JACC Vol . 23, No . 1
January 1994: 2 29 --32
229
WONCominvent
Does MYOC37 :10,71
Portend Poor :- :PRAKASH C . DEEDWANIA, MD, FACC
Fresno, California
Although considerable work has been done to evaluate the
prognostic importance of myocardial ischemia, the debate
continues . Undoubtedly, myocardial ischemia is the most
reliable predictor of physiologically significant coronary
artery disease (1,2) . As a matter of fact, some recent rhea
have shown that excrcise-irlduced myocardial ischemia as
evidenced by ST segment depression is a better marker of
clinically important coronary artery disease than is exerciseinduced angina (3) . Numerous previous reports (4-18) have
demonstrated that exercise-induced ischemia provides reliable and clinically meaningful prognosticc information in
patients with coronary artery disease .
In the past clinicians had to rely solely on ST segment
changes recorded by electrocardiography for detection of
isch4mia, but recent technologic advances have now made it
possible to detect ischemia based on functional abnormalities observed during various radionuclide and echocardiographic imaging studies . Clearly, with the advent of these
newer diagnostic techniques in conjunction with various
modes of pharmacologic stress testing, clinicians now have a
wide array of choices available for evaluation of patients
with coronary artery disease . It is becoming increasingly
apparent that in certain areas it is now customary to use one
of these newer techniques in conjunction with, or in preference over, the traditional method of exercise electrocardiography . Despite the widespread use of these newer techniques in the evaluation of patients with coronary artery
disease, it is not clear whether the data available from these
studies provide meaningful information in predicting the
clinical outcome and the future risk of cardiac events . The
results of the study by Miller and coworkers (19) in this issue
of the Journal have raised this question again by showing
that the presence of severe exercise-induced ischemia as
detected by exercise radionuclide ventriculography in medically treated patients with one- or two-vessel coronary
artery disease and normal left ventricular function was not
predictive of an increased risk of cardiac events . These
*Editorials published in Journal of the American College of Cardiology
reflect the views of the authors and do not necessarily represent the views of
JACC or the American College of Cardiology .
From the Camsiology Section, Department of Medicine, Veterans Affairs
Medical Center/University of California . San Francisco Program at Fresno,
Fresno, California .
Address far co espondence : Dr. Prakash C. Deedwania . Cardiology
Section (11 1), Veterans Affairs Medical Center, University of Cal-icbmia, San
Francisco Program, 2615 East Clinton venue, Fresno, California 93703 .
9 1994 by the American College of Cardiology
results raise several clinically important questions : 1) Is the
presence of myocardial ischernia prognostirally important?
2) Are there some inherent limitations in the study that make
it difficult to generalize these results to other patients with
one- or two-vessel disease? 3) The information available
from exercise radionuclide ventriculography is prognostically not as reliable as traditional markers of myocardial
ischemia on exercise electrocardiography .
The present study . Because the study by Miller et al . (19)
is not a randomized controlled study, it is essential to
examine the clinical characteristics of the study population
and the criteria used to define "severe exercise-induced
ischernia" before any of the preceding questions can be
answered. It is quite clear that the study subjects were a
select subgroup of patients drawn from a pool of 420 patients
with on or two-vessel coronary artery disease and normal
left ventricular ejection fraction who had undergone evaluation by exercise radionuclide ventriculography . At the
discretion of their primary physicians, 140 patients underwent revascularization and were excluded from the study
group . As stated by Miller et al ., the patients referred for
re%ascularization were more likely to have anginal symptoms, the presence of exercise-induced ST segment depression, greater reductions in exercise left ventricular ejection
fraction and proximal left anterior descena . •g coronary
artery disease . Clearly, many of these factors trust have
played a role in the decision-making process by the primary
physicians who obviously did an excellent job of selecting
the patients at highest risk and referring them for revascalarization . The remaining group comprised mostly low risk
patients who were treated medically and form the primary
focus of the study . Although the investigators claim that
selection of patients for revascularization did not remove the
high risk pat" ., nts from their study, a close examination of
the available data for the group with severe ischemia would
clearly refute that . Of the 59 patients classified as having
"severe ischemia," only 15% had proximal left anterior
descending artery disease, and only half of the patients had
a clinical history of angina pectoris . Both of these variables
were significantly different from those in the revascularization group . Thus, on the basis of the most generally accepted
criteria, this group would indeed be described as a low risk
subset that would be expected to have an excellent prognosis
with medical therapy .
The second obvious concern in this study is related to
the definition of "severe ischemia" based on work load
X600 kg-m/ in, ?1 .0 mir ST segment depression and decrease in left ventricular ejection fraction with exercise .
Whereas these criteria are well accepted as indicators of
exercise-induced ischemia, they might not necessarily represent severe ischemia and as such could be somewhat
misleading . The results of a previous study (20) indicated
that although exercise radionuclide ventriculography was
quite helpful n identifying patients with no coronary artery
disease and those with nuldvessel disease, it had low
0735-1097194156.00
230
DEEDWANtA
EDITORIAL COMMENT
specificity and low average predictive accuracy in patients
with one- or two-vessel disease . Thus, it is conceivable that
some of the findings described as indicative of severe ischemia may not even correlate with evidence of ischemia,
particularly in women (37% of the severe ischemia group), in
whom electrocardiographic (ECG) changes may also be
unreliable. It is widely believed that regional wall motion
abnormalities on exercise radionuclide ventriculography are
more specific markers of ischemia but unfortunately Miller
et al . (19) provide no data regarding such abnormalities .
Although the low rate of cardiac events in the group of
selected low risk patients studied by Miller et al . is not
surprising, these data may not be applicable to unselected
patients with one- or two-vessel disease, particularly those
with proximal left anterior descending coronary artery disease . The findings of this study, however, do convey an
important message by emphasizing that most low risk patients with one- or two-vessel coronary artery disease and
normal left ventricular ejection fraction have an excellent
prognosis on medical therapy . Therefore, the decisions to
recommend revascularization in these patients should be
based on individualized, critical appraisal of all available
data and for symptoms refractory to medical therapy rather
than rushing for intervention largely based on abnormal
exercise ECG and radionuclide ventriculographic findings .
Previous studies . Several previous studies have evaluated
the prognostic importance of exercise radionuclide ventriculographic findings in various groups of patients with coronary artery disease (4-5) . In a majority of these studies, the
ischemic response during exercise radionuclide ventriculography was associated with poor prognosis and increased risk
of cardiac events . In many of these previous studies (4,5),
the patients evaluated differed considerably from those
studied by Miller et al . Some of these earlier studies (4)
included patients with three-vessel disease, whereas others
included patients with impaired left ventricular function (5) .
However, in a few previous studies (6-8), the patients and
their clinical characteristics were comparable to those in the
present study by Miller et al . One such study by Lee and
coworkers (7) in 571 patients with stable, symptomatic
coronary artery disease compared the prognostic value of
exercise radionuclide ventriculography with various clinical
and angiographic variables . The vast majority of patients in
that study had one-vessel (39%) or two-vessel (34%) coronary artery disease and a normal left ventricular ejection
fraction . During an average follow-up interval of 5 .4 years,
the infarct-free S-year survival rate was 76% and the single
best predictor of coronary events and cardiac death was
exercise left ventricular ejection fraction . Neither the rest
left ventricular ejection fraction nor the changes in ejection
fraction with exercise contributed further prognostic value
to that derived from exercise ejection fraction alone . In
contrast to the extremely low prevalence (15%) of proximal
left anterior descending coronary artery disease in the study
by Miller et al ., almost 30% of the patients in the study by
Lee et al . had proximal left anterior descending disease, a
JACC Vol . 23, No . I
January 1994 :229-32
finding that may account for the difference in the cardiac
event rates in the two studies . These comparisons clearly
emphasize the importance of the Bayesian concept of probability, which indicates that in a select group of patients with
an extremely low pretest probability of cardiac events, no
single test can accurately identify the high risk subset .
Does nay r . i be provide re . le prognostic information? Indeed, it does, and there is ample evidence
(9-17) to support this view . Several previous studies (9-17)
have evaluated the prognostic importance of ST segment
depression observed during exercise testing . Most of them
(10-15) had demonstrated that exercise-induced ST segment
depression (silent or symptomatic) identifies a group of
patients with coronary artery disease who are at high risk of
subsequent cardiac events . Even in patients with previously
asymptomatic coronary artery disease, the presence of
exercise-induced ST segment depression has been shown
(10,13,16,17) to predict a fourfold to fivefold increase in
cardiac mortality during a long-term follow-up period of 5 to
7 years. Some studies (16,18) have also shown that increasing magnitude of ST segment depression (a-1 .5 mm) predicts
higher risk of coronary events and cardiac death. Thus, the
available data from these previous studies clearly show that
exercise-induced myocardial ischemia is by no means benign, and in most patients with coronary artery disease its
presence implies a relatively increased risk of coronary
events and cardiac death .
The v ieties of myocardial ischemia . The various clinical
settings in which myocardial ischemia occurs are not identical . Because the prognostic value of myocardial ischemia
would vary depending on the clinical syndromes and the
setting in which it is encountered, it is essential to classify
myocardial ischemia (Fig . 1) . Most previous studies have
concentrated primarily on the evaluation of inducible ischemia in the laboratory, and although it is well recognized that
exercise-induced ischemia denotes significant coronary artery disease, the information available from inducible ischemia may be of limited value because most patients do not
indulge in activities during daily life that reach the ischemic
threshold obtained during exercise testing . This is particularly important because it is now established (21) that
spontaneous ischemia during daily life (most of which is
silent) is the most common form of myocardial ischemia
encountered in patients with chronic and acute ischemic
syndromes . Several recent studies (21-24) have demonstrated that the presence of ischemia during daily life in
pat :dnts with acute as well as chronic ischemic syndromes is
a powerful and independent predictor of an increased risk of
coronary events and cardiac death . Some recent studies
(21-23) have also shown that ischemia during daily life
provides significant additional prognostic information to that
available from various established exercise test variables in
patients with stable coronary artery disease who have inducible ischemia in the laboratory . The added prognostic value
of spontaneous ischemia during daily life may be related to
the pathophysiologic consequences of repeated episodes of
JACC Vol . 23, No, I
January 1994_229-32
DEEDWANIA
EDITORIAL COMMENT
231
MVOCMSOIAL ISCHE€Mh.
r
Acute ischemic
Syndr®tnas
S onlaneaus Ischam a
- Unstable angina
Acute phase of MI
Chronic Isctaernic
Syndromas
letducib9a Ischernta J sta n ss,pit a r rn ace loge e)
Past • rnraect ~n~
Pcast-lnstable angina
Spontaneous Ischemia
Stable angina
- During Calls lire
Inducible Ischemia (stress,phartnacologie)
; Slzble angina
l!~ :Asymptomatic
- Peon-q wave MI
Figure t . Classification of etyocardial ischemia in various clinical
settings . lit = ryecardial Infatctitio .
ischemia . Several histopathologic studies in patients with
stable coronary artery disease (25,26) have shown that
repeated episodes of myocardial ischemia (silent or otherwise) lead to cell death, depletion of energy stores, subendocardial necrosis arid areas of myocardial fibrosis that
can eventually lead to left ventricular dysfunction .
From the preceding discussion, it seems reasonable to
conclude that in patients with coronary artery disease and
inducible ischemia in the laboratory, evaluation of the risk
for spontaneous ischemia during daily life could provide
additional prognostic information . Such evaluation might be
particularly useful in the patients with one- or two-vessel
coronary artery disease similar to those studied by Miller et
al ., because it has the potential of further stratifying these
patients into high risk and low-risk categories .
Clinical implications . Thus, the available data indicate
that myocardial ischehnia is not benign and that in most cases
its presence denotes relatively poor prognosis . However, the
prognostic value of myocardial ischemia would vary considerably depending on the clinical setting in which it is
encountered . A thorough evalu4tiorl of myocardial ischemia
in patients with coronary artery disease should include
assessment of the risk for spontaneous ischemia during daily
life . It is also important to recognize that the low risk
patients (similar to those studied by Miller et al .) generally
have an excellent prognosis with medical therapy and should
not be subjected to unnecessary further evaluation or revascularization procedures, or both, simply on the basis of
abnormal findings detected during exercise testing .
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