236
47.
48.
49.
50.
51.
CIRCULATION
hypothesis for the mechanism of action of nitrates. J Pharmacol
Exp Ther 168: 70, 1960
Come P, Flaherty J, Baird MG, Rouleau JR, Weisfeldt M,
Greene L, Becker L, Pitt B: Reversal by phenylephrine of the
beneficial effects of intravenous nitroglycerin in patients with
acute myocardial infarction. N Engi J Med 293: 1003, 1975
Borer JS, Redwood DR, Levitt B, Cagin N, Bianchi C, Vallin
H, Epstein SE: Reduction in myocardial ischemia with
nitroglycerin or nitroglycerin plus phenylephrine administered
during acute myocardial infarction. N Engl J Med 293: 1008,
1975
Becker LC, Fortuin JN, Pitt B: Effect of ischemic and antianginal drugs on the distribution of radioactive microspheres
in the canine left ventricle. Circ Res 28: 263, 1971
Becker LC: Conditions for "coronary steal" with dipyridamole.
Am J Cardiol 37: 120, 1976
Rees JR, Redding VJ: Effects of dipyridamole on anastomotic
52.
53.
54.
55.
56.
VOL 61, No 2, FEBRUARY 1980
blood flow in experimental myocardial infarction. Cardiovasc
Res 1: 179, 1967
Cohen MV, Downey JM, Sonnenblick EH, Kirk ES: The
effects of nitroglycerin on coronary collaterals and myocardial
contractility. J Clin Invest 52: 2836, 1973
Griffith GC, Boggs RP: Clinical use of heparin. Am J Cardiol
14: 39, 1964
Saliba MJ Jr: Effects of heparin in large doses on the extent of
myocardial ischemia after acute coronary occlusion in the dog.
Am J Cardiol 37: 599, 1976
Philip RB, Francey I, McElroy F: Effects of dipyridamole and
five related agents on human platelet aggregation and adenosine
uptake. Thromb Res 3: 35, 1973
Moschos CB, Lahiri K, Lyons M, Weisse AB, Oldewurtel HA,
Regan TJ: Relation of microcirculatory thrombosis in the proximal coronary artery: effect of aspirin, dipyridamole and thrombolysis. Am Heart J 86: 61, 1973
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
Prognostic Value of a Single Exercise Test 3 Weeks
after Uncomplicated Myocardial Infarction
DENNIS M. DAVIDSON, M.D., AND ROBERT F. DEBUSK, M.D.
SUMMARY The prognostic value of exercise testing was assessed in 195 men, mean age 54 ± 8 years, 3
weeks after uncomplicated myocardial infarction. In the first 82 men, effort was terminated at a heart rate of
130 beats/min in the absence of limiting symptoms, exertional hypotension or ventricular tachycardia. In the
last 113 men, heart rate was not used as an end point. No complications of exercise testing were noted. From
13 clinical and treadmill test characteristics, a stepwise multiple logistic regression program identified
exercise-induced ST-segment depression (ST;) 0.2 mV, angina pectoris and maximal work load < 4 multiples of resting energy expenditure (mets) as "risk factors" predictive of combined medical and surgical events
(myocardial infarction, sudden death, cardiac arrest and coronary artery bypass surgery) in a subset of 92
patients followed 2 years or more. Clinical characteristics and exercise-induced ventricular ectopic activity
were not predictive of such events. Life-table analysis in the entire population of 195 men confirmed the increased probability of combined medical and surgical events in patients with one or more "risk factors." For
medical events alone, STI 0.2 mV and maximal work load < 4 mets were predictive, whereas angina pectoris was not. STI > 0.2 mV and exercise-induced angina pectoris were predictive of surgical events. We conclude that patients without evidence of congestive heart failure 3 weeks after uncomplicated myocardial infarction can safely underg6 symptom-limited exercise testing. Valuable prognostic information is gained that is
independent of selected clinical characteristics.
IDENTIFICATION of patients soon after myocardial infarction who are at relatively high risk for subsequent cardiac events offers two major benefits.
High-risk patients could be identified for more
aggressive medical or surgical therapy to reduce their
morbidity and mortality. Patients at low risk could be
spared needless invasive studies and unwarranted
restriction of their physical activities.
Routine clinical methods are sufficient to identify
certain subgroups of patients at increased risk for subFrom the Division of Cardiology, Stanford University School of
Medicine, Stanford, California.
Supported in part by NIH grants ROI HL-18907 and HL-5866.
Address for correspondence: Dennis M. Davidson, M.D., Cardiology Division, Stanford University Medical Center, Stanford,
California 94305.
Received March 2. 1979; revision accepted August 7, 1979.
Circulation 61, No. 2, 1980.
sequent cardiac events after acute myocardial infarction. A history of congestive heart failure or shock in
the coronary care unit, cardiomegaly on chest x-ray,
audible third heart sound (S3) and a history of digitalis
usage are all features of left ventricular dysfunction
that have been associated with increased mortality
during the year after myocardial infarction.1-4 In contrast, these abnormalities are absent in the majority of
patients who survive myocardial infarction.
Hypothetically, the risk of subsequent cardiac events
in these clinically uncomplicated patients may be
further stratified by treadmill exercise testing performed soon after the acute event.
The present study was designed to determine
whether treadmill exercise testing, performed soon
after uncomplicated infarction, further defines the risk
of subsequent cardiac events and, if so, which specific
exercise test characteristics are most predictive of such
events in this population.
PROGNOSIS AFTER POST-MI EXERCISE TESTING/Davidson and DeBusk
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Materials and Methods
Men aged 70 years or younger who were
hospitalized at Stanford University Medical Center
and associated hospitals for myocardial infarction
during the years 1974-1978 were considered for the
study. Patients with clinical or radiologic evidence of
pulmonary congestion or cardiac enlargement during
hospitalization and those with one or more of the
following characteristics 3 weeks after hospital admission were excluded: rest or unstable angina pectoris,
clinical congestive heart failure, an audible S,, digoxin
or propranolol therapy, significant cardiac valvular
disease, hypertension >180/100 mm Hg, pulmonary
disease or musculoskeletal disorders limiting exercise
capacity, previous coronary artery bypass graft surgery, and cardiac conditions complicating electrocardiographic interpretation, such as left bundle branch
block or atrial fibrillation.
Men hospitalized at Stanford University Medical
Center constituted 72% of the patients in the study
population. Of 542 consecutive patients treated for
myocardial infarction at our institution, 81 (15%) died
in the hospital. Of the 461 survivors, 184 (40%) were
excluded for medical reasons: 118 for the cardiac conditions listed above, 57 for pulmonary disease or
musculoskeletal disorders limiting exercise, and nine
because of digoxin or propranolol therapy. One hundred thirty-six other men (30%) whose medical
characteristics were similar to those undergoing exercise testing were unavailable for the study (nonmedical
exclusions): 42 for patient or physician refusal, 34 for
transfer to other hospitals and 60 for residence outside
the San Francisco Bay Area. The remaining 141 men
(30% of survivors) joined the study. Because patients
with nonmedical exclusions were similar to those who
participated in the study, we concluded that the
patients described in this report are representative of
approximately 60% of the entire population of men
aged 70 years or younger who were treated for
myocardial infarction in our institution.
The final study population consisted of 195 patients.
Infarction was inferior transmural in 119 patients
(61%), anterior transmural in 56 (29%), and nontransmural in 20 (10%). The mean maximal elevation
of serum creatine kinase was 833 ± 657 IU (normal
range for men 5-90 IU). Complications during the
first 5 days of hospitalization included ventricular
tachycardia in 42 patients (22%), ventricular fibrillation in six patients (3%), second-degree atrioventricular block in 13 patients (7%) and third-degree
atrioventricular block in six patients (3%). Twenty-five
patients (13%) had experienced angina pectoris in the
3 months before infarction and 16 (8%) had a history
of prior myocardial infarction. Eight patients (4%)
were taking quinidine, mean daily dose 787 ± 203 mg,
and four patients were taking procainamide, mean
daily dose 1750 + 645 mg. Two patients (1%) were
taking long-acting nitrates in a daily dose of 20 mg
each. These medications were withheld for 16-24
hours before exercise testing.
Before testing, patients were interviewed and ex-
237
amined by a physician and informed consent was obtained. A physician and a specially trained cardiovascular nurse conducted the test. All tests were
performed between 1-5 p.m., at least 2 hours after
eating or smoking. Twelve-lead ECGs were recorded
at rest, at the end of each 3-minute stage of exercise,
and at 1, 3, 5, 7 and 10 minutes of recovery. In addition, leads V4 through V6 were displayed continuously
on a three-channel oscilloscopic monitor and recorded
on magnetic tape for 3 minutes before exercise and
during each minute of exercise and recovery. STsegment depression was defined as horizontal or
downsloping displacement of the ST segment
measured 80 msec after the J point relative to a
baseline drawn tangentially through the PQ segment.
At rest, 55% of patients had no ST depression and
42% had ST depression less than 0.1 mV. During exercise, the maximal change from rest was measured to
the nearest 0.05 mV in leads 2, 3, aVF, and V1 through
V6. Systolic blood pressures were recorded by cuff
sphygmomanometer at the end of each 3-minute stage
of exercise and at 1-minute intervals if the systolic
pressure did not rise from one stage of exercise to the
next.
Exercise was performed on a motor-driven treadmill using the protocol given in table 1. Exercise commenced at a work load of 3 mets and work loads were
increased every 3 minutes. The first 82 patients completed a "heart-rate-limited" protocol in which testing
was stopped at an arbitrary heart rate of 130
beats/min (37 cases) unless any of the end points listed
below occurred sooner (45 cases). Because no complications were noted in this group, the next 113
patients, clinically indistinguishable from the first 82,
completed a "symptom-limited" protocol in which
maximal heart rate was not used as an end point. End
points included: 1) limiting symptoms of chest pain,
dyspnea, fatigue, leg cramps or dizziness; 2) exertional
hypotension, defined as a fall in systolic pressure of 10
mm Hg or more from the peak value attained earlier
during exercise; and 3) ventricular tachycardia,
defined as three or more consecutive premature venTABLE 1. Treadmill Exercise Test Protocol
Grade
Speed
Stage*
2
3
4
5
6
7
8
9
10
(mph)
(%)
Mets
2
2
2
2
2
2
3
3
3
0
3.5
7
10.5
2
3
4
5
14.0
17.5
12.5
15.0
17.5
7
8
9
10
*3 minutes each.
Abbreviation: Mets
penditure (estimated).
=
multiples of resting
6
energy ex-
238
C IRCU LATION
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tricular complexes (PVCs). The magnitude of STsegment depression was not used as an end point.
Patients returned for follow-up visits 11 weeks, 6
months and 1 year after infarction. After the first year
of the study, contact with patients or their physicians
was maintained by annual telephone calls or letters.
Subsequent cardiac events were defined as medical
(sudden death, ventricular fibrillation with survival,
acute myocardial infarction) or surgical (coronary
artery bypass graft surgery).
A stepwise logistic regression analysis5 was used to
identify clinical and treadmill variables predictive of
subsequent cardiac events (table 2). Because this
analysis requires a standard follow-up period, a subset
of 92 patients, followed for 24 months after infarction
or until the occurrence of a medical or surgical event,
was used. In the analysis, the variable that best
predicts the outcome is selected and designated "most
valuable." Each of the remaining variables is combined with the previously selected "most valuable"
variable and that one is selected which in combination
with the previously selected variable best predicts the
outcome. This process continues until the addition of a
variable does not significantly augment prognostic information, as assessed by a chi-square test. Some
variables that are unilaterally associated with the outcome are not selected by this stepwise process because
the information they contain is better expressed by
previously selected variables. Thus, the value of a
given variable in this analysis represents not only its
correlation with outcome but also its independence
from previously selected variables.
Variables significantly associated with clinical outcome in the subgroup of 92 patients with a 24-month
follow-up were then used to stratify the risk of subsequent cardiac events within the entire population, of
195 patients. Censored survival curves were compiled
to estimate the probability of cardiac events in
patients with one or more risk factors. Statistical
significance was assessed by the method of Kaplan and
Meier.6
Because of the nonrandom process of selection for
surgery and because of the uncertain influence of coronary artery bypass graft surgery on prognosis,
clinical outcomes were defined in two ways: 1) combined medical and surgical events - tantamount to
TABLE 2. Variables Used in Prognostic Stratification
Clinical
Treadmill
Age
M\aximal heart rate
Previous MI
Maximal systolic blood pressure
Angina within 3
months of MI
Maximal rate-pressure product
Site of MI
Maximal work load
Peak creatine kinase
level
ST-segment depression
Angina pectoris
Exercise-induced hypotension
Ventricular ectopic activity
Abbreviation: MI = myocardial infarction.
VOL 61, No 2, FEBRUARY 1980
assuming that all patients undergoing surgery would
have had medical events otherwise, and 2) medical
events only - equivalent to assuming that no patient
who had surgery would have otherwise had a medical
event. The predictive power of clinical and treadmill
test characteristics was evaluated within the bounds of
these two extreme assumptions.
Results
Clinical Characteristics
Within the entire population of 195 patients, no
significant differences in age, maximal level of creatine
kinase activity, prevalence of angina pectoris before
infarction or history of prior infarction were noted in
comparing the following subgroups: 1) the 92 patients
followed for 2 years compared with the 103 patients
with shorter follow-up, 2) the 19 patients who underwent coronary artery bypass graft surgery compared with the 176 patients who did not, 3) the 56
patients with anterior infarction compared with the
119 patients with inferior infarction, and 4) the 82
patients who underwent a heart-rate-limited test
protocol compared with the subsequent 113 patients
who underwent a symptom-limited test protocol.
Treadmill Test Results
No complications of treadmill exercise were noted.
Of the 82 patients who completed a heart-rate-limited
protocol, 30 (37%) stopped because of dyspnea or
fatigue, eight (10%) stopped for angina pectoris, six
(7%) were stopped after exercise-induced hypotension
was noted, one (1%) was stopped because of ventricular tachycardia and 37 (45%) had no symptoms
before reaching the limiting heart rate of 130
beats/min. Of the 82 men, 15 (18%) had ST-segment
depression > 0.1 mV and 12 (15%) had ST depression
> 0.2 mV.
Of the 113 patients who completed a symptomlimited protocol, 86 (77%) stopped because of dyspnea
or fatigue, 13 (11%) for angina pectoris, 14 (12%)
because of exercise-induced hypotension and none for
ventricular tachycardia. Of the 1 13 men, 29 (26%) had
ST-segment depression > 0.1 mV and 13 (12%) had
ST depression > 0.2 mV.
The mean duration of treadmill exercise after the
appearance of 0.1 mV of ST-segment depression for
the entire group was 1.9 ± 2.0 minutes (range 0-7
minutes).
Treadmill test characteristics for the total population of 195 patients are summarized in table 3. These
characteristics were not significantly different 1) in the
subgroup of patients followed for 2 years compared
with those with a shorter follow-up, 2) in those who
had coronary artery bypass graft surgery compared
with those who did not, and 3) in patients with inferior
infarction compared with those with anterior infarction. Exercise-induced angina pectoris was noted in
one-third of patients with ST-segment depression
> 0.1 mV and in one-half of patients with ST-segment
depression > 0.2 mV. Ventricular ectopic activity was
PROGNOSIS AFTER POST-MI EXERCISE TESTING/Davidson and DeBusk
TABLE 3. Treadmill Exercise Test Characteristics (n = 195)
Mean values:
18
131
Maximal heart rate (beats/min)
Maximal systolic blood pressure
164 25
(mm Hg)
5.8 1.7
Maximal work load (mets)
Frequency:
30/195 (15.4%)
Exercise-induced angina pectoris
Exercise-induced ST depression
> 0.1 mV
42/195 (21.8%)
Exercise-induced ventricular
73/195 (37.8%)
ectopic activity
Abbreviation: mets = multiples of resting energy expenditure.
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not significantly more frequent in patients with
exercise-induced ST-segment depression than in those
without it.
Clinical Outcome (fig. 1)
The median duration of follow-up was 26 months
(range 1-64 months). To date, 150 patients have been
followed at least 1 year, 92 for at least 2 years, and 48
for at least 3 years. Of the 195 men, three died
suddenly, two had nonfatal cardiac arrest, 12 had nonfatal myocardial infarction and 19 underwent coronary artery bypass surgery. In the 150 patients
followed for at least 1 year, the rate of combined
medical and surgical events within the first year of
follow-up was 19%. The rate of medical events only
within the first year of follow-up was 8%.
Prognostic Stratification
The stepwise multiple logistic regression analysis
identified (in descending order of importance) ST0.2 mV, exercise-induced
segment depression
angina pectoris and a maximal treadmill work load
< 4 mets as the most important "risk factors"
associated with combined medical and surgical events
in a subgroup of 92 patients followed for 2 years or
more. Among the clinical and treadmill test
characteristics listed in table 2, only ST-segment
2 VF
1
NO EV
12 MI
FIGURE 1. Medical and surgical events in 195 men
followed for 1- 64 months after uncomplicated myocardial
infarction. SD = sudden cardiac death; VF= ventricular
fibrillation (successful resuscitation); MI = myocardial infarction; CABS = coronary artery bypass graft surgery.
239
depression, low maximal work load and angina pectoris were identified as risk factors.
The relationship between risk factors and the
probability of combined medical and surgical events in
the entire population of 195 patients was evaluated by
censored survival curves (fig. 2). ST-segment depression > 0.2 mV was the variable most highly associated
with combined events (p < 0.0001). ST-segment
depression 0.1-0.19 mV was of no greater predictive
value than ST-segment depression < 0.1 mV. In
patients with < 0.2 mV ST-segment depression, those
with exercise-induced angina or a maximal treadmill
work load of < 4 mets had an increased probability of
combined events (p < 0.0001) when compared with
those with neither abnormality.
The risk of medical events alone was higher in
patients with ST-segment depression . 0.2 mV
(p < 0.001) or maximal work load < 4 mets
(p < 0.07) compared with patients with neither of
these features. In contrast, exercise-induced angina
pectoris was not associated with a significantly higher
probability of subsequent medical events (fig. 2).
Nineteen of the 195 patients underwent coronary
artery bypass surgery. This group includes two of 10
patients (20%) with exercise-induced angina and ST
depression > 0.2 mV, four of 22 (18%) with angina
only, five of 13 (38%) with ST-segment depression
> 0.2 mV but no angina and eight of 150 (5%) with
neither angina nor ST-segment depression . 0.2 mV.
Thus, surgery was ultimately performed in six of 32
patients (19%) with angina compared with 13 of 163
patients (8%) without exercise-induced angina.
Of the five episodes of sudden death or nonfatal ventricular fibrillation, three occurred 3-11 weeks after
infarction. All three patients had ST-segment depression > 0.2 mV on the treadmill test performed 3
weeks after infarction. No patients with < 0.2 mV ST
segment depression had sudden death or ventricular
fibrillation during this early posthospital period.
Discussion
We sought to evaluate the prognosis of postinfarction patients without clinical evidence of severe left
ventricular dysfunction. Within this selected population, we found that certain treadmill test
characteristics permitted prognostic stratification, but
clinical characteristics such as age, extent of creatine
kinase elevation, site of infarction and prior history of
angina pectoris or infarction did not. Our study thus
complements the prognostic evaluations of Bigger et
al.' in patients with a high prevalence of severe left
ventricular dysfunction and of Moss et al.3 in a population with an intermediate prevalence of clinically
severe left ventricular dysfunction.
The prognostic significance of ST-segment depression during exercise testing soon after infarction has
not been reported. Granath et al.7 and Ericsson et al.8
performed bicycle exercise testing 3 weeks after infarction in a population with a high prevalence of left
ventricular dysfunction, but the use of digitalis complicates the evaluation of ST-segment responses
VOL 61, No 2, FEBRUARY 1980
CIRCULATION
240
MEDICAL AND SURGICAL EVENTS
1.0 1
FIGURE 2. Probability of subsequent cardiac events in 195 men after myocardial infarction, as calculated by censored survival
data. STB = ST-segment depression;
mets = maximal treadmill work load
achieved. Left) Medical and surgical events.
Men with SBT > 0.2 mV (*) had a higher
probability of events than those with < 0.2
m V ST; who had exercise-induced angina
pectoris (**) (p < 0.01) or maximal work
load < 4 mets (***) (p < 0.001) or neither
of these features (p < 0.0001). Among men
with SBT < 0.2 m V, those with angina pectoris (**) or mets < 4 (** *) had a higher risk
than those with neither feature (p < 0.001),
but there was no significant difference in risk
for men with angina (**) compared with
those with mets < 4 (***). Right) Medical
events only. Men with ST; > 0.2 m V(t) had
a higher probability of events than those
with SBT < 0.2 mV who had mets < 4 (tt)
(p < 0.15) or exercise-induced angina
(p < 0.01) or neither of these features
(p <0.001). Men with ST <0.2 mV and
mets < 4 (tt) had a higher probability of
events than those with STB < 0.2 m V and
angina (p < 0.09) or neither feature
(p < 0.07).
MEDICAL EVENTS
1
ST t 20.2 mV (n=23)
ST <0.2 mV(n=22)
ANGINA (+)
-- ST t <0.2 mV In=13)
ANGINA (-)
0.8 P
METS <4
.*"
ALL OTHERS
/
(n=137)
- --
*
0.6
m
0
0W
0.4
Li
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0.2
0
1- '
1
1
2
0
1
4
YEARS
within this
Ibsen et al.9 noted ischemic
large proportion of patients undergoing
bicycle exercise testing 3 weeks after infarction, but
the prognostic significance of this finding was not
reported. Weld and Bigger,10 whose patients performed treadmill exercise tests 2 weeks after infarction, did not note an increased rate of subsequent coronary events in patients with "ST deviation" > 0.2
group.
responses in a
mV.
The influence of recent myocardial infarction on the
ST-segment response to exercise has only recently
been examined. Castellanet et al.11 found that exercise
testing had a low sensitivity (52%) for the detection of
significant coronary artery stenosis in noninfarcted
regions 2 months or more after anterior myocardial
infarction. The authors attributed this low sensitivity
to the opposing effects of anterior ventricular
aneurysm on the exercise-induced ischemic vector. In
their patients with inferior infarctions, aneurysm was
less frequent and the sensitivity of exercise testing for
the detection of coronary lesions was 84%. In the present study, the prevalence of exercise-induced STsegment depression was not significantly different
when patients with anterior and with inferior infarction were compared. The exclusion of patients with an
audible S3 or radiologic evidence of cardiomegaly may
have "normalized" our population, such that an
equivalent degree of left ventricular dysfunction was
present in patients with anterior and with inferior
transmural infarctions. In fact, the site of infarction
did not significantly influence the occurrence or degree
of ST-segment depression in our patients.
exercise laboratories, tests are terminated
ST-segment depression.
While this policy partly reflects a concern with safety,
there are few data to substantiate the greater safety of
this policy compared with that of testing to limiting
symptoms, regardless of the extent of ST-segment
depression. In addition, the present study indicated
that ST-segment depression was of prognostic
significance only when it was > 0.2 mV. Thus, if the
tests are terminated at 0.1 mV of ST depression or if
an arbitrary heart rate limit is imposed, some patients
may not have the opportunity to exhibit 0.2 mV of ST
depression.
In the absence of ST depression
0.2 mV, exerciseinduced angina pectoris was not associated with a
higher likelihood of subsequent medical events. In
contrast, the risk of combined medical and surgical
events in patients with angina pectoris was increased,
because patients with angina, regardless of ST depression, were three to four times more likely to undergo
bypass surgery than patients with neither angina nor
ST depression > 0.2 mV.
We found a low maximal work load (< 4 mets) to
be predictive of subsequent cardiac events in patients
without ST depression > 0.2 mV or angina pectoris.
Weld et al.10 also noted that patients with a maximal
work load of 3 mets or less 2 weeks after infarction
had an increased risk of subsequent cardiac events.
Factors contributing to peak work load include not
only left ventricular function, but also physical activity patterns before infarction, natural endowment
of the patient and the length of bedrest and reduced
In
many
at the onset of 0.1 mV of
PROGNOSIS AFTER POST-MI EXERCISE TESTING/Davidson and DeBusk
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physical activity after infarction.12 Nevertheless, good
correlation between 1) the duration of exercise and 2)
the ejection fraction and extent of regional wall motion abnormalities was documented by Paine et al.'3 in
patients tested several months after infarction.
Because the extent of left ventricular dysfunction correlates with long-term prognosis,'4 it is not surprising
that our patients with a decreased maximal work load
experienced a higher rate of subsequent cardiac
events.
We found that ventricular ectopy on a single exercise test 3 weeks after infarction had no independent
prognostic value, even in patients with complex configurations or a high frequency of PVCs. This experience is contrary to that of Weld et al.,10 who noted
an increased risk of subsequent cardiac events in
patients with 1 or more PVCs on treadmill exercise
testing performed 2 weeks after infarction. Granath et
al.7 also noted an increased subsequent mortality in
patients with exercise-induced PVCs 3 weeks after infarction. This difference probably reflects the
prevalence of left ventricular dysfunction, because we
excluded patients with clinically evident left ventricular dysfunction and those taking digitalis. In contrast, nearly half of the patients studied by Bigger et
al.4 had cardiomegaly on chest x-ray and nearly half of
the patients of Granath et al.7 were taking digitalis.
Several studies have shown a close relationship
between the prevalence of PVCs and the extent of left
ventricular dysfunction in patients with chronic
ischemic heart disease.'5 16 Previously we reported a
lack of prognostic significance of PVCs recorded during exercise tests or on ambulatory ECGs 3 weeks
after uncomplicated myocardial infarction.17 Our findings are similar to those of Schulze et al.,'4 who noted
that complex PVCs recorded by ambulatory ECGs
were not associated with an increased rate of sudden
death in patients with an ejection fraction > 40% patients likely to resemble those of the present study.
Thus, the prognostic significance of PVCs appears to
be closely related to the extent of left ventricular
dysfunction.
Others have also shown that exercise testing can be
safely performed as early as 3 weeks after infarction.7 8 Is there an advantage in performing testing
this soon? During the month after their 3-week test,
one of our patients died suddenly, one had a nonfatal
cardiac arrest and one had a fatal reinfarction. All
three of these patients showed exercise-induced STsegment depression . 0.2 mV 3 weeks after infarction. The identification of such high-risk patients soon
after infarction is crucial to the evaluation of newer
medical and surgical techniques for improving
prognosis.
The nonrandom process of selection for coronary
artery bypass surgery and the uncertain influences of
bypass surgery on prognosis complicate the evaluation
of prognosis after myocardial infarction. To exclude
the subgroup of patients having bypass surgery from
analysis introduces a potential bias that we addressed
by considering outcome events as combined medical
and surgical events and as medical events only.
241
Because the exercise test results may have contributed
to the decision to perform surgery, it was important to
show that the treadmill test was predictive of medical
events alone (sudden death, nonfatal cardiac arrest,
myocardial infarction) as well as combined medical
and surgical events. Indeed, ST-segment depression
> 0.2 mV and maximal treadmill work load < 4 mets
were found to be predictive of subsequent medical
events. Thus, consideration of clinical outcomes in
these two ways helped to avoid any bias introduced by
performance of coronary artery bypass surgery during
the follow-up period.
We conclude that in patients with clinically uncomplicated myocardial infarction, treadmill exercise
testing performed 3 weeks after the acute event further
defines the risk of subsequent cardiac events, and that
within this population, prognosis is more closely
related to exercise-induced ischemic abnormalities
(ST-segment depression > 0.2 mV and angina pectoris) or to mechanical abnormalities (low maximal
work load) than to electrical abnormalities (ventricular ectopic activity).
Addendum
While this manuscript was in press, Theroux et al. reported on
1-year follow-up of 210 patients without heart failure who had exercise testing before discharge from hospitalization for acute myocardial infarction (N Engl J Med 301: 341, 1979). They had no complications of testing. ST-segment depression was the exercise test
variable of most prognostic significance. One-year mortality rates
and the incidence of sudden death were both more than 10 times
greater for patients who had 0.1 mV or greater ST-segment depression than for patients without this ST-segment response.
References
1. Norris RM, Caughey DE, Mercer CJ, Deeming LW, Scott PJ:
Coronary prognostic index for predicting survival after
recovery from acute myocardial infarction. Lancet 2: 485, 1970
2. Kentala E, Pyorala K, Heikkila J, Sarna S, Luurila 0: Factors
related to long-term prognosis following acute myocardial infarction. Importance of left ventricular function. Scand J
Rehab Med 7: 118, 1975
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242
CIRCULATION
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VOL 61, No 2, FEBRUARY 1980
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Regional Assessment of Myocardial Metabolic
Integrity in Vivo by Positron-emission Tomography
with "C-labeled Palmitate
Downloaded from http://circ.ahajournals.org/ by guest on June 16, 2017
MICHEL M. TER-POGOSSIAN, PH.D., MILTON S. KLEIN, M.D., JOANNE MARKHAM, MS.,
ROBERT ROBERTS, M.D., AND BURTON E. SOBEL, M.D.
SUMMARY To determine whether positron emission tomography (PET) after the combined administration
of 1'C-palmitate intravenously to image myocardium and `CO by inhalation to image the cardiac blood pool
with `CO-hemoglobin provides quantitative delineation of the locus and extent of myocardial infarction, 28
patients with suspected myocardial infarction were studied. Twenty-one patients had electrocardiographically
documented transmural infarction and in seven, the diagnosis of infarction was ultimately excluded based on
enzymatic and electrocardiographic criteria. To assess reproducibility, four patients were studied on two occasions 1 month apart. Inferior and apical infarcts were readily localized with sagittal and coronal as opposed
to transaxial reconstructions. Complete electrocardiographic and tomographic concordance was observed for
the locus of all transmural infarcts. Reproducibility of tomographic estimates was within 10%. Tomographic
estimation of the extent of infarction with "C-palmitate in a subset of patients in whom right ventricular contributions to overall enzyme release could be exluded was facilitated by delineation of the endocardial border
with the "CO-hemoglobin cardiac blood pool image in the same plane. The correlation between enzymatic
(serial plasma MB-CK method) and tomographic estimates of infarct size was close (r = 0.92). Thus, as has
been shown in experimental animals, PET with "C-palmitate permits quantification and localization of
myocardial infarcts in patients.
THE EXTENT of myocardium undergoing irreversible injury is an important determinant of prognosis
after acute myocardial infarction.'`5 Because it may be
possible to limit the extent of infarction during its
early evolution,6-8 accurate, reliable and serially
applicable objective indexes are needed to define both
the extent of tissue jeopardized by ischemia and the
magnitude of irreversible injury evolving ultimately.
During the past several years we have been exploring the possibility of assessing the metabolic integrity
From the Division of Radiation Sciences and Cardiovascular
Division, Washington University School of Medicine, St. Louis,
Missouri.
Supported in part by NIH grants HL 17646 (SCOR in Ischemic
Heart Disease) and HL 13851, and by Washington University
School of Medicine.
Address for correspondence: Burton E. Sobel, M.D., Director,
Cardiovascular Division, Washington University School of
Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110.
Received June 14, 1979; revision accepted September 4, 1979.
Circulation 61, No. 2. 1980.
of myocardium quantitatively and noninvasively by
positron tomography with radioactively labeled
metabolic substrates of myocardium, based on the
premise that prolonged depression of regional
myocardial metabolism will quantitatively reflect underlying pathology.9-" The application of this approach requires that the fate of the labeled substrate
and of the radioactive label itself reflect changes in endogenous metabolites indicative of the altered
metabolic state - a condition best fulfilled by
radionuclides with chemical identities akin to
physiologic substrates such as "C, 1'0 and '3N, in contrast to the case when substrates such as fatty acids are
labeled with an atom such as 1231.14. 15 The brief
physical half-lives of these radionuclides (`C-20
minutes, '3N-10 minutes, 1'0-2 minutes) permit
repeated measurements within a brief interval and
delivery of only a modest dose of radiation to the
patient. Unfortunately, because of their fleeting
existence, these isotopes must be prepared in the immediate vicinity of their application, generally requir-
Prognostic value of a single exercise test 3 weeks after uncomplicated myocardial
infarction.
D M Davidson and R F DeBusk
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Circulation. 1980;61:236-242
doi: 10.1161/01.CIR.61.2.236
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Copyright © 1980 American Heart Association, Inc. All rights reserved.
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