Skip main navigation

Assessment of Coronary Reperfusion After Thrombolysis With a Model Combining Myoglobin, Creatine Kinase–MB, and Clinical Variables

Originally published 1997;96:1776–1782


    Background Several biochemical markers have been investigated for the noninvasive assessment of reperfusion after myocardial infarction. Because myoglobin is released very soon after myocardial injury and clears rapidly after reperfusion, it may prove to be an excellent marker of occlusion and reperfusion.

    Methods and Results We examined the relation between various myoglobin measures and Thrombolysis In Myocardial Infarction (TIMI) flow grade in 96 patients enrolled in a study of front-loaded thrombolysis who underwent 90-minute angiography. We also combined myoglobin measures with models that include clinical and creatine kinase–MB variables. The myoglobin level measured within 10 minutes of acute angiography showed the best overall performance and was used for later analyses. Of the clinical variables examined, only time from symptom onset to thrombolysis and chest pain grade at angiography discriminated among TIMI flow grades. Combining the 90-minute myoglobin level and these clinical variables showed a significant difference (P<.0001) between both TIMI 3 versus TIMI 0 through 2 and TIMI 2 or 3 versus TIMI 0 or 1 flow. When the 90-minute myoglobin level was added to an established predictive model containing clinical variables and creatine kinase–MB measures, its contribution remained significant (P=.044). The area under the receiver operator characteristic curve for this combined model was .88.

    Conclusions A single myoglobin measurement obtained 90 minutes after the start of thrombolysis, combined with select clinical variables and creatine kinase–MB levels, enhances the noninvasive prediction of reperfusion after myocardial infarction.

    The importance of establishing coronary artery reperfusion with thrombolytic agents has been demonstrated clearly.12345 The “open-artery hypothesis” has been proven by better outcomes6789 and increased left ventricular function10 as a result of reestablishment of patency in the coronary artery responsible for the MI. Thus, assessment of coronary patency is important because rescue angioplasty or another intervention may be appropriate if thrombolysis fails.67891011

    Coronary angiography remains the “gold standard” for assessment of coronary patency. However, because it is associated with high cost, limited availability, and increased morbidity when performed acutely, this invasive procedure is not practical or prudent for all patients receiving thrombolytic therapy.12131415 Hence, there is substantial interest in noninvasive methods to identify the 20% to 25% of patients in whom the coronary occlusion persists.57 Clinical indicators such as cessation of pain and “reperfusion” arrhythmias have been proposed as noninvasive markers of coronary artery patency; however, these indicators alone were found to be relatively unreliable.16171819

    There has been substantial interest in biochemical markers such as CK-MB,2021222324 the MM and MB subtypes of creatine kinase,25262728 and troponin T29 for the noninvasive assessment of reperfusion. However, no biochemical marker shows the early release characteristics of myoglobin, which is elevated as early as 1 hour after myocardial injury303132 and is washed out rapidly after coronary reperfusion.303233343536

    CK-MB release measurement strategies, including a single sample obtained 90 minutes after thrombolytic therapy, Δ(90-minute value/prethrombolytic therapy level), slope of CK-MB release, and CK-MB ratio (90-minute value/prethrombolytic level), have been compared directly.20 Of these, the slope of CK-MB release yielded the greatest separation between groups of patients having TIMI 0 or 1 and TIMI 2 or 3 flow (χ2=12.9, P<.0003).20

    In the present study, we examined various myoglobin measures in a cohort of MI patients who received thrombolytic therapy and underwent acute angiography. We sought to identify the value of myoglobin and the CK-MB release measurement strategy, in combination with clinical variables, for the noninvasive assessment of patency after thrombolysis.


    Patient Population

    Of the total 207 patients enrolled in the TAMI-7 study of accelerated tissue plasminogen activator dose regimens,37 96 had blood specimens collected within 10 minutes of cardiac catheterization and were included in the present study. TAMI-7 included patients younger than 76 years old who had symptoms of acute MI for <6 hours and ECG ST-segment elevation; excluded were patients with prior stroke, bleeding diathesis, recent surgery or trauma, uncontrolled hypertension, or prior Q-wave infarction in the same ECG distribution. The procedures followed in TAMI-7 were in accordance with each participating center’s Institutional Review Board policies.

    Acute Coronary Angiography

    To evaluate patency in the infarct-related artery, all patients were to undergo acute angiography 90 minutes after thrombolytic therapy was given. Coronary blood flow in the infarct-related artery was graded according to the TIMI classifications.4 Two classifications of successful reperfusion were analyzed. The first defined reperfusion as TIMI grade 2 or 3 flow in the infarct artery; grade 0 or 1 flow denoted failed thrombolysis. The second defined reperfusion as only TIMI grade 3 flow in the infarct artery; grade 0, 1, or 2 flow was considered unsuccessful thrombolysis.3839 All angiograms were interpreted in the angiographic core laboratory by personnel blinded to the enzyme results and patient information.

    Specimen Collection

    Blood was collected in tubes containing no anticoagulant, allowed to clot, and centrifuged at 1000g for 10 minutes. The resulting serum aliquots were poured into freezer vials, then frozen within 90 minutes and maintained at −70°C until analysis. Blood was collected at the following time windows: baseline, ranging between 0 and 10 minutes from the start of thrombolytic therapy (mean±SD, 0.14±1.02 minutes; median [25th, 75th percentiles], 0 [0, 0] minutes); 30 minutes, which was defined as 12 to 60 minutes after beginning thrombolytic therapy (34.3±8.03 and 32 [30, 37] minutes); 90 minutes, defined as 62 to 135 minutes after thrombolytic therapy (97.7±16 and 93 [89, 105 minutes]); and 3 hours, defined as 138 to 239 minutes after thrombolytic therapy (175±26.8 and 175 [152, 195] minutes). All 96 of the patients in this study had a specimen collected within 10 minutes of acute angiography; this blood specimen is subsequently referred to as the “near-catheterization” sample. Specimens were categorized according to these time windows; however, the exact time of collection was recorded for all specimens and used to calculate rates of release (slopes) and other time-dependent variables. For myoglobin measurement, the near-catheterization and baseline specimens were used for analysis. For the analyses that included the established model,20 the other sampling times listed above were also used.

    Myoglobin Measurement

    All myoglobin measurements were performed with the instrumentation and associated reagents available with the Stratus II system (Dade International, Inc). This quantitative 10-minute assay uses two monoclonal antibodies in a “sandwich” radial-partition immunoassay format. The detection limit of this test is 2.2 μg/L, and the typical coefficient of variation is 5%. Other characteristics of this assay have been defined elsewhere.40

    Myoglobin Variables

    We performed analyses with the following four myoglobin variables:

    Ratio. The myoglobin value in the near-catheterization sample divided by the value in the baseline sample (Ratio=Near Catheterization/Baseline).

    Δ. The difference in myoglobin value between the near-catheterization and the baseline samples (Δ=Near Catheterization−Baseline).

    Slope. The rate of myoglobin release from baseline to near catheterization (Slope=[Near Catheterization−Baseline]/Elapsed Time).

    Near-catheterization value. The myoglobin concentration in the near-catheterization sample.

    Clinical Variables

    The age, sex, race, time from symptom onset to thrombolytic therapy, time of first dye injection for angiography, and ECG location of infarction were recorded for all patients enrolled in TAMI-7. In addition, patients graded the intensity of their infarction-related pain on a scale of 0 (no pain) to 10 at the time of acute catheterization.

    CK-MB Measurement

    All reported CK-MB measurements were quantified with devices and associated reagents available with the ICON CK-MB kit (Hybritech, Inc) and were performed according to the manufacturer’s instructions. This two-site immunoassay, or mass assay, has a claimed detection limit of 2 ng/L; all values <2 ng/L were reported as 0 ng/L. All analyses were performed in an enzymatic core laboratory by personnel who were unaware of the treatment or patency status of the patients.

    Statistical Analysis

    Continuous variables are presented as mean±SD and medians with 25th and 75th percentiles. Discrete variables are expressed as percentages. Only patients who had blood collected at least twice before acute angiography were included in the analysis. Logistic multiple regression was used to construct predictive models for patency.41 The following models were constructed: the myoglobin variables alone, selected clinical variables, myoglobin and clinical variables combined, and myoglobin combined with an established model that contains CK-MB slope, time from chest pain onset to thrombolytic therapy, and chest pain grade (from 0 to 10, with 0 being no pain) at catheterization.20 A C-index, which reflects the area under the ROC curve, was calculated for each model to evaluate its ability to predict patency. In all analyses, P<.05 was considered significant. All statistics and plots were generated using S-Plus 3.3 software (Statistical Sciences, Inc).


    The baseline characteristics of the 96 patients are shown in Table 1 according to TIMI flow grade at 90 minutes. There were significant differences among the groups with regard to chest pain grade at catheterization and time from chest pain onset to thrombolytic therapy.

    The discriminating abilities of the ratio, Δ, slope, and near-catheterization myoglobin variables to predict patency in the infarct-related artery are indicated in Table 2. The near-catherization variable, which represented a single myoglobin measurement, demonstrated the best overall performance and was used for all subsequent analyses. For the near-catherization myoglobin variable alone, logistic regression model output for TIMI grade 3 flow ranged from 0.21 to 0.68 (0.28/0.44/0.68, 25th percentile/median/75th percentile) versus a range of 0.27 to 0.68 (0.49/0.68/0.68) for TIMI grade 0, 1, or 2 flow. When the TIMI 2 or 3 patency group was considered successful reperfusion, model output ranged from 0.11 to 0.68 (0.11/0.11/0.27), whereas the TIMI 0 or 1 group ranged from 0.11 to 0.62 (0.21/0.46/0.56).

    Table 3 displays the results for all patients having measurements of myoglobin in the near-catherization sample, graded chest pain at catheterization, and time from chest pain to thrombolytic therapy variables as well as the results from combining these variables. Myoglobin measurement in the near-catherization sample contributed significantly to the ability of the model to discriminate patency both alone and in combination with the other variables. The C-index values for the combined model were .82 and .71 for the discrimination of TIMI grade 2 or 3 flow versus grade 0 or 1 flow and TIMI grade 3 versus grade 0 or 2 flow, respectively.

    Fig 1 (A and B) displays the distribution of patient data from the logistic regression model combining the near-catherization myoglobin level and the clinical variables of time from chest pain to thrombolytic therapy and chest pain graded from 0 to 10. In Fig 1A, patency classified as TIMI 3 flow showed model output results that were 0.31/0.42/0.64 (25th percentile/median/75th percentile) and 0.52/0.66/0.72 for TIMI 0, 1, or 2. For Fig 1B, TIMI 2 or 3 model output values were 0.06/0.11/0.21, whereas the values were 0.31/0.40/0.58 for TIMI 0 or 1. Fig 1C and 1D show the distribution of model outputs for combining myoglobin in the near-catherization sample with the established model, which included CK-MB slope from baseline to the near-catherization time and clinical variables of time from chest pain to thrombolytic therapy and chest pain graded from 0 to 10. Fig 1C model outputs were 0.22/0.35/0.62 for TIMI 3 flow and 0.56/0.63/0.70 for TIMI 0, 1, or 2 flow. For Fig 1D, the model output values were 0.04/0.08/0.17 for TIMI 2 or 3 flow and 0.33/0.44/0.78 for TIMI 0-1 flow.

    Fig 2 displays the ROC curve for the plot displayed in Fig 1D. By standard ROC curve interpretation, the model output of 0.24 indicated in both Fig 1D and Fig 2 would be considered the optimum decision limit if the consequences of false-negative results (predicting the artery is open when it is actually closed) and false-positive results (predicting the artery is closed when it is actually open) were equal. At this example of a decision limit, 18 of the 71 open-artery patients and 5 of the 25 closed-artery patients (24% overall) would have been misclassified. Positions on the ROC curve corresponding to higher sensitivity (model output of 0.10) and higher specificity (model output of 0.40) are also indicated in both Fig 2 and Fig 1D. At the output value of 0.1, 39 of the 71 open-artery patients and 3 of the 25 closed-artery patients would have been misclassified (43.7% overall); at an output of 0.4, 14 of the 71 open-artery patients and 15 of the 25 closed-artery patients would have been misclassified (30.2% overall).

    Table 4 shows the performance of a model that combined near-catherization myoglobin with an established model that included clinical variables and CK-MB slope measures.20 The contribution of near-catherization myoglobin to this combined model was significant, having a χ2 of 4.04 (P=.044). When the 28 patients having TIMI 1 and 2 flow were considered nonexistent, a C-index of .93 resulted for the near-catherization myoglobin sample combined with the established model; the contribution of myoglobin remained significant (χ2=5.19; P<.023).


    Myoglobin, alone or in combination with other biochemical markers, has been investigated for noninvasive assessment of myocardial perfusion after thrombolytic therapy.21222427283033343536 The present study included early and frequent myoglobin sampling in patients whose infarct-artery patency status was confirmed by angiography. Building on an established strategy that included the slope of CK-MB release and clinical variables,20 we showed that inclusion of a second biochemical marker, ie, a single myoglobin measurement obtained 90 minutes after beginning thrombolytic therapy, contributed significant information, as shown in Table 4.

    Recent reports have indicated that TIMI grade 3 blood flow results in improved patient outcomes compared with TIMI grade 2 flow.38 The improved survival of patients with TIMI grade 3 flow provides indirect evidence that TIMI grade 2 flow represents an intermediate point between grade 0 or 1 flow and grade 3 flow.3839 For this reason, we examined the data considering successful reperfusion both as TIMI grade 3 flow only and as the original TAMI-7 end point of TIMI grade 2 or 3 flow.37 As shown in Table 2, the C-index values for the more rigorous definition of TIMI grade 3 flow alone were less satisfactory, and thus discriminating TIMI grade 3 from TIMI grade 0 or 2 may be problematic for clinical use, even with the approach presented here.

    Among the various myoglobin variables examined, the single value collected between 60 and 150 minutes after initiating thrombolytic therapy had the best performance for indicating successful reperfusion. This single-sample strategy also represents the most convenient and least costly alternative. The near-catherization myoglobin sample alone and combined strategies were compared using the C-index, which directly corresponds to the area under the ROC curve. When tests or strategies are compared, those having the largest C-index (approaching unity) demonstrate the best diagnostic performance. The C-index values for the near-catheterization myoglobin sample alone were .78 and .73 for the prediction of TIMI grade 2 or 3 versus grade 0 or 1 flow and TIMI grade 3 versus grade 0, 1, or 2 flow, respectively. All other strategies included more than one myoglobin level; these additional measurements did not contribute substantial additional prognostic information and would be more expensive.

    Selected clinical variables by themselves have been reported to show significant ability to discriminate between patients with TIMI grade 0 or 1 flow and those with grade 2 or 3 coronary flow; however, these indicators are unreliable for routine clinical use.16 We found that clinical variables, including chest pain graded from 0 to 10 at catheterization and time from symptom onset to thrombolytic therapy, achieved significance for indicating reperfusion. These clinical variables added to the performance of the near-catheterization myoglobin sample, as shown by the respective C-index values of .82 for TIMI grade 2 or 3 versus 0 or 1 flow and .71 for TIMI grade 3 versus grade 0, 1, or 2 flow.

    Obtaining a myoglobin measurement significantly contributed to an established model that included serial CK-MB measurements and clinical variables.20 In the present study, the combined model that included the near-catheterization myoglobin value, CK-MB slope, and clinical variables had the largest C-index values for indicating successful reperfusion: .88 for TIMI grade 2 or 3 blood flow (versus grade 0 or 1 flow) and .74 for TIMI grade 3 flow (versus grade 0, 1, or 2 flow).

    The ROC curve displayed in Fig 2 indicates three examples of decision limits. If the consequences of a false-positive result (predicting the artery is closed when it is actually open) or false-negative result (predicting that the artery is open when it is closed) are equal, then the optimum decision limit would be a model output of 0.24; ≈24% of patients would have been misclassified at this decision limit. Use of the other decision limits indicated in Fig 2 will either improve sensitivity at the expense of specificity or improve specificity at the expense of sensitivity. For example, when model output is changed from 0.24 to 0.1, the number of false negatives decreased by 2 from 5 to 3 (40% improvement); however, false-positive results increased by 21 from 18 to 39 (117%). When model output is changed from 0.24 to 0.4, the number of false positives decreased by 4 from 18 to 14 (22% improvement); on the other hand, false-negative results increased by 10 from 5 to 15 (200%). Clearly there is a need to test any potential decision limits derived from the present study in an appropriately designed prospective trial.

    Although combining near-catheterization myoglobin samples, CK-MB, and clinical variables yielded a C-index of .88, the model will not accurately predict reperfusion status in all patients. This may be unavoidable for at least three physiologically based reasons. First, strategies that use biochemical markers are based on differences in the washout phenomenon that occurs after patency has been reestablished.42 The washout model often used to characterize biochemical markers showing promise for the assessment of patency is acute angioplasty. However, this model may not rigorously simulate the washout phenomenon that occurs after thrombolytic therapy, because angioplasty restores patency abruptly, resulting in dramatic increases in the biochemical markers.43 In contrast, the restoration of patency after thrombolytic therapy is a more dynamic process in which many patients have repeated opening and closing of the infarct-related artery in a stuttering pattern. Intermittent patency is probably caused by alterations in coagulation factors, platelet function, or other potentiating factors that affect procoagulant activity and contractility of coronary arterial muscle, which could blunt the washout of biochemical markers. Second, individual patient variables such as extent of infarction, collateral flow to the infarcted area, and blood pressure may influence noninvasive strategies for assessing patency. A third issue involves the use of angiography to adjudicate patency. Although it is the “gold standard” for evaluating coronary patency, angiography cannot show how long the measured perfusion status has existed in the infarct-related artery, which would influence washout. Thus, some discrepancy must be expected because of the dynamic physiological nature of patency restoration after thrombolytic therapy and the uncertainties in angiographic measurement.


    This study included 96 patients, which must be considered a relatively small sample. The C-index values resulted from multiple comparisons and may be lower in actual practice. Thus, these data must be considered a “learning” data set that should be validated prospectively.

    Although the state-of-the-art mass assay used for CK-MB measurement in the present study demonstrates good correlation with other CK-MB tests, we have also shown that results of CK-MB curves can show significant differences despite good agreement.44 This issue, which may be true for myoglobin as well, indicates that the models developed are valid only for the assays used.

    The combined model used to predict patency includes data from both the laboratory and clinical areas. For effective use, facile means of combining these data must be developed with future technology.

    The present study shows that a single myoglobin measurement obtained between 60 and 150 minutes after thrombolytic therapy adds significantly to a model that includes CK-MB levels and clinical variables. The high C-index for this strategy suggests that it may provide an important clinical tool to assess patency after thrombolytic therapy.

    Selected Abbreviations and Acronyms

    C-index=concordance probability index
    CK-MB=creatine kinase–MB
    MI=myocardial infarction
    ROC=receiver operator characteristic
    TAMI-7=Thrombolysis and Angioplasty in Myocardial Infarction-7
    TIMI=Thrombolysis In Myocardial Infarction

          Figure 1.

    Figure 1. Box-and-whiskers plots showing the range (whiskers) and 25th percentile/median/75th percentile (box) of predicted probabilities from the logistic regression model for open- and closed-artery patient groups. A, Predicted probabilities resulting from modeling myoglobin plus clinical variables for TIMI 3 versus TIMI 0, 1, or 2 patency. B, Predicted probabilities for modeling myoglobin plus clinical variables for TIMI 2 or 3 versus TIMI 0 or 1 patency. C, Predicted probabilities for the established model plus near-catheterization myoglobin for TIMI 3 versus TIMI 0, 1, or 2 patency. D, Predicted probabilities resulting from the established model plus near-catheterization myoglobin for TIMI 2 or 3 versus TIMI 0 or 1 patency. The broken lines in Fig 1D correspond to various cutoffs indicated in the ROC curve plotted in Fig 2. Myoglobin refers to a single myoglobin value in a blood sample obtained within 10 minutes of cardiac catheterization. Clinical variables included were time from chest pain to thrombolytic therapy, and chest pain graded from 0 to 10. Established model refers to a published model20 that included CK-MB slope between baseline and the near-catheterization time and clinical variables including time from chest pain to thrombolytic therapy and chest pain graded from 0 to 10.

          Figure 2.

    Figure 2. ROC curve for assessing performance of the established model (CK-MB slope and clinical variables) plus near-catheterization myoglobin for predicting TIMI 2 or 3 versus TIMI 0 or 1 patency. This ROC curve represents the data displayed in Fig 1D; the points indicated on the curve correspond to the broken lines in Fig 1D.

    Table 1. Patient Characteristics in the TAMI-7 Study

    TIMI Flow Grade at 90 Min
    Age, y
    Median (25th, 75th percentiles)58 (46, 63)56 (53, 67)60 (52, 70)61 (50, 68)
    Male sex, %85677476
    White race, %87789278
    Anterior infarction, %40724642
    Time from symptom onset to thrombolytic therapy, min1
    Median (25th, 75th percentiles)138 (100, 215)118 (105, 170)148 (103, 223)177 (130, 237)
    Chest pain grade at angiography, median (25th, 75th percentiles)22 (0, 4)1.5 (0, 5)0 (0, 1)0 (0, 1)
    Time from thrombolytic therapy to acute angiography, min
    Median (25th, 75th percentiles)143 (93, 188)161 (113, 191)111 (90, 157)145.5 (106, 208)
    Peak total creatine kinase, U/L
    Median (25th, 75th percentiles)1867 (915, 3383)1751 (674, 1703)1419 (716, 3210)1812 (1011, 3255)
    Peak creatine kinase-MB, ng/mL
    Median (25th, 75th percentiles)223 (120, 400)203 (120, 320)185 (81, 340)240 (102, 410)
    Peak myoglobin, ng/mL
    Median (25th, 75th percentiles)1287 (608, 2922)1156 (816, 1366)1561 (434, 3295)1642 (727, 2862)

    1P=.02 for TIMI grade 3 vs grades 0-2.

    2On a scale of 0 (no pain) to 10 (maximum pain); P=.01 for TIMI grades 2-3 vs grades 0-1.

    Table 2. Strategies for Discrimination of Patency With Myoglobin Only

    TIMI Grades 2-3 vs Grades 0-1TIMI Grade 3 vs Grades 0-2
    Near-catheterization level17.30.78.000112.80.73.0004

    Table 3. Modeling With Myoglobin and Clinical Variables

    TIMI Grades 2-3 vs Grades 0-1TIMI Grade 3 vs Grades 0-2
    χ2P χ2P
    Near-catheterization level, truncated at 800 ng/mL15.05.000110.75.001
    With addition of time to thrombolytic therapy115.05.00110.75.001
    Chest pain at catheterization (0-10 scale)6.76.0091.99.16
    With addition of time to thrombolytic therapy5.60.0181.66.20
    Time to thrombolytic therapy2.
    Combined myoglobin and chest pain at catheterization23.95<.000113.73.001
    With addition of time to thrombolytic therapy27.02<.000114.54.0006

    1Represents time from onset of symptoms to thrombolytic therapy.

    Table 4. Comparison of Myoglobin and an Established Model for the Prediction of Reperfusion

    TIMI Grades 2-3 vs Grades 0-1TIMI Grade 3 vs Grades 0-2
    Established model129.97.87<.000117.10.73.0043
    Established model plus myoglobin34.02.88<.000118.88.74.0044
    Myoglobin contribution alone4.04<.0441.78.18

    1Contains CK-MB slope, time from symptom onset to thrombolytic therapy, and chest pain grade (from 0 [least] to 10) at angiography.20

    The TAMI-7 study was funded in part by grants from Hybritech Inc, San Diego, Calif; Genentech, Inc, South San Francisco, Calif; and Eli Lilly, Indianapolis, Ind. The authors gratefully acknowledge the exceptional contributions of Carol K. Pizzo (technical assistance) and Pat Williams (editorial assistance).


    Correspondence to Dr Robert H. Christenson, Clinical Pathology, University of Maryland Medical Center, 22 S Greene St, Baltimore, MD 21201.


    • 1 Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet.1986; 1:397-402.MedlineGoogle Scholar
    • 2 Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet.1988; 2:525-530.CrossrefMedlineGoogle Scholar
    • 3 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet.1988; 2:349-360.MedlineGoogle Scholar
    • 4 The TIMI Study Group. Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Med.1985; 312:932-936.CrossrefMedlineGoogle Scholar
    • 5 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med.1993; 329:673-682.CrossrefMedlineGoogle Scholar
    • 6 The GUSTO Angiographic Investigators. The effects of issue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med.1993; 329:1615-1622.CrossrefMedlineGoogle Scholar
    • 7 Tiefenbrunn AJ, Sobel BE. The impact of coronary thrombosis on myocardial infarction. Fibrinolysis.1989; 3:1-15.CrossrefGoogle Scholar
    • 8 Califf RM, Topol EJ, George BS, Kereiakes DJ, Aronson LG, Lee KL, Martin L, Candela R, Abbottsmith C, O’Neill WW, Pryor DB, Stack RS, for the TAMI Study Group. One-year outcome after therapy with tissue plasminogen activator: report from the Thrombolysis and Angioplasty in Myocardial Infarction trial. Am Heart J.1990; 119:777-785.CrossrefMedlineGoogle Scholar
    • 9 Stack RS, O’Connor CM, Mark DB, Hinohara T, Phillips HR, Lee MM, Ramirez NM, O’Callaghan WG, Simonton CA, Carlson EB. Coronary reperfusion during acute myocardial infarction with a combined therapy of coronary angioplasty and high-dose intravenous streptokinase. Circulation.1988; 77:151-161.CrossrefMedlineGoogle Scholar
    • 10 White HD, Norris RM, Brown MA, Takayama M, Maslowski A, Bass NM, Ormiston JA, Whitlock T. Effect of intravenous streptokinase on left ventricular function and early survival after acute myocardial infarction. N Engl J Med.1987; 317:850-855.CrossrefMedlineGoogle Scholar
    • 11 White HD, Cross DB, Norris RM, Williams DB. Early infarct artery patency after intravenous streptokinase, intracoronary contrast, and intracoronary rt-PA. J Am Coll Cardiol. 1992;19(suppl A):275A. Abstract.Google Scholar
    • 12 Guerci AD, Ross RS. TIMI II and the role of angioplasty in acute myocardial infarction. N Engl J Med.1989; 320:663-665.CrossrefMedlineGoogle Scholar
    • 13 Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS, O’Neill WW, and the TAMI Study Group. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogen activator in acute myocardial infarction. N Engl J Med.1987; 317:581-588.CrossrefMedlineGoogle Scholar
    • 14 The TIMI Research Group. Immediate vs delayed catheterization and angioplasty following thrombolytic therapy for acute myocardial infarction. JAMA.1988; 260:2849-2858.CrossrefMedlineGoogle Scholar
    • 15 Simoons ML, Arnold AE, Betriu A, de Bono DP, Col J, Dougherty FC, von Essen R, Lambertz H, Lubsen J, Meier B, Michel PL, Raynaud P, Rutsch W, Sanz GA, Schmidt W, Serruys P, Thery C, Uebis R, Vahanian A, van de Werf F, Willems GM, Wood D, Verstraete M. Thrombolysis with tissue plasminogen activator in acute myocardial infarction: no additional benefit from immediate percutaneous coronary angioplasty. Lancet.1988; 1:197-203.CrossrefMedlineGoogle Scholar
    • 16 Califf RM, O’Neill W, Stack RS, Aronson L, Mark DB, Mantell S, George BS, Candela RJ, Kereiakes DJ, Abbottsmith C. Failure of simple clinical measurements to predict perfusion status after intravenous thrombolysis. Ann Intern Med.1988; 108:658-662.CrossrefMedlineGoogle Scholar
    • 17 Gore JM, Ball SP, Corrdao JM, Goldberg RH. Arrhythmias in the assessment of coronary artery reperfusion following thrombolytic therapy. Chest.1988; 94:727-730.CrossrefMedlineGoogle Scholar
    • 18 Miller FC, Krucoff MW, Satler LF, Green CE, Fletcher RD, Del Negro AA, Pearle DL, Kent KM, Rackley CE. Ventricular arrhythmias during reperfusion. Am Heart J.1986; 112:928-932.CrossrefMedlineGoogle Scholar
    • 19 Hohnloser SH, Zabel M, Kasper W, Meinertz T, Just H. Assessment of coronary artery patency after thrombolytic therapy: accurate prediction utilizing the combined analysis of three noninvasive markers. J Am Coll Cardiol.1991; 18:44-49.CrossrefMedlineGoogle Scholar
    • 20 Ohman EM, Christenson RH, Califf RM, George BS, Samaha JK, Kereiakes DJ, Worley SJ, Wall TC, Berrios E, Sigmon KN, for the TAMI 7 Study Group. Noninvasive detection of reperfusion after thrombolysis based on serum creatine kinase MB changes and clinical variables: Thrombolysis and Angioplasty in Myocardial Infarction. Am Heart J.1993; 126:819-826.CrossrefMedlineGoogle Scholar
    • 21 Zabel M, Hohnloser SH, Koster W, Prinz M, Kasper W, Just H. Analysis of creatine kinase, CK-MB, myoglobin, and troponin T time-activity curves for early assessment of coronary artery reperfusion after intravenous thrombolysis. Circulation.1993; 87:1542-1550.CrossrefMedlineGoogle Scholar
    • 22 Katus HA, Diederich KW, Scheffold T, Uellner M, Schwartz F, Kubler W. Noninvasive assessment of infarct reperfusion: the predictive power of the time to peak value of myoglobin, CKMB, and CK in serum. Eur Heart J.1988; 9:619-624.CrossrefMedlineGoogle Scholar
    • 23 Garabedian HD, Gold HK, Yasuda T, Johns JA, Finkelstein DM, Gaivin RJ, Cobbaert C, Leinbach RC, Collen D. Detection of coronary artery reperfusion with creatine kinase–MB determinations during thrombolytic therapy: correlation with acute angiography. J Am Coll Cardiol.1988; 11:729-734.CrossrefMedlineGoogle Scholar
    • 24 Klootwijk P, Cobbaert C, Fioretti P, Kint PP, Simoons ML. Noninvasive assessment of reperfusion and reocclusion after thrombolysis in acute myocardial infarction. Am J Cardiol.1993; 72:75G-84G.MedlineGoogle Scholar
    • 25 Christenson RH, Ohman EM, Topol EJ, O’Hanesian MA, Sigmon KN, Duh SH, Kereiakes D, Worley SJ, George BS, Pizzo CK, for the TAMI Study Group. Creatine kinase MM and MB isoforms in patients receiving thrombolytic therapy and acute angiography. Clin Chem.1995; 41:844-852.CrossrefMedlineGoogle Scholar
    • 26 Puleo PR, Perryman MB, Bresser MA, Rokey R, Pratt CM, Roberts R. Creatine kinase isoform analysis in the detection and assessment of thrombolysis in man. Circulation.1987; 75:1162-1169.CrossrefMedlineGoogle Scholar
    • 27 Abendschein DR, Ellis AK, Eisenberg PR, Klocke FJ, Sobel BE, Jaffe AJ. Prompt detection of coronary recanalization by analysis of rates of changes of concentrations of macromolecular markers in plasma. Coron Artery Dis.1991; 2:201-212.CrossrefGoogle Scholar
    • 28 Laperche T, Steg C, Benessiano J, Dehoux M, Juliard JM, Himbert D, Gourgon R. Patterns of myoglobin and MM creatine kinase isoforms release after intravenous thrombolysis or direct transluminal coronary angioplasty for acute myocardial infarction, and implications of the early noninvasive diagnosis of reperfusion. Am J Cardiol.1992; 70:1129-1134.CrossrefMedlineGoogle Scholar
    • 29 Remppis A, Scheffold T, Karrer O, Zehelein J, Hamm C, Grunig E, Bode C, Kubler W, Katus HA. Assessment of reperfusion of the infarct zone after acute myocardial infarction by serial cardiac troponin T measurements in serum. Br Heart J.1994; 71:242-248.CrossrefMedlineGoogle Scholar
    • 30 Vaidya HC. Myoglobin. Lab Med.1992; 23:306-310.CrossrefGoogle Scholar
    • 31 Puleo P, Roberts R. Early biochemical markers. Cardiovasc Clin.1989; 20:143-154.MedlineGoogle Scholar
    • 32 Kragen LJ. Extension of myocardial infarction and serum myoglobin. Int J Cardiol.1984; 6:337-339.CrossrefGoogle Scholar
    • 33 Apple FA. Acute myocardial infarction and coronary reperfusion: serum cardiac markers for the 1990’s. Am J Clin Pathol.1992; 97:217-226.CrossrefMedlineGoogle Scholar
    • 34 Ishii J, Nomura M, Ando T, Hasegawa H, Kimura M, Kurokawa H, Iwase M, Kondo T, Watanabe Y, Hishida H. Early detection of successful coronary reperfusion based on serum myoglobin concentration: comparison with serum creatine kinase isoenzyme MB activity. Am Heart J.1994; 128:641-648.CrossrefMedlineGoogle Scholar
    • 35 Miyata M, Abe S, Arima S, Nomoto K, Kawataki M, Ueno M, Yamashita T, Hamasaki S, Toda H, Tahara M. Rapid diagnosis of coronary reperfusion by measurement of myoglobin level every 15 min in acute myocardial infarction. J Am Coll Cardiol.1994; 23:1009-1015.CrossrefMedlineGoogle Scholar
    • 36 Abe J, Yamaguchi T, Isshiki T, Naka H, Taguchi J, Ishizaka N, Kurokawa K, Saeki F, Ishizaka Y, Ui K. Myocardial reperfusion can be predicted by myoglobin/creatine kinase ratio of a single blood sample obtained at the time of admission. Am Heart J.1993; 126:279-285.CrossrefMedlineGoogle Scholar
    • 37 Wall TC, Califf RM, George BS, Ellis SG, Samaha JK, Kereiakes DJ, Worley SJ, Sigmon K, Topol EJ, for the TAMI-7 Study Group. Accelerated plasminogen activator dose regimens for coronary thrombolysis. J Am Coll Cardiol.1992; 19:482-489.CrossrefMedlineGoogle Scholar
    • 38 Anderson JL, Karagounis LA, Becker LC, Sorensen SG, Menlove RL. TIMI perfusion grade 3 but not grade 2 results in improved outcome after thrombolysis for myocardial infarction: ventriculographic, enzymatic, and electrocardiographic evidence from the TEAM-3 Study. Circulation.1993; 87:1829-1839.CrossrefMedlineGoogle Scholar
    • 39 Karagounis L, Sorensen SG, Menlove RL, Moreno F, Anderson JL, for the TEAM-2 Investigators. Does thrombolysis in myocardial infarction (TIMI) perfusion grade 2 represent a mostly patent artery or a mostly occluded artery? Enzymatic and electrocardiographic evidence from the TEAM-2 study. J Am Coll Cardiol.1992; 19:1-10.CrossrefMedlineGoogle Scholar
    • 40 Carraro P, Plebani M, Varagnolo MC, Zaninotto M, Rossetti M, Burlina A. A new immunoassay for the measurement of myoglobin in serum. J Clin Lab Anal.1994; 8:70-75.CrossrefMedlineGoogle Scholar
    • 41 Lee KL, Pryor DB, Harrell FE Jr, Califf RM, Behar VS, Floyd WL, Morris JJ, Waugh RA, Whalen RE, Rosati RA. Predicting outcome in coronary disease: statistical models versus expert clinicians. Am J Med.1986; 80:553-560.CrossrefMedlineGoogle Scholar
    • 42 Reimer KA, Jennings RB. The ‘wavefront phenomenon’ of myocardial ischemic cell death, II: transmural progression of necrosis within the framework of ischemic bed size (myocardium at risk) and collateral flow. Lab Invest.1979; 40:633-644.MedlineGoogle Scholar
    • 43 Christenson RH, Ohman EM, Clemmensen P, Grande P, Toffaletti J, Silverman LM, Vollmer RT, Wagner GS. Characteristics of creatine kinase–MB and MB isoforms in serum after reperfusion in acute myocardial infarction. Clin Chem.1989; 35:2179-2185.CrossrefMedlineGoogle Scholar
    • 44 Christenson RH, Clemmensen P, Ohman EM, Toffaletti J, Silverman LM, Grande P, Vollmer RT, Wagner GS. Relative increase in creatine kinase MB isoenzyme during reperfusion after myocardial infarction is method dependent. Clin Chem.1990; 36:1444-1449.CrossrefMedlineGoogle Scholar


    eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

    Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.