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(Circulation. 1995;91:291-297.)
© 1995 American Heart Association, Inc.
Articles |
Prodromal Angina Limits Infarct Size
A Role for Ischemic Preconditioning
From Divisione di Cardiologia and Fondazione Cardiologica "M.Z. Sacco," Ospedale G.B. Morgagni, Forlì, Italy.
Correspondence to Filippo Ottani, MD, Fondazione Cardiologica "M.Z. Sacco," P.le Solieri 1, 47100 Forlì, Italy.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background In the experimental setting, it has been demonstrated that preconditioning myocardium before prolonged occlusion with brief ischemic episodes affords substantial protection to the cells by delaying lethal injury, thereby limiting infarct size. Whether the same occurs in humans remains unknown.
Methods and Results This study was undertaken to determine
whether new-onset prodromal angina, defined as chest pain episodes
limited to the 24 hours before myocardial infarction, is the clinical
correlate of the ischemic preconditioning phenomenon. Twenty-five
patients with their first anterior myocardial infarction treated with
thrombolysis (recombinant tissue plasminogen activator [r-TPA], 100
mg/3 hours) were retrospectively included in the study because they met
the following criteria: (1) <120 minutes from onset of symptoms to
reperfusion therapy, (2) <90 minutes from the beginning of
thrombolytic therapy to reperfusion (defined as rapid ST elevation
reduction >50%), (3) a patent infarct-related coronary artery with
TIMI 3 flow and complete absence of collateral circulation to the
infarct related artery (assessed at 24±5 days), and (4) the presence
of new-onset prodromal angina, ie, typical chest pain episodes
occurring at rest within 24 hours or, alternatively, a complete absence
of symptoms before onset of infarction. Therefore, on the basis of
their clinical status before infarction, the patients were divided into
two groups: group 1, 13 patients without prodromal angina, and group 2,
12 patients with prodromal angina. Despite no difference in time to
treatment (81±19 versus 75±21 minutes in group 1 and group 2,
respectively; P=NS) and time to reperfusion (58±34
versus
46±24 minutes; P=NS), the peak of CKMB release was
markedly
lower in group 2 (86.3±66 versus 192.3±108.3 IU/L;
P<.01). In addition, although both groups were comparable
in terms of area at risk (amount of myocardium beyond the
infarct-related stenosis; 15.1±4.6 versus 13.7±4.6 hypokinetic
segments in group 1 and group 2, respectively, P=NS), the
final infarct size (11±7.5 versus 5.6±4 hypokinetic segments,
P<.04) was smaller in group 2. Thus, the limitation of the
infarct size was significantly greater in group 2 (69% versus 36%;
P<.05), and this represents an additional 33%
reduction (95% confidence intervals, 7.1% to 58.9%;
P=.01) in the group of patients with prodromal angina. Also,
the third index, that is, the ECG, showed a favorable trend toward a
lesser number of Q waves and a higher 
R waves, although the values
did not reach statistical significance.
Conclusions Despite a similar area at risk, patients with new-onset prodromal angina showed a significantly smaller infarct size compared with patients without prodromal symptoms. Since the two groups had similar times to reperfusion and no evidence of collateral circulation to the infarct related artery, the protection afforded by angina in group 2 patients might be explained by the occurrence of ischemic preconditioning.
Key Words: ischemia • preconditioning • myocardial infarction • myocardium
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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The recent discovery of the phenomenon of ischemic preconditioning has focused attention on the ability of the myocardium to protect itself. It has been well demonstrated in several animal models that brief ischemic episodes preceding prolonged coronary occlusion cause a significant reduction of infarct size.1 2 3 4 Preconditioning delays lethal cell injury in ischemic myocardium, although the mechanism is still unclear. Its protective role appears to be related to the length of coronary occlusion; a delay in cell death is detectable up to a maximum of 180 minutes of vessel occlusion, after which no further benefits are present.5
Such a phenomenon could have clinical implications in the setting of successful reperfusion after thrombolytic therapy for acute myocardial infarction. New-onset prodromal angina, defined as chest pain episodes limited to the 24 hours before infarction, could be regarded as a clinical correlate of ischemic preconditioning.
To verify this hypothesis and demonstrate a role for ischemic preconditioning in humans, we set up an arbitrary template (including prodromal angina and time to treatment plus time to reperfusion) that could approximate as closely as possible the experimental conditions. Thus, applying this arbitrary human model, we retrospectively reviewed all patients diagnosed as having their first anterior myocardial infarction treated with thrombolytic therapy who were admitted to our coronary care unit during a period of 18 months.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Selection of Patients
Between January 1991 and July 1992, 84 patients were consecutively admitted to our coronary care unit with their first suspected acute anterior myocardial infarction. They were retrospectively included in the study if they satisfied the following features: (1) typical chest pain <120 minutes from symptom onset to reperfusion therapy (approximating as much as possible the time limits delineated by Murry et al1 in their experimental model); (2) ST elevation of >2 mm in two contiguous precordial leads (V1,V6); (3) reperfusion therapy with recombinant tissue plasminogen activator (r-TPA); (4) <90 minutes from the beginning of thrombolysis to reperfusion (defined as rapid ST elevation reduction >50%); (5) Killip class 1 on admission; (6) a patent infarct-related coronary artery showing TIMI 3 flow and complete absence of collateral circulation to the infarct-related artery (assessed at 24±5 days); and (7) the presence of new-onset prodromal angina, that is, typical chest pain episodes at rest within the previous 24 hours or a complete absence of any symptoms before the onset of myocardial infarction. Symptom status before infarction was elicited by specific questioning by the treating physician at the time of admission, using a standardized history form, and was reviewed retrospectively by a single observer (D.P.). For the purpose of this study, prior angina was defined as recurrent ischemic chest pain beginning more than 24 hours before admission, regardless of whether or not any kind of prior medical therapy had been instituted. Fourteen patients showing this feature were excluded from the study. In addition, 30 patients were excluded because they showed >120-minute delay between symptom onset and treatment, 8 patients because reperfusion time was >90 minutes, and 7 patients because they refused to undergo cardiac catheterization. Therefore, 25 patients were finally selected to be included in the study. Clinical status, as previously defined, formed the basis for dividing the patients included into two groups: group 1, 13 patients who showed no chest pain in their life before the episode leading to admission, and group 2, 12 patients who showed new-onset prodromal angina (episodes of chest pain at rest within 24 hours before myocardial infarction). None of these patients were taking cardiovascular drugs before admission to the coronary care unit.
Reperfusion and Adjunctive Therapy
All patients were given
r-TPA (Actilyse, Boehringer Ingelheim)
at the standard regimen of 100 mg (10 mg as a bolus, 50 mg in the first
hour, 40 mg during the subsequent 2 hours). At the end of thrombolytic
infusion, all patients received a 5000-IU heparin bolus followed by a
1000 IU/h infusion in order to maintain the APTT at two times the basal
value. Aspirin at the dosage of 165 mg was given orally on admission.
ß-Blockers and nitrates were left to the discretion of the treating
physicians.
Study Protocol and Parameters Evaluated
ECG
A
standard 12-lead ECG using a Hewlett-Packard
electrocardiograph was recorded before the initiation of thrombolytic
therapy, at the end of the r-TPA infusion, at 24 hours, and on day 7.
In all patients the location of leads V1 through
V6 were marked on each patient's chest on admission to
ensure consistent electrode placement in the recording of subsequent
ECGs.
ECG Measurements.The following parameters were
calculated as
reported by Blanke et al6 : (1) ST V1
through V6 (the sum of ST elevation above the baseline
defined by the preceding TP segment in leads V1 through
V6), (2) n Q V1 through V6 (the
number of pathological Q waves in the precordial leads, with any Q
waves in leads V1 through V3, Q waves wider
than 20 milliseconds in V4, and wider than 30 milliseconds
in V5 and V6, considered pathological), and (3)
R V1 through V6 (the sum of R wave height in
V1 through V6).
Continuous ST-Segment Monitoring.The precordial lead showing maximum ST-segment elevation in the qualifying ECG was selected for continuous monitoring (Space Lab, Inc), which was initiated concurrently with the commencement of reperfusion therapy and continued throughout thrombolysis. Reperfusion was believed to occur when ST-segment elevation abruptly decreased more than 50% relative to the most abnormal peak documented at any time.20 21 Twelve-lead ECGs were recorded at 10- to 15-minute intervals and when a change in chest pain, rhythm, or heart rate was noted. The magnitude of ST-segment elevation was measured 80 milliseconds after the J-point.
Enzymes
Blood samples for measuring CK and CKMB plasma levels
were taken
on admission, every 2 hours for the first 16 hours, and subsequently at
20, 24, 28, 32, 36, 48, 60, and 72 hours after the beginning of
thrombolysis. For our laboratory, the upper limits of normal range were
200 and 16 IU/L for plasma CK and CKMB, respectively. A 72-hour
time-activity curve then was plotted from the CKMB values in both
groups of patients for detecting any difference in enzyme release over
time. The time to CKMB peak was timed from the onset of myocardial
infarction symptoms.
Cardiac Catheterization and Quantitative Left Ventriculography
Coronary angiography and left ventriculography were delayed
until 3 to 4 weeks after infarction to minimize the effects of
myocardial stunning on the determination of final infarct size. Left
ventricular volumes were calculated from an angiogram in the 30°
right anterior oblique projection according to the area-length method.
The infarct-related artery was identified by correlating the coronary
anatomy with the site of ST-segment elevation on the admission ECG and
the distribution of impairment of contractility in the left
ventriculogram. Patency of the infarct-related artery was classified
according to the criteria of the TIMI trial.7 Stenoses
occluding more than 50% of the arterial diameter were regarded as
significant. In addition, after dividing patients into one-, two-, and
three-vessel disease, we evaluated the two patient groups on the basis
of the angiographic scoring system used at Green Lane Hospital,
Auckland, New Zealand. This system, fully reported
elsewhere,8 incorporates the location, length, and
severity of the coronary stenosis as well as the amount of the
myocardium supplied. Briefly, using the grade of stenosis and the
myocardial value (the total number of units of myocardium supplied by
that artery distal to the stenosis), each artery is given an
angiographic score according to a prespecified grading system.
Therefore, for each artery or group of arteries, it is possible to
calculate a separate angiographic score, which, summated with the
others, gives the total angiographic score for that patient.
Regional Wall Motion Analysis
Regional wall motion
analysis was performed with the Kontron
200 system. A modification for determination of the area of myocardium
at risk was also introduced in the procedure. The
end-diastolic and end-systolic silhouettes of the left
ventricle, obtained during sinus rhythm in the 30° right anterior
oblique projection, were first traced onto paper and subsequently
entered into a computer with an x-y digitizer (Fig 1
).
Then, from the center of the left ventricle, 36 equally spaced radii
were drawn to intersect the endocardial outlines for
end-diastolic and end-systolic images, thus dividing images
into 36 areas. In our laboratory, normal wall motion for each area was
derived from ventriculograms of 48 patients with normal left
ventricular function and no coronary artery or valvular disease.
Ventriculograms were filmed at 50 frames per second, and a grid filmed
at the level of the patient's heart was used for calibration. No
attempt was made to correct for rotational changes because such
corrections increase rather than decrease variability.9
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Area at Risk
The area of myocardium at risk was
defined following the
procedure proposed by Cross et al.10 Briefly, this area
was defined as the number of segments depicted on the 30° right
anterior oblique ventriculogram supplied by the infarct-related artery.
The proximal limit was set at the level of the "culprit" lesion
(the lesion associated with evidence of thrombus or the most proximal
severe stenosis). The distal limit of the area at risk was defined as
the termination of the infarct-related artery as viewed in the right
anterior oblique projection. The proximal and distal limits were marked
by the two readers (F.O. and M.G.) who performed the measurements
blinded to the clinical conditions, on the diastolic contour, and the
areas in between were considered at risk. Areas 1,2 and 35,36 were
excluded from analysis because they reflected movements of the
mitral valve and the aortic root. The interobserver and the
intraobserver variability for the area at risk was 0.61±0.65 and
0.56±0.65 segments, respectively, while the interobserver and
intraobserver variability for infarct size was 0.20±0.37 and
0.10±0.28 segments, respectively. This means <5% difference between
repeated calculations for both sets of measurements.
Infarct Size
Shortening of segmental areas by <2
SD of the normal range for
systolic shortening in healthy subjects was considered to indicate an
abnormal area. Therefore, all segments, which at ventriculography
showed an inward motion depressed below the threshold specified above,
were indicated as hypokinetic and considered to form the final infarct
size.
Severity of Regional Abnormalities in Wall Motion
Because the measurement of hypokinetic segment length indicates
only the percentage of the contour suffering decreased wall motion and
provides no information concerning the magnitude of dysfunction in any
specific region, we also evaluated the measurement of inward motion
expressed as severity of hypokinesis. The difference between systolic
shortening of each involved area and the lower limit of the normal
range for systolic shortening in healthy subjects
represented the severity of hypokinesis in that specific
area. The index of the severity of hypokinesis was calculated as
follows.
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where HI denotes the hypokinesis index; AN, the percentage of systolic area shortening in healthy subjects minus 2 SD; AD, the percentage of systolic shortening of the corresponding dissynergic area; and nAD, the number of dissynergic areas.
Statistical Analysis
Data are presented as mean values
±SD. Continuous
variables were analyzed with an unpaired t test or
Mann-Whitney test when appropriate. Two-sided P values are
reported, and a value of P<.05 was considered significant.
Differences in ECG measurements among groups at several time points
were evaluated by ANOVA for repeated measures. Significance was
computed by Scheffe's F test; a P value <5% was
considered significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Clinical and Angiographic Data
The evaluated variables characterizing the two groups are listed in the Table
. No significant differences were detected
between the two sets of patients. Patients were quite well matched for
age, sex, and risk factors. The time to commencement of thrombolytic
drug infusion was similar (81±19 minutes in group 1 versus 75±21
minutes in group 2), and angiographic variables showed no differences
among the two study groups. Particularly, the angiographic score was
similar in the two groups. Neither the total value (5.8±2.7 versus
5.2±2.7, respectively; P=NS) nor the value referring
only
to the left anterior descending coronary artery territory (4.0±1.5
versus 3.6±1.6, respectively; P=NS) showed a
statistically
significant difference. There were 17 anginal attacks, all at rest,
before infarction in the angina-positive patient group, which accounted
for a mean 1.4±0.5 angina episodes per patient (range, 1 to 2
episodes). A single chest pain episode had a mean duration of 13±6
minutes (range, 5 to 25 minutes), while the total amount of chest pain
duration per patient averaged 19±10 minutes (range, 10 to 45 minutes).
The mean time interval between the last episode and the onset of
infarction was 11.2±6.7 hours, ranging from 1 to 20 hours.
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Continuous ST-Segment Monitoring and Reperfusion Time
By
means of continuous monitoring of the lead showing maximum ST
elevation, the reperfusion time (that is, the time at which ST-segment
elevation dropped to at least 50% of the most abnormal peak documented
at any time during the study) was 58±34 minutes (ranging from 15 to 95
minutes) for angina-negative patients and 46±24 minutes (ranging from
15 to 90 minutes) for angina-positive patients (P=NS). The
initial mean value of ST elevation was similar (4.0±1.7 mm versus
3.0±0.9 mm; P=NS) between the patient groups. After
reperfusion was believed to occur, the trend toward ST elevation
resolution was continuous and progressive until-at the end of the
thrombolytic infusion-a final value of 0.7±0.2 mm was reached by
both
groups. This accounted for a mean final ST elevation decrease of
77±6% in angina-negative patients and 82±9% in angina-positive
patients.
ECG Measurements
ST Elevation
The sum of
ST elevation was similar (11.1±3.8 versus 17.4±11.3
mm; P=NS) in both groups on baseline ECG (Fig
2). There were no statistically significant differences
at any evaluated time among the two groups.
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Number of Q
Waves
The number of Q waves was similar at all times. However, a
nonsignificant trend toward a higher number of Q waves was observed at
each time interval in the angina-negative group (P=.1).
R Waves
R waves were higher at each ECG
sampling point in
angina-positive patients. This difference was statistically significant
at baseline (24.9±13.5 versus 43.1±20.6 mm; P<.05),
at
the end of r-TPA infusion, and at 24 hours, but not at predischarge
evaluation.
Enzymatic Infarct Size
In both groups, cardiac enzymes peaked
early (9.3±2.6
hours and 8.6±4.7 hours after onset of pain in angina-positive and
angina-negative patients, respectively; P=NS). The peak of
CKMB release was markedly lower in angina-positive patients (86.3±66
versus 192.3±108.3 IU/L; P<.01).
Fig
3 shows the time-activity curves in both groups.
These curves separate with statistically significant differences
(P<.01) at each sampling point between the 6th and the 28th
hour.
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Ventriculographic Infarct Size
Both groups were comparable in
terms of myocardium at risk
(15.1±4.6 versus 13.7±4.6 hypokinetic segments in group 1 and
group
2, respectively, P=NS). However, infarct size was
significantly lower in patients with prodromal angina (5.6±4 versus
11.0±7.5 segments, respectively; P<.04), which means a
significantly greater percentage of infarct size limitation (69%
versus 36%; P<.05 in group 2 patients). Thus, an
additional 33% of myocardium at risk was salvaged (95% confidence
intervals, 7.1% to 58.9%; P<.01) in patients with
prodromal angina. Individual values of area at risk and the correlated
final infarct size are illustrated in Fig 4. The
measurement of inward motion in the whole final infarct area, expressed
as severity of hypokinesis, was also positively associated with
prodromal symptoms, being the hypokinetic index less than in patients
without prodromal angina (11±8.6% versus 19±10.1%;
P<.05). There were no significant differences between the
two groups for left ventricular volumes and ejection fraction.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The major finding of this study is that patients with anterior myocardial infarction treated with thrombolytic therapy within 2 hours of the onset of symptoms who have had prodromal angina in the previous 24 hours have smaller infarcts as assessed by cardiac enzymes and ventriculography than patients without prodromal angina.
Limitation of Infarct Size
Prodromal angina may therefore
have a protective role in patients
successfully reperfused with thrombolytic therapy. Patients were well
matched at baseline, and two independent indexes, CKMB time-activity
curves and left ventricular angiogram analysis, showed decreased
infarct size in patients with prodromal angina. Patients without
prodromal angina had more than twice as much CKMB release, though
reperfusion occurred at the similar time, as assessed by time to
ST-segment recovery. Left ventriculogram analysis showed a lesser
number of hypokinetic segments in the patients with prodromal angina
(5.6±4 versus 11.0±7.5; P<.04), and the degree of
hypokinesis was less than in the patients without prodromal angina.
Correction for area at risk, that is, the area subtended by the infarct
related artery in each individual patient, partially controls for one
source of variation between the two different groups. In the conscious
dog model of myocardial infarction, 66% of the variation in infarct
size was due to the variation in the anatomic area at
risk.11 This method may be particularly useful in small
studies, like this one, where absence of correction for variation in
patterns of coronary artery supply would have limited the ability to
detect important differences between groups.
The relation between the
third index of infarct size used in the
study, the ECG, and the protective role of new-onset prodromal angina
was less clear. The R wave voltages showed statistically significant
differences between the two patients groups at each time interval
except for the predischarge evaluation. There was also a trend toward
less Q wave development, but this did not reach statistical
significance. There may have been a type 2 error in evaluation of the
ECG criteria, and greater precision may have been obtained by using
more ECG leads.
Pathogenetic Mechanisms Underlying the Beneficial Role of Prodromal
Angina
On the basis of our findings, the most reasonable mechanism to
explain the beneficial role of prodromal angina is ischemic
preconditioning. Also, Deutsch et al12 support the
occurrence of this phenomenon in humans, showing that in patients
undergoing elective percutaneous transluminal coronary angioplasty,
angina, ST-segment changes, myocardial lactate production, and coronary
vein flow were all attenuated during the second balloon inflation as
compared with the first one.
However, other possible explanations such as collateral circulation should be taken into account. The presence of angiographic collaterals is very dynamic,13 and a transient role may be important14 in the acute phase of myocardial infarction. In the present study, early angiography was not performed; therefore the presence or absence of collateral circulation at that time was not able to be documented, and this might have constituted a potential limitation of the study. Rentrop et al15 suggested that well-developed collaterals may extend the "time window" for the beneficial effect of pharmacological reperfusion. Habib et al,16 in a detailed post hoc analysis from the TIMI Phase I study, reported a 35% reduction of enzymatically estimated infarct size and an 11% difference (53.4±1.8% versus 47.8±1.7%) in predischarge ejection fraction in patients with collaterals compared with patients without collaterals. However, this finding applied only to patients who failed to reperfuse at 90 minutes after intravenous thrombolytic therapy. In patients in whom the extent of necrosis is limited by reperfusion, the impact of collaterals may be less important. Our patients all had a marked decrease in ST elevation and rapid normalization of the ECG during the acute phase, suggesting early reperfusion,17 and they also had a patent infarct-related artery with TIMI 3 flow documented at late angiography. Additionally, collaterals of any degree were an exclusion criterion for the study.
Limitations of the Study
This is a retrospective evaluation.
However, the criteria for the
inclusion of patients, selected to closely approximate the experimental
conditions, were defined before starting to review the patient records.
The protection afforded by preconditioning declines progressively as
the reperfusion time between the last ischemic episode and prolonged
coronary occlusion becomes longer, as demonstrated by Murry et
al5 in the experimental setting. After 120 minutes, in
fact, there was considerable attenuation of infarct size reduction,
falling from 92% to 54% in their canine model. We defined prodromal
angina as episodes of new-onset angina in the 24 hours before
myocardial infarction. The reperfusion time from the last episode of
angina and the index infarction was 11.2 hours (range, 1 to 20 hours),
which, on the basis of the available animal experience, could be
regarded as too long to confer an appreciable protection to jeopardized
myocardium. Whether this applies in the same way to humans is not
known. Furthermore, in humans, silent ischemia also accounts for the
major part of the total ischemic burden.18 19
Obviously,
silent myocardial ischemia could have occurred in the group with as
well as in the group without prodromal angina. However, in a group of
52 patients admitted to the coronary care unit because of unstable
angina, Nademanee et al19 found that those who complained
of at least one symptomatic episode of ischemia had a higher number
(12.3±14 versus 8±7.5) of episodes of silent ischemia on 24-hour
Holter ECG recordings compared with the patients showing only
asymptomatic transient myocardial ischemia. The lack of a statistically
significant difference was probably due to a type 2 error related to
the small number of study patients. In addition, in a similar
population of patients with unstable angina, Langer et
al27 found that the duration of symptomatic episodes was
significantly longer and the magnitude of ST-segment shift was greater
compared with asymptomatic episodes of transient myocardial ischemia.
We do not know how many of our patients had recurrent episodes of
silent ischemia in the 24 hours before infarction; however, our group
of patients with prodromal angina reasonably may be regarded as more
likely to be preconditioned than the group without symptoms before
their index infarction. Finally, while coronary angiography during TPA
therapy provides the best evidence of reperfusion of the infarct
related artery, the use of ECG ST-segment monitoring as a predictor
of coronary artery reperfusion, as well as reocclusion after initial
restoration of flow, has been validated in a number of
studies.20 21 22
Clinical Implications and Conclusions
There have been a
number of conflicting reports as to the
prognostic significance of angina preceding an acute myocardial
infarction. Several studies23 24 have found a better
outcome in patients with antecedent angina, even when patients had
other important risk factors including severe coronary artery disease,
while others25 26 have reported a worse hospital
course in
patients with previous angina. Differences in patient selection and
study protocols, as well as inconsistency in the definition of
antecedent angina, could explain the discordant results. None of these
studies limited the period of antecedent angina to the 24 hours
immediately before infarction. Our study was small, and we are not able
to draw any conclusions regarding the prognostic role of prodromal
angina.
Conclusions
Our study demonstrated that new-onset prodromal
angina appears to
afford protection to ischemic myocardium, at least in patients with
evolving myocardial infarction who have undergone successful
thrombolytic therapy less than 2 hours from the onset of symptoms.
Further investigations are needed to elucidate the exact role of this
phenomenon in humans and its relation to various treatments and risk
factors that affect outcome in patients with acute myocardial
infarction.
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Acknowledgments |
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We thank Jean Ellen Page, RN, for her invaluable assitance throughout the study. We are also indebted to Dr Harvey D. White, from Green Lane Hospital, Auckland, New Zealand, for his support and helpful criticism in improving the manuscript.
Received May 13, 1994; accepted August 23, 1994.
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