice in
our laboratory, that allows easy subjective interpretation of
large enough myocardial regions with respect to coronary
artery anatomy. Wall motion was graded in a semiquantitative
fashion from 1 (normal) to 4 (dyskinetic). Grades 2 and 3
corresponded to hypokinetic and akinetic regions, respectively.
An abnormal exercise echocardiographie response was de-
JACC Vol. 25, No. 7
June 1995:1507-12
Table 1. Exercise ElectrocardiographicResults in Patients With
Painless and Painful MyocardialIschemia (mean _+ SD)
Exercise duration (min)
Work load (METs)
Peak RPP
Peak systolic blood
pressure (mm Hg)
Heart rate (beats/min)
Rest
Peak
% maximal predicted
ST segment depression
Maximal (mm)
Onset (min)
Duration into
recovery (min)
Painless
Ischemia
(n = 31)
Painful
lschemia
(n = 58)
p
Value
13.9 _+ 4.2
6.5 _+ 2.5
25,377 _+ 6,090
173.5 _+ 36.7
9.4 _+ 3.9
5.4 + 3
19,378 -+ 5,181
166.9 _+ 25.2
<0.001
0.09
<0.001
0.3
72 + 14
133 _+ 25
96 _+ 10
77 -+ 13
126 _+ 15
89 _+ 11
0.1
0.1
0.004
2.3 _+ 1.1
7.9 + 5.8
3.2 _+ 2.9
2.1 + 0.8
6.3 _+ 4.1
5.3 _+ 3.8
0.3
0.13
0.009
METs = metabolic equivalents; RPP
product achieved.
maximal rate-blood pressure
fined as an increase from rest to immediately after exercise of
one grade or more for any of the 11 regions analyzed. The total
number of myocardial segments per patient was graded, and
the extent of myocardial ischemia was derived from the total
number of segments involved. A normal wall motion score was
equal to 11, and any value greater than this implied myocardial
ischemia. The greater the wall motion score, the greater the
amount of myocardial ischemia (ischemic score). Although the
normal response to exercise would produce myocardial hyperkinesia, this was graded as normal so that the total wall
motion score appropriately depicted only the ischemic segments and not the ability of normal segments to compensate.
Statistical analysis. Results are expressed as mean value _+
1 SD. Differences between patient groups with painless and
painful myocardial ischemia were obtained by the unpaired
two-tailed t test or chi-square test with Yates correction, as
appropriate. A probability value <0.05 was considered
significant.
Results
Of the 89 patients studied, 31 (35%) had painless and 58
(65%) painful myocardial ischemia during exercise (p < 0.01).
The results of exercise stress testing in the two groups are
summarized in Table 1. All patients had positive ECG criteria
for ischemia because this was one of the entry criteria for the
study. Patients with painless ischemia performed better during
exercise, with longer exercise duration (13.9 _+ 4.2 vs. 9.4 _+
3.9 min, p < 0.001), greater maximal workload attained (6.5 _+
2.5 vs. 5.4 _+ 3 metabolic equivalents) and higher rate-blood
pressure product (25,377 _+ 6,090 vs. 19,378 _+ 5,181) than
those with painful ischemia. Both groups were comparable in
age, gender, risk factors and extent of coronary artery disease
as defined by the number of diseased vessels, although patients
with painless ischemia tended to have a higher incidence of
JACC Vol. 25, No. 7
June 1995:1507-12
NIHOYANNOPOULOS ET AL.
EXERCISE ECHOCARDIOGRAPHY IN MYOCARDIAL ISCHEMIA
Table 2. Clinical and Angiographic Data for Patients With Painless
and Painful Myocardial Ischemia During Exercise
Female/male
Age (yr)
Diabetes mellitus
Systemic hypertension
Hypercholesterolemia
No. of diseased vessels
1
2
3
Painless Ischemia
(n = 31)
Painful Ischemia
(n = 58)
p
Value
9/22
61.5 + 7.8
"9(29%)
13 (42%)
8 (26%)
13/45
58.7 _+ 8.8
16 (28%)
19 (33%)
11 (19%)
0.7
0.14
0.9
0.5
0.6
11 (35%)
14 (45%)
6 (19%)
14 (24%)
26 (45%)
18 (31%)
0.4
Data presented are mean value _+ SD or number (%) of patients.
single-vessel disease, and patients with painful ischemia a
higher incidence of three-vessel disease (Table 2).
The majority of patients in both groups had one- or
two-vessel disease with >70% stenoses. Of 25 patients with
predominantly single-vessel disease, 17 had right coronary
artery stenosis, 10 of whom were in the painless group, and 6
others had circumflex artery stenosis, 1 in the painless and 5 in
the painful group. The remaining two patients had mid-left
anterior descending coronary artery stenosis, and both had
painful ischemia. No patient had left main stem disease, and
left ventricular function was good in all.
Exercise eehoeardiography. No patients had regional wall
motion abnormalities at rest. Acquisition of echocardiographic
imaging started 16.7 _+2.7 s after the end of exercise testing for
patients with painless myocardial ischemia and was completed
within 56 + 9.2 s. Similarly, in patients with painful myocardial
ischemia, image acquisition started at 16.9 + 3.3 s and was
completed within 60.9 _+ 8.3 s. Importantly, image acquisition
began while ECG changes were still present in the immediate
postexercise period in each patient. Of the 58 patients with
painful myocardial ischemia, 54 (93%) had at least one hypokinetic or akinetic segment detected immediately after exercise. Conversely, of 31 patients with painless myocardial ischemia 17 (55%) had at least one new wall motion abnormality
detected (p < 0.001). In the remaining patients, no regional
wall motion abnormalities were identified at any time. Overall,
there was a higher incidence of negative exercise echocardiographic findings in patients with painless myocardial ischemia
(Table 3).
Eleven (79%) of 14 patients with no regional wall motion
abnormalities and painless ischemia had single-vessel disease,
and the remaining 3 had two-vessel coronary artery disease. No
patient with negative exercise echocardiographic findings and
painless myocardial ischemia had severe three-vessel coronary
artery disease. All four patients with painful ischemia and
negative exercise echocardiographic findings had single-vessel
disease.
Regional wall motion abnormalities. A total of 979 myocardial regions (segments) were analyzed for wall motion
abnormalities semiquantitatively (11 regions/patient) side by
1509
Table 3. Exercise Echocardiographic Results in Patients With
Painless and Painful Myocardial Ischemia
Digital acquisition start (s)
Digital acquisition completed (s)
New wall motion abnormalities
No wall motion abnormalities
Total ischemic score
Total segments involved
Extent of ischemia
Painless
Ischemia
(n = 31)
Painful
Ischemia
(n - 58)
p
Value
16.7 + 2.7
56 -+ 9.2
17 (55%)
14 (45%)
12 _+ 1.4
21 (6%)
0.5 _+0.6
16.9 +_3.3
60.9 +_8.3
54 (93%)
4 (7%)
15.9 + 3.7
101 (16%)
1.7 _+0.9
0.8
0.01
<0.001
<0.001
<0.001
<0.001
<0.001
Data presented are mean value + SD or number (%) of patients or
segments.
side before and immediately after exercise. In patients with
painful ischemia, 101 (16%) of 638 myocardial regions became hypokinetic or akinetic versus only 21 (6%) of 341
regions in patients with painless ischemia (p < 0.001). Furthermore, in patients with painful ischemia, 2 had four abnormal myocardial regions (36% of total myocardium); 9 had
three abnormal regions (27% of myocardium); 23 had two
abnormal regions (18% of myocardium); and 20 had only one
abnormal region (9% of myocardium). Conversely, only 1
patient with silent ischemia had three abnormal regions (27%
of myocardium); 2 had two abnormal regions (18% of total
myocardium); and the remaining 14 had one abnormal region
(9% of the total myocardium).
Total ischemic score was greater in patients with painful
myocardial ischemia, with an average of 15.9 +_ 3.7 versus 12 ±
1.4 in those with painful versus painless ischemia, respectively
(Table 3). These data indicate that in this cohort of patients
with coronary artery disease and no previous myocardial
infarction, the extent and severity of jeopardized myocardium
in patients with silent ischemia are more limited compared
with patients having painful episodes. However, there is a wide
overlap between patients with painful and silent ischemia when
just a single myocardial segment becomes abnormal (9% of
total myocardium).
Follow-up. After completion of the exercise echocardiographic testing, patients were followed up for an average of 25
months (range 20 to 29). During that time all patients with a
positive exercise test result were taking standard antianginal
medications irrespective of their symptomatic status. Eightythree percent were taking beta-blockers, 72% calcium channel
blockers and 48% (24 patients) nitrates, 20 of whom were in
the group with painful ischemia. All patients in the painless
group remained in stable condition throughout the follow-up
period, whereas five patients with painful ischemia had coronary artery bypass surgery, nine had angioplasty, and two were
admitted with acute myocardial infarction.
Discussion
To our knowledge, this is the first study to use echocardiography to demonstrate that exercise-induced angina is asso-
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N I H O Y A N N O P O U L O S E T AL.
EXERCISE E C H O C A R D I O G R A P H Y IN M Y O C A R D I A L ISCHEMIA
ciated with a greater magnitude of myocardial dysfunction
than painless ischemic episodes in patients with no previous
myocardial infarction.
Exercise echocardiography. The fundamental advantage of
exercise echocardiography over other forms of stress, particularly pharmacologic, is that it combines excellent physiologic
cardiovascular stress, physician familiarity with ECG changes
and symptoms with cross-sectional echocardiography to detect
ischemia-induced wall motion abnormalities. Its diagnostic
accuracy has previously been documented in atherosclerotic
coronary artery disease producing regional myocardial dysfunction in patients with angina (13-17) in contrast to patients
with syndrome X in whom no regional wall motion abnormalities are identified (14).
In the present study, assessment of the sensitivity of exercise echocardiography was not attempted because of the
selective inclusion criteria (positive exercise ECG findings).
However, no false positive exercise echocardiographic findings
were obtained. Overall, only 18 patients (20%) with a positive
exercise ECG result for ischemia failed to demonstrate any
regional myocardial dysfunction. It is possible that the high
incidence of relatively mild coronary artery disease (28%
single- and 45% two-vessel disease) was a contributory factor
(13,18). In addition, the apparent low "sensitivity" of exercise
echocardiography in the present study was predominantly seen
in the patients with painless ischemia (55%vs. 93% in patients
with painful ischemia), further supporting our hypothesis of
milder ischemia during painless episodes (see later). In very
mild forms of inducible myocardial ischemia, there could be
interpretive dilficulties in attempting to define the limits of
normal wall motion. Myocardial segments that lose only slight
systolic thickening (hypokinesia) may not be identified (19).
It may be argued that the time elapsing between termination of exercise and onset of imaging acquisition is responsible
for failure to detect wall motion abnormalities in rapidly
resolving ischemic changes. However, in one study (20) in
which peak exercise imaging was compared with that immediately after exercise, it was found that such rapid recovery is
exceptional and occurs in only a minority of patients with mild
ischemia. Furthermore, in our study, image acquisition started
while diagnostic ECG changes were still present in all patients,
so that it is highly unlikely that echocardiographic imaging was
started too late after resolution of ischemia.
However, it remains possible that when <20% of a transmural myocardial region becomes ischemic, this is not perceived as hypokinesia or akinesia (19). Nevertheless, the
finding that there was a higher prevalence of negative exercise
echocardiographic studies in patients with painless ischemia
strengthens the argument that this group had milder ischemia.
Painless versus painful ischemic episodes. It was not surprising that patents with painless ischemia achieved a better
exercise performance than those with painful ischemia because
the occurrence of angina was an end point of the stress test.
There is persisting uncertainty as to whether the amount of
myocardium involved during an ischemic episode is similar in
relation to the perception of pain or no pain. Chierchia et al.
JACC Vol. 25, No. 7
June 1995:1507-12
(6) elegantly demonstrated, during continuous hemodynamic
monitoring, a threefold increase in left ventricular and pulmonary artery diastolic pressures during painful ischemic episodes
compared with that during painless events, even though 63%
of painless episodes in the same patients were associated with
a significant increase in left ventricular end-diastolic pressure.
The remaining 37% showed little or no evidence of ischemia
despite suggestive ECG findings. The present study implies
that the magnitude of myocardial ischemia is less in painless
than painful events. However, other studies (7,21) using continuous ECG monitoring for several days failed to demonstrate
differences between painless and painful episodes, but this may
reflect different selection criteria or the lack of specificity of
electrocardiography when used alone.
Several other groups attempted to investigate directly myocardial function during painful and painless ischemic events
(8-11,22-25), but these studies used different imaging modalities in patients with a variety of coronary syndromes, including
previous myocardial infarction. Therefore, the results from
these were conflicting. Patients in our study were selected for
presence of chronic stable angina and a positive exercise
test result to ensure that all patients would have inducible
ischemia. We chose not to include patients with a previous myocardial infarction to optimize echocardiographic
interpretation.
In the present study the magnitude of myocardium in
jeopardy was greater in patients with painful myocardial
ischemia. This finding is consistent with those of some previous
hemodynamic (6) or radionuclide (8,11) studies but differs
from those of others (9,10). Echocardiography images the
myocardium in its entirety, with attention to regional myocardial thickening. This makes it ideal for noninvasive assessment
of regional ventricular function. In the only two previous
studies that we are aware of, Marwick et al. (23) and Hecht et
al. (24) failed to demonstrate differences between painful and
painless ischemic events, but >70% of their patients were
taking standard antianginal medication, which limits the extent
and severity of inducible myocardial dysfunction (26) and can
render "silent" normally painful events. Other echocardiographic studies (27,28) that failed to demonstrate a difference
between painful and painless myocardial dysfunction used
dipyridamole, which is a less effective myocardial stressor.
Patients in our study achieved an optimal hemodynamic response to exercise while they were not taking antianginal
medications, and the majority developed painful myocardial
ischemia. Of 58 patients with painful ischemia, total ischemic
score was greater in 11 (19%) with three or more ischemic
myocardial segments (>27% of total myocardium) despite a
blunted exercise performance compared with that in patients
with painless ischemia.
Pathophysiologic considerations. There is little doubt that
myocardial ischemia occurring with one of the many variations
on the Heberden theme or in the absence of pain involves the
same sequence of biochemical, hemodynamic and electrophysiologic events documented during painful ischemia, except
that the pain is not present (29).
JACC Vol. 25, No. 7
June 1995:1507-12
NIHOYANNOPOULOS ET AL.
EXERCISE ECHOCARDIOGRAPHY IN MYOCARDIAL ISCHEMIA
Previous studies (2-5) using continuous ECG monitoring
have demonstrated that the majority of patients with chronic
stable angina exhibit a mixture of painful and painless ischemic
episodes with a high proportion of silent ischemic events
occurring at lower heart rates than during exercise. This
finding suggests that transient ECG changes occurring in daily
life may be predominantly related to dynamic mechanisms
limiting coronary arterial supply, such as changes in blood
pressure or coronary artery tone. In our study we examined
patients in whom ischemia occurred during treadmill exercise
in which demand-driven ischemia dominates, and the majority
of patients had a painful event. Although our data do not
permit firm conclusions about the mechanism of painless and
painful ischemia, it is possible to speculate that in predomi. nantly demand-driven ischemia, patients with chronic stable
angina have a higher incidence of painful ischemia. Whether
the amount of myocardial dysfunction is the same during a
predominantly supply- or demand-driven ischemia remains to
be established. This would require longitudinal monitoring of
regional myocardial contraction, which is difficult in practice.
It has been suggested (6-8) that differences in the amount
of myocardium in jeopardy during painful and painless ischemic episodes could account for the presence or absence of
symptoms during an ischemic episode. However, among different patient populations, it is likely that individual variations
in ischemic pain threshold and perception may be explained by
visceral neuropathy (diabetes mellitus), presence of myocardial infarction, previous coronary artery bypass surgery or
simply by a defective perception of painful stimuli (30,31). In
the present study we selected a homogeneous patient cohort
and demonstrated that during demand-driven painful myocardial ischemia, patients generally exhibit a more extensive area
of myocardial dysfunction than those with painless ischemia,
suggesting that the severity of myocardial ischemia was greater
in the patients with painful ischemia.
Patients with painless ischemia had an uneventful outcome
during the follow-up period, suggesting that asymptomatic
patients with good left ventricular function at rest have a good
prognosis, in line with the mildly ischemic or negative exercise
echocardiography test results.
Clinical implications. There is a complex and variable
interplay between spontaneous supply- and demand-related
factors, with ischemia developing when the latter exceed the
former. In our study we investigated patients with exercise
(demand)-related myocardial ischemia, and it would therefore
be inappropriate to extrapolate our findings to those derived
from studies involving ambulatory monitoring because pathophysiologic mechanisms producing myocardial ischemia both
silent and painful may differ in the two situations. Although
defective pain perception may still be responsible for painless
ischemic episodes in some patients, we demonstrated that the
extent and severity of myocardial ischemia appear to be largely
symptom-related during exercise in patients with chronic stable
angina.
1511
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EXERCISE ECHOCARDIOGRAPHY IN MYOCARDIAL ISCHEMIA
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