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Circulation. 1995;92:710-719

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(Circulation. 1995;92:710-719.)
© 1995 American Heart Association, Inc.

Articles

Relation Between Ischemia Time, Infarct Size, and Left Ventricular Function in Humans

Edmund T. Hasche, MBBS; Clyne Fernandes, MBBS; S. Ben Freedman, MBBS, PhD; Richmond W. Jeremy, MBBS, PhD

From the Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia.

Correspondence to Dr Richmond W. Jeremy, Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, 2050, New South Wales, Australia.


*    Abstract
up arrowTop
 *Abstract
down arrowIntroduction
 down arrowMethods
down arrowResults
down arrowDiscussion
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Background Experimental studies indicate that duration of ischemia is a major determinant of myocardial infarct size, but only limited information is available about the relation between ischemia time and infarct size in individual patients. This prospective study sought to document the role of ischemia time as a determinant of infarct size in humans.

Methods and Results We studied 61 patients (50 men, 11 women) 57±11 years old admitted with a first infarct (31 anterior, 30 inferior) who underwent continuous 12-lead ECG monitoring to document ischemia time. Infarct size (32-point QRS score on day 7) and changes in regional myocardial wall motion (echocardiography) during the following month were related to ischemia time. Among patients with <3 hours of ischemia (n=16), mean infarct size on day 7 was 21±13% of potential infarct size; in patients with 3 to 6 hours of ischemia (n=23), infarct size was 38±18% of potential (P<.05 versus 0 to 3 hours of ischemia); and in patients with 6 to 9 hours of ischemia (n=10), infarct size was 66±14% of potential (P<.05 versus 3 to 6 hours). In contrast, the 12 patients with an ischemia time >9 hours had a final infarct size of 77±10% of potential (P<.01 versus 3 to 6 hours). Multivariate regression identified size of risk region, duration of ischemia, and degree of initial ST-segment elevation as independent predictors of infarct size, of which the most important variable was ischemia time. The regression models accurately predicted both individual absolute infarct size (R2=.83) and individual infarct/risk ratio (R2=.74). Patients with <6 hours of ischemia exhibited significant recovery of myocardial wall motion by day 7 (wall motion score, 2.1±1.4 versus 5.7±3.2 on day 1, P<.01). Patients with 6 to 9 hours of ischemia had some recovery by 1 month (score, 6.3±4.4 versus 10.9±3.8 on day 1, P<.01), but patients with >9 hours of ischemia had little recovery of wall motion by 1 month (score, 10.3±4.5 versus 12.8±3.1 on day 1, P<.05).

Conclusions Measurement of ischemia time allows improved prediction of infarct size in humans. Significant myocardial salvage and functional recovery may be achieved by reperfusion up to 9 hours after coronary occlusion. Continuous ST-segment monitoring should be used to measure ischemia time and guide interventions to reperfuse the infarct artery.


Key Words: myocardial infarction • reperfusion • ischemia • electrocardiography


*    Introduction
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 up arrowAbstract
 *Introduction
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down arrowResults
down arrowDiscussion
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The benefits of thrombolytic therapy in acute myocardial infarction are well established.1 2 3 Large-scale clinical trials have shown that early thrombolytic therapy is associated with better ventricular function4 5 and improved survival after infarction.1 2 3 6 The benefits of thrombolysis in individual patients have been more difficult to ascertain.7 One important question relates to the time window in which thrombolysis may salvage myocardium in the individual patient. The answer to this question requires definition of the relation between ischemia time and infarct size in the individual.8 9 A second question concerns the recovery of regional myocardial function after ischemia. There is evidence to support the hypothesis that postischemic contractile dysfunction (stunning) is a significant entity in humans,10 but the time course of recovery of stunning and its determinants remain uncertain.

Experimental studies have shown that the major determinants of infarct size are the extent of the ischemic risk region, the duration of ischemia, and collateral blood flow to the ischemic region.11 12 13 14 15 Myocardial necrosis is a time-dependent phenomenon following coronary occlusion, and in the canine model, necrosis is largely complete after 6 hours.14 15 Similarly, the severity and duration of ischemia have also been shown to be determinants of the severity of postischemic stunning.16 Although these findings form an important basis for the clinical application of thrombolytic therapy, the role of ischemia time as a determinant of infarct size and subsequent regional contractile function in individual patients has not been documented. Previously, estimates of ischemia time have been based on the time from onset of symptoms to initiation of thrombolytic therapy,8 17 but the variable response of individual patients to thrombolytic therapy confounds this approach. The findings of a recent angioplasty study do, however, support a relation between ischemia time and recovery of regional myocardial function after anterior infarction.18

The application of ECG ST-segment monitoring offers a means for measuring ischemia time during myocardial infarction in humans. Reperfusion of the infarct artery is associated with a rapid decrease in ST-segment elevation, while persistent occlusion of the infarct artery is associated with prolonged ST elevation.19 20 21 Angiographic studies have confirmed the utility of ST-segment monitoring as a marker of myocardial ischemia.22 23 This study therefore used continuous 12-lead ST-segment monitoring to measure ischemia time in patients presenting with acute infarction and to determine the relations between ischemia time, infarct size, and subsequent recovery of myocardial contractile function. It was hypothesized that measurement of ischemia time would improve prediction of infarct size in individual patients and that shorter ischemia times would correlate with smaller infarct sizes and better left ventricular function in the convalescent period.


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
down arrowDiscussion
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Patient Group
Patients presenting with a first myocardial infarction were eligible for entry into the study. Transmural myocardial ischemia was diagnosed in the presence of typical central chest pain of >30 minutes' duration and ST-segment elevation of at least 100 µV in two or more contiguous leads on the 12-lead ECG. Exclusion criteria were age >75 years, valvular or myopathic heart disease, previous coronary artery bypass surgery, right or left bundle branch block, and presentation >12 hours after the onset of chest pain. All patients gave their written, informed consent to participate in the study, which was approved by the hospital ethics committee. Patients were treated with aspirin, oral or cutaneous nitrates, and thrombolytic therapy (streptokinase 1.5 million units IV over 60 minutes or tissue-type plasminogen activator 100 mg IV over 3 hours) unless contraindicated. Subsequently, patients received a continuous intravenous infusion of heparin to maintain the partial thromboplastin time at 80 to 100 seconds. Other treatment, including ß-adrenergic blockers and calcium antagonists, was at the discretion of the attending physician.

Measurement of Ischemia Time
A 12-lead ECG was acquired at the time of presentation, and subsequent ECGs at 4, 8, 12, and 24 hours after admission and daily thereafter. The lead positions were marked on the anterior chest wall for these serial recordings. Continuous 12-lead ST-segment monitoring was done with a portable, microprocessor-based unit (ID-12 electrocardiograph, Mortara Instrument Co), which was applied after the first 12-lead ECG. This monitor scanned the 12-lead ECG at 20-second intervals, storing the 12-lead recording every 15 minutes or if any ST-segment shift (>100 µV in two leads or >200 µV in one lead) was detected.19 The mean duration of ST-segment monitoring in this patient group was 926±584 minutes after presentation, and the data from the ST-segment monitor were then transferred to a personal computer for analysis.

The magnitude of ST-segment elevation was measured at 60 ms after the J-point in all leads with >100-µV ST elevation.20 The ST-segment elevation in excess of 100 µV in each of these leads was summed to calculate total ST elevation (STsum, µV). The admission ECG with maximal ST elevation (STmax) was identified as a measure of the severity of ischemia.24 Reperfusion of the infarct artery was defined as the time when STsum decreased to <=25% of STmax. If STsum had not decreased to <=25% of STmax within 12 hours of the onset of chest pain, the infarct artery was considered to have remained occluded. Ischemia time (Tisc) was calculated as the time from onset of persistent chest pain to the time of reperfusion, to a maximum of 12 hours. The total ischemic burden was indexed as the product of ischemia time and maximal ST elevation: ischemia index=STmaxxTisc.

ECG QRS Scores
Infarct size was estimated from the 12-lead ECG according to a 32-point QRS score,25 26 27 28 in which each point represents approximately 3% of the left ventricular mass. This scoring system, originally developed from anatomic studies of anterior and inferior infarcts,29 30 has since been used in clinical studies of infarct size limitation.31 32 The ECG showing maximum ST elevation at the time of admission and the ECG on day 7 were each scored by two independent observers who were unaware of the data on ischemia times. Differences between observers were resolved by consensus with a third observer. On the admission ECG, all leads exhibiting >=100-µV ST segment elevation were assigned the maximum potential QRS score for that lead. For patients with inferior infarcts, leads V1 and V2 were included as a posterior extension of the risk region if there was >=100-µV ST depression in these leads on the admission ECG. Previous studies in our department have shown that such ST depression in leads V1 and V2 is associated with posterior extension of 201Tl perfusion defects in patients with inferior infarcts.33 34 The sum of these initial scores (QRS0) was considered to represent potential maximum infarct size for that patient (analogous to extent of the ischemic risk region). The QRS score at 7 days (QRS7) was considered to represent the actual size of the infarct in each patient. The ratio (QRS7/QRS0) was a measure of actual infarct size relative to potential infarct size. Validation studies in our laboratory have shown that QRS0 is correlated with the extent of the perfusion defect on 201Tl single photon emission computed tomography (SPECT) scan (r=.79). The QRS score on day 7 is also correlated with the extent of infarction on predischarge 99mTc-pyrophosphate SPECT (r=.78) and is inversely correlated with left ventricular ejection fraction at 1 month after infarction (r=-.74).

Coronary Angiography
Coronary angiography was performed in 40 patients (65%) at a mean of 6±3 days after infarction. Angiography was performed via the right femoral artery by standard percutaneous techniques, and multiple views were obtained of each coronary artery. Perfusion of the infarct artery was graded according to the criteria of the TIMI study group35 by an independent observer. A TIMI score of 0 or 1 indicated an occluded infarct artery and a score of 2 or 3, a patent infarct artery. The angiographic findings were compared with the ST-segment data to correlate changes in ST-segment elevation with subsequent perfusion status of the infarct artery.

Echocardiography
Serial measurements of regional myocardial wall motion were made in each patient by echocardiography (Hewlett Packard Sonos 1000). The first echocardiogram was obtained within 24 hours of the onset of chest pain, and subsequent echocardiograms were obtained on days 3 and 7 and at 1 month after infarction. Cross-sectional views of the left ventricle were obtained from left parasternal and apical windows and recorded on videotape. Only patients in whom the entire left ventricle could be clearly visualized on each occasion were analyzed. Those patients who underwent coronary artery bypass surgery or angioplasty during the month after infarction were excluded. Regional myocardial wall motion was scored by an observer blinded to the electrocardiographic and angiographic data. The left ventricle was divided into 14 regions, and wall motion in each region was graded as normal (score of 0), hypokinetic (1), akinetic (2), or dyskinetic (3). The sum of the scores for the individual regions yielded a total left ventricular wall motion score, with higher scores being associated with more severe contractile impairment.

Data Analysis
Demographic variables were compared between patient groups by Student's t test or {chi}2 testing as appropriate.36 Differences in infarct size and left ventricular wall motion scores were compared between groups by ANOVA, with comparison of group means by Newman-Keuls test. Results are reported as mean±SD, and a value of P<.05 is reported as significant. The relations between the independent variables of risk region size, severity of ischemia (indexed by STmax), and duration of ischemia and the dependent variable of infarct size were determined by both univariate and multivariate regression.37 The accuracy of the regression model was then tested by comparing the predicted and observed infarct sizes and infarct/risk ratios for each patient.


*    Results
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
*Results
down arrowDiscussion
down arrowReferences
 
Sixty-one patients (50 men, 11 women) with a mean age of 57±11 years were enrolled. There were 31 patients with anterior infarcts and 30 with inferior infarcts. Forty-four patients (72%) had a history of smoking, 19 (31%) had hypercholesterolemia, 27 (43%) were hypertensive, and 12 (20%) were diabetic. The mean time from onset of chest pain to hospital admission was 148±104 minutes in patients with anterior infarcts and 118±91 minutes in patients with inferior infarcts (P=NS). Fifty-one patients (23 with anterior, 28 with inferior infarcts) received thrombolytic therapy. The time from chest pain to initiation of thrombolytic therapy was similar in patients with anterior (199±119 minutes) and inferior (157±97 minutes) infarcts. One patient died on day 4, and his day 4 QRS score was included as final infarct size. No other patients died before hospital discharge.

ST-Segment Monitoring
The mean duration of ST-segment monitoring was 926±584 minutes. There were 50 patients (23 with anterior, 27 with inferior infarcts) who exhibited resolution of ST-segment elevation, consistent with reperfusion of the infarct artery, within 12 hours of the onset of chest pain. Sixteen patients exhibited a decrease in ST-segment elevation within 3 hours of the onset of chest pain, 23 between 3 and 6 hours, and 10 between 6 and 9 hours. Twelve patients had prolonged ischemia, of whom 1 had resolution of ST elevation between 9 and 12 hours, and the remaining 11 (8 with anterior, 3 with inferior infarcts) had persistent ST-segment elevation for at least 12 hours after the onset of chest pain. The clinical features of these patients are compared in Table 1Down. Among the 40 patients who underwent coronary angiography, 33 had a patent infarct artery, of whom 31 had exhibited resolution of ST elevation within 12 hours of chest pain, consistent with reperfusion of the infarct artery. The remaining 2 patients did not have early resolution of ST elevation, suggesting late recanalization of the infarct artery. There were 7 patients with an occluded infarct artery, of whom 6 had no resolution of ST elevation during monitoring. The seventh patient showed initial resolution of ST elevation but developed further chest pain and ST elevation of >12 hours' duration on day 2, consistent with late reocclusion of the infarct artery.


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  		Table 1. Clinical Characteristics of Patients According to Ischemia Time

The ST-segment changes that occurred during the ischemic period are compared for 2 patients with anterior infarcts in Fig 1Down. The top panel shows the pattern of early resolution of ST elevation, which was associated with a subsequent small infarct (day 7 QRS score of 2). In contrast, the pattern of persistent ST elevation (bottom panel) was associated with a large infarct (day 7 QRS score of 8). The principal difference between these patients in the acute phase was the duration of ischemia, since infarct site and extent and degree of early ST elevation were similar.



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  		Figure 1. Graphs showing comparison of the pattern of ST elevation, plotted against time after onset of chest pain, in two patients with similar initial ST elevation. Top, Example of early reperfusion of the infarct artery, with a rapid decrease in the magnitude of ST elevation. The infarct artery was patent (TIMI grade 3) at angiography on day 3, and there appeared to be significant myocardial salvage (QRS score day 7=2; infarct/risk=22%). Bottom, Persistent ST segment elevation in a patient with peptic ulcer who presented 252 minutes after onset of chest pain and did not receive thrombolytic therapy. There is no resolution of ST elevation, and there appeared to be little myocardial salvage (QRS score day 7=8; infarct/risk=89%).

Univariate Predictors of Infarct Size
Infarct size, measured by the QRS score at 7 days, is compared with the potential maximum QRS score for each patient in Fig 2Down. There is considerable variation in the observed infarct sizes, but nearly all patients exhibited a lower QRS score at day 7 than was predicted from the initial ECG, consistent with the hypothesis that infarct size is dependent on several factors in addition to extent of the risk region. The relation between maximum ST sum (STmax) at the time of presentation and subsequent infarct size (QRS7) is shown in Fig 3Down. There is a moderate correlation between STmax and subsequent absolute infarct size (top panel, r=.54), but STmax alone is a poor predictor of the individual infarct/risk ratio (bottom panel, r=.37).



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  		Figure 2. Graph showing comparison of observed infarct size (QRS score at 7 days, QRS7) with potential infarct size (potential maximum QRS score calculated from admission ECG, QRS0). The line of identity is shown as a dashed line. The final QRS score is related to the extent of the ischemic risk region, but there is considerable variation in the relation. In nearly all cases, the QRS score at day 7 is less than the potential maximum QRS score.



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  		Figure 3. Scatterplots showing (top) the univariate relation between the severity of the acute ischemia, indexed by the maximum ST segment elevation at time of admission (STmax), and the observed infarct size, indexed by the day 7 QRS score (QRS7). Bottom, The relation between the severity of ischemia (STmax) and the infarct/risk ratio on day 7 (ratio of QRS7/QRS0).

The relation between ischemia time and infarct size is shown in Fig 4Down. The absolute infarct size was related to the duration of ischemia (top panel, r=.69), and the infarct/risk ratio was closely related to the ischemia time (bottom panel, r=.83). This nonlinear relation shows that the infarct/risk ratio increases most rapidly during the first few hours after coronary occlusion, with a slower rate of increase beyond 6 hours of ischemia.



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  		Figure 4. Scatterplots showing (top) the univariate relation between ischemia time (Tisc) and infarct size, measured by the QRS score, at day 7. There is some overlap of data points for patients with anterior infarcts at Tisc=720 minutes. Bottom, The relation between ischemia time and the infarct/risk ratio at day 7 (ratio of QRS7/QRS0).

There were no significant differences in age or hemodynamics between patients with short ischemia times and those with prolonged ischemia (Table 1Up). The extent of the ischemic risk region (potential QRS score) was independent of ischemia time. There were, however, major differences in the QRS score at day 7 between patients with short ischemia times and those with prolonged ischemia. In both the anterior and inferior infarct groups, the QRS score at day 7 increased as ischemia time increased. Among the 16 patients with an ischemia time <3 hours, the mean infarct/risk ratio was 21±13%. In contrast, among patients with an ischemia time of 6 to 9 hours, the mean infarct/risk ratio was 66±14% (P<.01 versus 0 to 3 hours), and among the 12 patients with an ischemia time >9 hours, the mean infarct/risk ratio was 77±10% (P<.01 versus 3 to 6 hours).

The relation between the ischemia (ST) index (product of ischemia time and maximum sum of ST elevation) and the QRS score at 7 days is illustrated in Fig 5Down (top panel). Similarly, the proportion of the ischemic risk region undergoing infarction (ratio of observed to potential QRS score, bottom panel) was related to the ischemia index. This curvilinear relation illustrates the role of the ischemia burden as a determinant of infarct size. Those patients with a low ischemia index, reflecting a short ischemia time, less severe ischemia, or both, have a low infarct/risk ratio. In contrast, patients with a high ischemia index, due to either more severe ischemia or a prolonged ischemia time, have a larger infarct/risk ratio. The patients at greatest risk are those who have both severe ischemia and a prolonged ischemia time, in whom the infarct/risk ratio approaches 100%.



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  		Figure 5. Scatterplots showing (top) the relation between the ischemia index (product of STmax and ischemia time) and observed infarct size (QRS score on day 7). This relation illustrates the combined influences of the severity and duration of ischemia on infarct size. Bottom, The relation between the ischemia index and the infarct/risk ratio at day 7 (ratio of QRS7/QRS0).

Multivariate Predictors of Infarct Size
The univariate regression relations between individual independent variables and the dependent variable of infarct size at 7 days are summarized in Table 2Down. Univariate analysis identified heart rate, potential QRS score, STmax, and ischemia time as significant predictors of final infarct size. The most significant univariate predictor was the ischemia (ST) index (r=.86), reflecting the combined contributions of ischemia time and severity of ischemia. The relative contributions of heart rate, rate-pressure product, potential infarct size, and severity and duration of ischemia to prediction of final infarct size were determined by multiple linear regression (Table 3Down). In the first model, the dependent variable was infarct size as a percentage of the total left ventricle. This model accounted for 83% of the variation in final infarct size and identified rate-pressure product, potential maximum QRS score, STmax, and ischemia time as significant independent predictors of infarct size. In this model, duration of ischemia was the most significant predictor identified. In the second model, the dependent variable was infarct size as a percentage of the ischemic risk region. This model accounted for 74% of the observed variation in infarct size, identifying ischemia time and STmax as independent predictors of the proportion of the risk region undergoing infarction. The absolute infarct size and the infarct/risk ratio for each patient, predicted by these multivariate regression models, are compared with observed infarct size in Fig 6Down. The model accurately predicted absolute infarct size (top panel). The correlation between predicted and observed infarct size was .92, and the regression relation did not differ from the line of identity. Overall, the predicted and observed infarct sizes differed by <5% of left ventricular mass in 50 of 61 patients (82%) and by <7% in 58 of 61 patients (95%). Similarly, the multivariate model accurately predicted the individual infarct/risk ratio (bottom panel), and the relation between predicted and observed ratios (r=.87) did not differ from the line of identity. With application of this model, predicted and observed infarct sizes differed by <10% of the risk region in 37 of 61 patients (61%) and by <15% in 45 of 61 patients (74%). This model, however, tended to overestimate infarct size in patients with small infarcts.


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  		Table 2. Univariate Predictors of Infarct Size


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  		Table 3. Multivariate Predictors of Infarct Size



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  		Figure 6. Scatterplots showing (top) the relation between infarct size, predicted by the multivariate regression model in Table 3Up, and actual infarct size (as fraction of total left ventricle [LV]) at day 7. Bottom, The relation between the infarct/risk ratio, predicted from the multivariate regression model in Table 3Up, and the actual infarct/risk ratio at day 7.

Regional Myocardial Wall Motion
Changes in regional myocardial wall motion that occurred during the month after infarction are compared in Table 4Down for patients with different ischemia times. There were 34 patients (30 male) who did not undergo surgical revascularization during this period and who had serial echocardiograms of sufficient quality to permit serial characterization of wall motion in each of the 14 left ventricular regions. All patients exhibited regional wall motion abnormalities on day 1, and more severe contractile impairment was observed in patients with ischemia times >6 hours. In patients with <6 hours of ischemia, some improvement in regional wall motion was evident by day 3, and further improvement was observed by day 7. Among patients with ischemia times between 6 and 9 hours, no improvement in regional wall motion was documented by day 7, but during the subsequent month, these patients did exhibit significant recovery of regional wall motion. The patients with ischemia times >9 hours exhibited the most severe wall motion abnormalities and had only limited functional recovery by 1 month.


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  		Table 4. Ischemia Time and Change in Regional Myocardial Wall Motion


*    Discussion
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 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
up arrowResults
*Discussion
down arrowReferences
 
This study describes the role of ischemia time as a determinant of infarct size and subsequent left ventricular function in individual patients with myocardial infarction. In experimental studies, the principal determinants of infarct size are extent of the ischemic risk region, duration of ischemia, collateral blood flow, and myocardial oxygen demand during ischemia.11 12 13 14 15 38 Quantification of the contribution of these factors in humans has been difficult, and previous clinical studies have been able to account for only {approx}50% of the variation in infarct size between patients.32 39 40 41 The recent radionuclide studies by Christian and coworkers8 demonstrated the relation between extent of the ischemic risk region and subsequent infarct size in humans, but the role of ischemia time in individuals has not been clearly defined to date. The present study, using continuous ST-segment monitoring, has shown that ischemia time is a major determinant of both infarct size and subsequent recovery of myocardial function in the individual patient. As with the experimental data, the severity and duration of ischemia are synergistic in determining infarct size. The present multivariate model accounted for {approx}80% of the individual variation in infarct size, and the factors identified as independent predictors of infarct size are analogous to those previously documented in the experimental setting. The rate of recovery of contractile function in the convalescent phase is inversely related to the duration of ischemia. Those patients with <6 hours of ischemia exhibited significant functional recovery within 7 days, in contrast to those with more prolonged ischemia.

Ischemia Time and Infarct Size
Myocardial necrosis in anesthetized dogs is time dependent,15 16 progressing as a wave front from subendocardium to subepicardium, with complete necrosis after 6 hours. Experimental thrombolytic studies also suggest that little myocardial salvage is achieved after more than 6 hours after coronary occlusion.42 These findings underlie the present clinical use of thrombolytic therapy.6 17 43

Measurement of ischemia time is critical. The gold standard would be continuous angiographic monitoring of the infarct artery, but this is not feasible in a large number of patients. The use of continuous ST-segment monitoring was first described by Krucoff et al,19 20 who showed that a rapid decrease in the extent and severity of ST-segment elevation was an indicator of reperfusion of the infarct artery. In contrast, prolonged ST elevation indicates persistent occlusion or very late reperfusion of the infarct artery.19 20 44 Subsequently, the use of changes in ST segment elevation as an indicator of reperfusion has become widespread.44 45 46 Our own group previously examined the utility of ST segment monitoring in predicting patency of the infarct artery and further extended the application of ST monitoring to include detection of reocclusion of the infarct artery after thrombolysis.21 22 The validity of rapid resolution of ST elevation as a marker of reperfusion has been confirmed by the angiographic studies of Shah and coworkers.23

One consideration in determining the time of reperfusion of the infarct artery is the threshold applied to the ST-segment measurements. It has been shown that each patient should serve as his or her own control and that the relative decrease in total ST elevation is a more accurate marker of reperfusion than is an absolute voltage threshold for the ST segment.44 The present study required at least a 75% reduction in the maximum ST elevation as a marker of reperfusion, similar to that previously used by our group.21 Other investigators, using serial 12-lead ECGs rather than continuous ST monitoring, have employed thresholds of 20% to 50% reduction in maximum ST elevation.44 45 A threshold of a 75% reduction in ST elevation may be less sensitive but will be more specific as a marker of reperfusion. Most patients exhibited a rapid and profound reduction in ST elevation at the time of reperfusion (see Fig 1Up). In these patients, the differences in ischemia time, calculated by a threshold of 50% or 75% reduction in ST elevation, would be small. A few patients who had a more gradual decline in ST elevation may have had some overestimation of ischemia time with the present threshold, but it should be noted that these patients clearly exhibited prolonged ST elevation.

Measurement of Infarct Size
Measurement of infarct size in humans is difficult, the two principal techniques being electrocardiography and radionuclide imaging. The present study used the Selvester QRS score, which was originally derived from computer modeling of the ECG. This score has subsequently been validated against anatomic measurements of infarct size29 30 and has also been correlated with the degree of impairment of left ventricular systolic function after infarction.46 To validate the use of the QRS score for estimating the extent of the ischemic risk region and subsequent infarct size, we previously compared the QRS measurements with radionuclide measurements of the risk region and infarct size (C. Juergens et al, unpublished observations). The QRS measurements of the risk region in this study were 12% to 51% of the left ventricle, with a few patients having very large risk regions of {approx}70% of the ventricle. These findings are comparable to our previous radionuclide findings47 and to those of other investigators.8 47 48 49

ECG measurements must contend with the variable relations between epicardial and skin surface potentials, according to body habitus. The presence of Q waves does not always mean complete infarction,50 but the QRS score makes some allowance for this by weighting lead scores according to size of Q-wave and R- and S-wave amplitudes. Within the individual, errors due to body habitus are likely to be common to the QRS measurements of risk region and infarct size. Such errors will largely cancel out in the calculation of infarct/risk ratio, which is the important outcome variable related to duration and severity of ischemia.

Ischemia Time and Myocardial Function
Despite restoration of coronary blood flow, the postischemic myocardium exhibits delayed recovery of contractile function. This phenomenon of myocardial stunning has been well documented in animal studies51 and has been described in humans after both regional and global ischemia.10 Experimental data indicate that the severity and duration of ischemia are important determinants of the degree of myocardial stunning.51 Our findings show that, in humans, ischemia time is also an important determinant of subsequent contractile dysfunction, and these findings are concordant with the QRS score results. Previous studies in humans have suggested that contractile function recovers over a period of 7 to 14 days after ischemia.18 52 Our data show that the rate of recovery of contractile function is variable and is inversely related to the duration of the ischemic insult. Patients with short (<3 hours) ischemia times have largely recovered function by the time of hospital discharge. Patients with more prolonged ischemia (6 to 9 hours) still exhibit some functional improvement but may not do so for up to 1 month after the ischemic event. This knowledge of the natural history of myocardial stunning in humans can guide the clinician's decisions regarding further intervention in patients with persistent wall motion defects after ischemia. In addition, these findings could provide a baseline reference for future investigations of adjunctive therapy, such as oxygen free radical scavengers, aimed at ameliorating myocardial stunning in humans.

Clinical Implications
The likely relation between ischemia time and myocardial salvage has been emphasized by Gersh and Anderson.53 The present study clearly demonstrates this relation, and the findings have important clinical implications. The multivariate regression models developed in this study may be used to predict infarct size in the individual patient. The accuracy of predicted absolute infarct size is approximately ±7% in 95% of patients. Prediction of the infarct/risk ratio is less accurate, because in patients with small infarcts, the model tends to overestimate infarct size.

The two predictors identified in this study that can be manipulated by the physician are heart rate and duration of ischemia. The role of heart rate as a determinant of infarct size is consistent with experimental data and with the results of trials of early ß-adrenergic blocker treatment in acute infarction.54 The duration of ischemia is the most important factor amenable to intervention. Intravenous thrombolytic therapy is the initial treatment for myocardial infarction in most centers, but the rate of reperfusion of the infarct artery is only 54% to 60% at 90 minutes in patients given streptokinase and up to 81% in patients given accelerated tissue-type plasminogen activator.55 The importance of ischemia time is highlighted by recent therapeutic trials. The GUSTO study showed that earlier patency of the infarct artery was associated with a better clinical outcome.55 56 Similarly, studies of primary angioplasty in acute infarction have shown that reduction in ischemia time is associated with a better patient outcome.57 58 In contrast, when thrombolytic therapy and angioplasty were associated with similar ischemia times, clinical outcome was not improved by angioplasty.59 Although routine angioplasty after thrombolytic therapy does not appear to improve patient outcome,60 angioplasty in high-risk patients who fail to reperfuse after thrombolytic therapy may be helpful,61 if prolonged ischemia times can be prevented.

Continuous ST monitoring allows measurement of ischemia time and detection of reperfusion. Other variables, including extent and degree of ST-segment elevation, allow the physician to decide how much myocardium is likely to be at risk and the degree of urgency required to establish reperfusion of the infarct artery. Patients with marked and extensive ST elevation are in greatest need of early reperfusion, which may be better achieved by immediate angioplasty. Similarly, those patients who exhibit persistent ST elevation after thrombolytic therapy may do well to undergo rescue angioplasty, according to the extent or severity of ST-segment elevation. In contrast, patients who have rapid resolution of ST elevation or only limited persistent ST elevation would probably not need early angioplasty.

Conclusions
The duration of ischemia is the most important determinant of infarct size and subsequent recovery of myocardial function in humans. The application of continuous ST-segment monitoring allows detection of reperfusion of the infarct artery, documentation of ischemia time, and prediction of subsequent injury to the heart. The management of patients with acute myocardial infarction may therefore be improved by the use of continuous ST-segment monitoring to guide thrombolytic therapy and other interventions such as early angioplasty.


*    Acknowledgments
 
This study was supported by grants from the National Health and Medical Research Council (917715) and the Clive and Vera Ramaciotti Foundation (N224) to Dr Jeremy and by the Medical Foundation of the University of Sydney. Dr Hasche was the recipient of a Postgraduate Research Scholarship from the National Heart Foundation of Australia. The authors gratefully acknowledge the assistance of Vijay Solanki and Krishna Kathir in analysis of the ECGs and the secretarial assistance of Yvonne Johnstone.

Received December 15, 1994; accepted February 7, 1995.


*    References
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