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Usefulness of a rapid initial increase in plasma creatine kinase activity as a marker of reperfusion during thrombolytic therapy for acute myocardial infarction
Usefulness of a Rapid Initial Increase in Plasma Creatine Kinase Activity as a Marker of Reperfusion During Thrombolytic Therapy for Acute Myocardial Infarction Basil S. Lewis, MD, William Ganz, MD, Pierre Laramee, MD, Bojan Cercek, Prediman K. Shah, MD, and Allan S. Lew, MD This study evaluates a new nonangiographic marker of reperfusion -a rapid initial increase in plasma creatine kinase (CK) and CK-MB activity-in 50 patients receiving intracoronary streptokinase. Blood for CK and CK-MB activity was sampled at 30.minute intervals and angiography performed at is-minute intervals or earlier if there were clinical signs suggestive of reperfusion. An absolute firsthour increase in CK activity of 480 f 345 Ill/liter (range 54 to 1,440 Ill/liter), or a relative first-hour increase of 34 f 18% (range 13 to 67% of the peak rise), or an absolute first-hour increase in CKMB activity of 48 f 36 Ill/titer (range 10 to 144 Ill/liter) or a relative first-hour increase of 27 f 13% (range 13 to 57%) was found in patients immediately after reperfusion with Thrombolysis In Myocardial Infarction (TIMI) grade 3 perfusion of the artery of infarction. The onset of rapid increase in CK and CK-MB activity closely reflected the time of angiographic documentation of reperfusion. In contrast, in the absence of reperfusion, the absolute rate of increase in CK activity measured in the last hour of the 2l!-hour period beginning with the start of treatment was only 15 f 9 IWliter on the average (range 2 to 30 IlJ/liter) and the relative rate of rise was 3 f 2% on the average (range 1 to 6%). The absolute rate of rise in CK-MB activity over the same period of time was 2 f 1 Ill/titer on the average (range 1 to 4 Ill/liter) and the relative rate of rise was 4 f 1% (range 1 to 6% of the peak rise). Thus, the data of this study indicate that reperfusion with TIMI grade 3 perfusion is followed by a rapid increase in plasma CK and CK-MB activity. Frequent (l/z hourly) determination of CK or CK-MB activity during thrombolytic therapy (at least for 2% hours) may provide one more tool for the recognition of reperfusion or its failure. (Am J Cardiol 1966;62:20-24) From the Division of Cardiology, Department of Medicine, CedarsSinai Medical Center, and the Department of Medicine, UCLA School of Medicine, Los Angeles, California. Dr. Lewis is a H.J. Mirisch Fellow, Cedars-Sinai Medical Center, Los Angeles, California; present address: Department of Cardiology, Lady Davis Carmel Hospital, Haifa, Israel. Manuscript received August 18, 1987; revised manuscript received and accepted March 15, 1988. Address for reprints: William Ganz, MD, Room No. 53 14, Division of Cardiology, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048.
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THE AMERICAN
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OF CARDIOLOGY
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MD,
Hanoch Hod,
MD,
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ntravenous thrombolytic therapy does not require pretreatment coronary angiography and can therefore be instituted earlier in the course of an evolving myocardial infarction than intracoronary thrombolysis. However, the physician administering intravenous thrombolytic therapy needs to know whether or not reperfusion of the artery of infarction has been achieved to decide whether to continue thrombolytic therapy or, in the case of failure, initiate angioplasty or discontinue anticoagulation. In the absence of angiography, recognition of reperfusion will have to be based on its nonangiographic manifestations. In prior studies, relief of chest pain,1,2 resolution of ST-segment elevations,3,4 occurrence of specific arrhythmiaP and early peaking of plasma creatine kinase (CK) and CK-MB activity7,8 were used as signs of reperfusion. In the present study we describe a new nonangiographic marker of reperfusion: the abrupt initial increase in plasma CK and CKMB activity. METHODS Patients: Changes in plasma CK and CK-MB activ-
ity occurring immediately following reperfusion were studied in 50 of the 81 patients receiving intracoronary streptokinase therapy within 3.3 f 0.7 hours of an evolving acute myocardial infarction, in whom the artery of infarction was totally occluded before the start of therapy and in whom CK and CK-MB activity curves were obtained. In the remaining 31 patients the artery of infarction was not totally occluded at the outset (18 patients) or the CK and CK-MB data were inadequate for analysis due to early bypass surgery, death or incomplete sampling of blood (13 patients). Angiography: The status of the artery of infarction was determined by contrast injection at 15-minute intervals or earlier if clinical signs suggested reperfusion. Reperfusion was defined as complete opacification and clearing of the artery of infarction as rapid as in the patent noninfarct-related arteries. This definition corresponds to the Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion.9 The status of coronary artery patency was defined by 2 angiographers not participating in this study prior to the availability of CK data. Creatine kinase and creatine kinase-MB studies:
Blood for determination of plasma CK and CK-MB activity was drawn at approximately 30-minute intervals for 2 to 3 hours and then every 1 to 3 hours up to 24 hours. The blood was sampled into ethyleneglycol-bis-
(beta-aminoethyl ether)-N,N’-tetraacetic acid (EGTA) (10 mM final concentration) and the plasma was harvested. Total CK activity was measured by the Rosalki methodic using Worthington reagents. CK-MB activity was analyzed following separation of the isoenzymes on column chromatography.” The upper limits of normal for these tests were 70 IU/liter for plasma CK activity and 5 III/liter for CK-MB activity. The CK and CK-MB time activity curves were analyzed with regard to the initial rate of rise immediately following reperfusion and the time of the onset of rise. The rate of rise of CK and CK-MB activity immediately following reperfusion was defined by 3 methods: (1)
the absolute rate of increase during the first hour fol-
lowing reperfusion, determined as the difference either between the first elevated and the preceding baseline value (Figure IA) or between the first 2 elevated values, whichever the higher (Figure lB), divided by the time interval between the 2 values in minutes and multiplied by 60; (2) the relative rate of increase during the first hour following reperfusion, determined by dividing the absolute first hour rate of increase by the peak increase on the time activity curve and expressed in percentage. The peak increase was the difference between the peak CK or CK-MB activity and the last baseline value; (3) in patients in whom reperfusion was not achieved, the l-hour rate of CK and CK-MB increase was measured in the last hour of the 2M-hour observation period. The 2M-hour interval beginning with the start of thrombolytic therapy was chosen because reperfusion beyond that time interval is not likely and did not occur in our study. Onset of rapid increase in plasma creative kinase and creatine kinase-MB activity: The last baseline val-
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FIGURE 1. A, time acttvity curve tram a patient with successfutrepsrfuskmafterintr aceronary streptokinase. The rate of increase in CK-MB activity between ths last baseline value and the first elevated valus is steeper than the increase between ths first and second elevated value and it is therefore usedfor meesurement of the initial rate of increase. The last badins vake is close to the ttme of angiegraphii documentation of reperrusion (secti 4wYow). The first arrow denotes total ocddon of the artery of infarction befere treatment. The rate of increase decreases with time giving the curve an upward convex shape. 6, time activtty curve fmm a patient with reperfusien. The initial rate of inwease is measured frem the ssgment between the first 2 slevatsd values and net hfn the segment between the lest basehe and ths first elevated value, whkh is tess stew. The time of m (second BIG row) is dosely apfmximated by extrapolation of the segment between first 2 elevated values. The ffrst arrow denotes total occlusion of the artery of infarction.
the
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FIGURE 2. A, the absolute first-hour rates of imrease in plasma creatine kinase activity in 41 patients with reperk&n (REP) and in 9 patients without repedusion (NO REP). B, the absobte first-hour rates of increase in plasma creative kinaseMB activity in 41 patients with reperfusion (REP) and in 9 patiis without reperfusion (NO REP). THE AMERICAN
JOURNAL
OF CARDIOLOGY
JULY 1,1988
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OF REPERWSION
ue was considered to reflect the onset of increase in enzyme activity when the rate of increase between the baseline value and the first elevated value was steeper than the increase between the first and second elevated values (Figure 1A). When this rate of increase was less steep, the point at which the line plotted through the first and second elevated value crossed the baseline was considered to most closely approximate the onset of rapid enzyme increase (Figure 1B). Statistical analysis: Differences between the rates of increase in CK and CK-MB activity in patients with and without reperfusion were analyzed using Student t test for unpaired data. The data are expressed as mean f standard deviation. A p value of <0.05 is considered significant. RESULTS Absolute rates of increase in plasma creatine kinase and creatine kinase-MB activity in the first hour after reperfusion: Figure 2B shows individual data on
absolute increase of CK and CK-MB activity in patients with and without reperfusion. In 41 of the 50 patients receiving intracoronary streptokinase, the totally occluded artery of infarction was recanalized with TIM1 grade 3 perfusion. In these patients, plasma CK activity increased by 54 to 1,440 II-l/liter, 480 f 345 II-l/liter on the average during the first hour following angiographic documentation of reperfusion (Figure 2A). The plasma CK-MB activity increased by 10 to 144 II-l/liter, 48 f 36 III/liter on the average over the same period (Figure 2B). Creatine kinase and creative kinase-MB changes in the absence of reperfusion: In 9 of the 50 patients re-
perfusion was not achieved. In these patients, the l-hour increase in plasma CK activity measured 1.5 to 2.5 hours after the start of treatment was 2 to 30 IU/liter,
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Creatine kinase and creatine kinase-MB changes in the absence of reperfusion: In 4 of the 9 patients in
whom reperfusion was not achieved, the peak of the plasma CK and CK-MB activity was not reached because of early bypass surgery. In the remaining 5 patients, the plasma CK activity increased in the last hour of the 2!&hour observation period by 1 to 6%, 3 f 2% on the average. The CK-MB activity increased by 1 to 6%, 4 f 1% on the average over the same period. The difference between patients with and without reperfusion was significant for both the increase in CK (p
onset of rapid increase in enzyme activity occurred an average of 4 f 9 minutes before the angiographic documentation of reperfusion, with a range from 23 minutes before to 17 minutes after. CK and CK-MB activity usually began to increase simultaneously.
11
DISCUSSION
NO REPERFUSION
flGURE 3. The relative first-hour rates croatins klnase (CK) activity and CK-MB tients with repehnion (REPERFUSION) without reperfusion (NO REPERFUSION). 22
on relative rise of CK and CK-MB activity in 35 patients with reperfusion and 5 patients without it. In 6 of the 41 patients in whom the absolute first hour enzyme increase was determined, the peak of the CK and CKMB time activity curve was not reached due to early coronary bypass surgery or death and, therefore, the relative rate of CK and CK-MB increase could not be measured. In the remaining 35 patients, the plasma CK activity increased in the first hour following reperfusion by 13 to 67% of the peak increase, 34 f 18% on the average. The plasma CK-MB activity increased by 13 to 57%, 27 f 13% on the average over the same period.
Temporal relations between the onset of rapid increase in creatine kinase and creatine kinase-MB activity and the angiographic documentation of reperfusiom In the 41 patients in the intracoronary group the
;
0
Relative rates of increase in plasma creative kinase and creatine kinase-MB activity in the first hour following reperfusion: Figure 3 presents individual data
patient, reperfusion was initially incomplete with TIM1 grade 2 perfusion. At that time the l-hour rate of increase in CK-MB activity was 7 II-J/liter or 4% of the peak rise, but, when perfusion improved to TIMI grade 3, there was an acceleration of the rate of increase to 32 II-J/liter/hour or 18% of the peak increase per hour (Figure 5). In 1 patient with initial TIM1 grade 1 perfusion there was no rise in CK or CK-MB activity.
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15 f 9 II-l/liter on the average (Figure 2A). The CKMB activity increased by 1 to 4 IU/liter, 2 f 1 IU/liter on the average over the same period (Figure 2B). The difference between patients with and without reperfusion was significant for both the changes in CK (p
of increase in plasma activity in 35 paand in 5 patients
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The rapid initial increase in plasma creatine kinase and creatine kinase-MB activity as a marker of reperfusion: Data from the intracoronary thrombolysis study
indicate that reperfusion of a totally occluded coronary artery with TIM1 grade 3 perfusion is followed by an
The abrupt increase in plasma enzyme activity after immediate rapid increase in plasma CK and CK-MB activity or by an immediate acceleration of the rate of reperfusion is due to the abrupt washout of enzymes increase when the activity was already on the rise. In released from the irreversibly damaged cells and accumost patients the CK activity was steady before the on- mulated in the poorly perfused myocardium. In experiset of rapid increase, giving this rise an appearance of mental studies, the washout of enzymes was detected in abruptness. The CK activity increased in the first hour the coronary sinus and in the systemic blood within secfollowing reperfusion by 34% of the peak increase on onds of the release of coronary artery occlusion.‘2-14 the average, by not less than 13%. When reperfusion The abrupt washout also explains why the rate of enwas not achieved or was incomplete with TIM1 grade 1 zyme increase is highest immediately after reperfusion perfusion, the rise was much smaller, not more than 6% and decreases thereafter, giving the time activity curve of the peak rise in the last hour of the 2M-hour observa- an upward convex shape. In contrast, in the absence of tion period. In the first hour following reperfusion, CK- reperfusion, the appearance of myocardial enzymes in MB activity increased by a mean of 21% of the peak the blood is initially the slowest but accelerates progresrise, by not less than 13%. In the absence of reperfusion sively, as both the amount of irreversibly damaged myothe l-hour increase did not exceed 6%. cardium and its perfusion by collateral blood flow inMeasuring relative rates of increase has the disad- crease, giving the initial portion of the time activity vantage that it requires knowledge of the peak increase, curve an upward concave shape. The onset of rapid enzyme increase as a marker of which becomes available only several hours later. The While the rapid initial increase relative rates of increase have therefore more a confir- the time of reperfusion: matory role and are not helpful during the administrain plasma enzyme activity suggests reperfusion, the ontion of the thrombolytic therapy itself. Accordingly, we set of the rapid increase marks the time of reopening of explored the potential utility of the absolute changes in the artery of infarction. That conclusion is based on the CK and CK-MB activity immediately following reper- close proximity between the time of angiographic docufusion not related to the peak increase. The absolute mentation of reperfusion and the time of the onset of increases in CK and CK-MB activity after reperfusion rapid enzyme increase. These findings are also in agreewere much higher than those seen in the absence of re- ment with experimental studies showing abrupt increase perfusion and completely separated the patients with re- in enzyme activity seconds after the release of an occluded coronary artery. I *-I4 perfusion from the patients without it. The relative rate of increase takes into account the Conclusions: The results of this study indicate that total magnitude of the increase and provides therefore a important information on the status of the artery of inbetter separation between reperfusion and no reperfu- farction can be obtained by observing the time course of sion than the absolute rate of increase, particularly in plasma CK or CK-MB activity during the conduction patients with small infarcts. When the amount of necro- of thrombolytic therapy. Sampling of blood for determisis is small and the total increase in enzyme activity is nation of either CK or CK-MB at intervals of 30 minlow, the absolute first-hour rate of increase will also be utes and immediate analysis of samples over a period of low and may approach the values seen in patients with- up to 2M-hours after initiation of treatment should alout reperfusion. low recognition of reperfusion or its absence. The folWhen patients are treated more than 5 hours after lowing stages of coronary artery patency can be recogthe onset of infarct symptoms, the CK and CK-MB ac- nized from changes in CK or CK-MB activity: (1) the tivity may already be rising spontaneously as a manifes- artery of infarction remains totally occluded. There is tation of the natural history and do so at an accelerating 180 rate reaching values usually associated with reperfusion. However, following reperfusion the rate of increase is highest initially and decreases thereafter.
FfGURE 4. lime activity curve from a patient without reperfusion. There is no abrupt initial increase. CK-MB activity increases by 2 ItJMer in the last hour of the 2lAour period. The rate of increase accelerates giving the initial portion of the curve an upward concave shape,
FIGURE 5. Time activity curve from a patient in whom the totally occluded atery of infarction (first arrow) was initially incompletely reperfused with TM grade 2 perfusion (second arrow) and later completely reperfused with TIMI grade 3 perfusion (fhird arrow). THE AMERICAN
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JULY 1.1988
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either no increase in CK and CK-MB activity during 2M-hours following the start of thrombolytic therapy or the absolute rate of increase is 130 II-J/liter/hour in CK and 55 IU/liter/hour in CK-MB activity, and the relative rate of increase does not exceed 6% of the peak increase; (2) the totally occluded artery of infarction is recanalized with TIMI grade 3fzow. There is an abrupt initial increase in CK activity by at least 50 IU/liter/ hour (but usually >lOO IU/liter/hour) or an increase in CK-MB activity by 110 II-J/liter/hour, or both, or by 113% of the peak increase; (3) the artery of infarction is patent prior to treatment with TZMI grade 3 flow.
The first CK and CK-MB activity values are already elevated and the activity continues to increase at a rapid but decreasing rate characteristic of reperfusion. In this way, the time course of CK or CK-MB activity may provide an additional tool for the nonangiographic recognition of reperfusion or the failure to reperfuse during the conduction of thrombolytic therapy in acute myocardial infarction. Acknowledgment: We wish to express our gratitude to Juliana Yano for excellent technical and clinical assistance and to Mira L. Aronovici for valuable assistance in the preparation of the manuscript.
REFERENCES 1. Ferguson DW, White CW, Schwartz JL, Brayden GP, Kelly KJ, Kioschos JM, Kirchner PT, Marcus ML. Influence of baseline ejection fracrion and success of thrombolysis on mortality and ventricular farction. Am J Cardiol 1984;54:705-7/l_
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function
after acute myocardial
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2. Davis GJ, Chierchia S, Maseri A. Prevention of myocardial infarction by very early treatment with intracoronory streptokinase. N Engl J Med 1984;311:14881492. 3. Von Lessen R, Schmidt W, Uebis R. Edelmann B, Effert S, Silny J, Rau G. Myocardial infirction and thrombolysis. Electrocardiographic short term and long term resulrs using precordial mapping. Br Heart J 1985;54:6-10. 4. Krucoff MW, Green CE, Satler LF. Miller FC, Pallas RS, Kent KM, Del Negro AA, Pearle DL, Fletcher RD. Rackley CE. Noniwasioe detection of coronary artery patency using continuous 1986;57:916-922.
ST-segment
monitoring.
Am J Cardiol
5. Goldberg S, Greenspon AJ, Urban PL, Muza B, Berger B, Walinsky P, Maroko PR. Reperfusion arrhyrhmia. A marker of restoration of antegradeflow during intracoronary 1983:105:26-32.
thrombolysis
for acute myocardial
infarction.
Am Heart J
6. Gorgels AP, Letsch IS, Bar FW, Janssen JH, Wellens HJ. Accelerafed
idioin persistent ischemic chest pain indicates necrosis and reper1986;74(suppl):2-1 I. 7. Wei, JY, Markis JE, Malagold M, Grossman W. Time course of serum cardiac enzymes after intracoronary thrombolytic therapy. Creatine kinase, creotine kinose MB isozyme, lactate dehydrogenase and serum glutamic-oxaloacetic fransaminase. Arch Intern Med 1985;145:1596-1600. 8. Dean LS, Smith LR, Rogers WJ. Prediction of successful myocardial reperfusion utilizing time interval until maximum CK-MB (abstr). Clin Res 1983: 3/:821A. 9. TIM1 Study Group. The Thrombolysis in Myocardiol Infarction (TIMI) trial: phase I findings. N Engl J Med 1985;312:932-936. 10. Rasalki SB. An improoedprocedureforserum creatine phosphokinase determination. J Lab Clin Med 1987,69:696-705. 11. Shell WE, Kligerman M, Rorke MP, Burnam S. Sensitivity and specificity of MB creatine kinase actiuity determined with column chromatography. Am J Cardiol 1979;44:67-75. 12. Blumenthal MR. Wang HH, Liu LMP. Experimental coronary artery occlusion and release. Effect on enzymes, electrocardiograms, myocardial contractility and reactive hyperemia. Am J Cardiol 1975;36:225-233. 13. Jarmakani JM, Limbird L, Graham TC, Marks RA. Effect of reperfusion on myocardial infarction and the accuracy of estimating infarct size from serum creotine phosphokinase in the dog. Cardiooasc Res 1976;10:245-253. 14. Vatner SF, Baig H, Manders WT. Maroko PR. Effecfs of coronary artery reperfusion on myocardiol infarct size calculated from creatine kinase. J C/in Invest 1978,61:2048-2056.
ventricular rhythm fusion. Circulation
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ntravenous thrombolytic therapy does not require pretreatment coronary angiography and can therefore be instituted earlier in the course of an evolving myocardial infarction than intracoronary thrombolysis. However, the physician administering intravenous thrombolytic therapy needs to know whether or not reperfusion of the artery of infarction has been achieved to decide whether to continue thrombolytic therapy or, in the case of failure, initiate angioplasty or discontinue anticoagulation. In the absence of angiography, recognition of reperfusion will have to be based on its nonangiographic manifestations. In prior studies, relief of chest pain,1,2 resolution of ST-segment elevations,3,4 occurrence of specific arrhythmiaP and early peaking of plasma creatine kinase (CK) and CK-MB activity7,8 were used as signs of reperfusion. In the present study we describe a new nonangiographic marker of reperfusion: the abrupt initial increase in plasma CK and CKMB activity. METHODS Patients: Changes in plasma CK and CK-MB activ-
ity occurring immediately following reperfusion were studied in 50 of the 81 patients receiving intracoronary streptokinase therapy within 3.3 f 0.7 hours of an evolving acute myocardial infarction, in whom the artery of infarction was totally occluded before the start of therapy and in whom CK and CK-MB activity curves were obtained. In the remaining 31 patients the artery of infarction was not totally occluded at the outset (18 patients) or the CK and CK-MB data were inadequate for analysis due to early bypass surgery, death or incomplete sampling of blood (13 patients). Angiography: The status of the artery of infarction was determined by contrast injection at 15-minute intervals or earlier if clinical signs suggested reperfusion. Reperfusion was defined as complete opacification and clearing of the artery of infarction as rapid as in the patent noninfarct-related arteries. This definition corresponds to the Thrombolysis in Myocardial Infarction (TIMI) grade 3 perfusion.9 The status of coronary artery patency was defined by 2 angiographers not participating in this study prior to the availability of CK data. Creatine kinase and creatine kinase-MB studies:
Blood for determination of plasma CK and CK-MB activity was drawn at approximately 30-minute intervals for 2 to 3 hours and then every 1 to 3 hours up to 24 hours. The blood was sampled into ethyleneglycol-bis-
(beta-aminoethyl ether)-N,N’-tetraacetic acid (EGTA) (10 mM final concentration) and the plasma was harvested. Total CK activity was measured by the Rosalki methodic using Worthington reagents. CK-MB activity was analyzed following separation of the isoenzymes on column chromatography.” The upper limits of normal for these tests were 70 IU/liter for plasma CK activity and 5 III/liter for CK-MB activity. The CK and CK-MB time activity curves were analyzed with regard to the initial rate of rise immediately following reperfusion and the time of the onset of rise. The rate of rise of CK and CK-MB activity immediately following reperfusion was defined by 3 methods: (1)
the absolute rate of increase during the first hour fol-
lowing reperfusion, determined as the difference either between the first elevated and the preceding baseline value (Figure IA) or between the first 2 elevated values, whichever the higher (Figure lB), divided by the time interval between the 2 values in minutes and multiplied by 60; (2) the relative rate of increase during the first hour following reperfusion, determined by dividing the absolute first hour rate of increase by the peak increase on the time activity curve and expressed in percentage. The peak increase was the difference between the peak CK or CK-MB activity and the last baseline value; (3) in patients in whom reperfusion was not achieved, the l-hour rate of CK and CK-MB increase was measured in the last hour of the 2M-hour observation period. The 2M-hour interval beginning with the start of thrombolytic therapy was chosen because reperfusion beyond that time interval is not likely and did not occur in our study. Onset of rapid increase in plasma creative kinase and creatine kinase-MB activity: The last baseline val-
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FIGURE 1. A, time acttvity curve tram a patient with successfutrepsrfuskmafterintr aceronary streptokinase. The rate of increase in CK-MB activity between ths last baseline value and the first elevated valus is steeper than the increase between ths first and second elevated value and it is therefore usedfor meesurement of the initial rate of increase. The last badins vake is close to the ttme of angiegraphii documentation of reperrusion (secti 4wYow). The first arrow denotes total ocddon of the artery of infarction befere treatment. The rate of increase decreases with time giving the curve an upward convex shape. 6, time activtty curve fmm a patient with reperfusien. The initial rate of inwease is measured frem the ssgment between the first 2 slevatsd values and net hfn the segment between the lest basehe and ths first elevated value, whkh is tess stew. The time of m (second BIG row) is dosely apfmximated by extrapolation of the segment between first 2 elevated values. The ffrst arrow denotes total occlusion of the artery of infarction.
the
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FIGURE 2. A, the absolute first-hour rates of imrease in plasma creatine kinase activity in 41 patients with reperk&n (REP) and in 9 patients without repedusion (NO REP). B, the absobte first-hour rates of increase in plasma creative kinaseMB activity in 41 patients with reperfusion (REP) and in 9 patiis without reperfusion (NO REP). THE AMERICAN
JOURNAL
OF CARDIOLOGY
JULY 1,1988
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CK RISE
A MARKER
OF REPERWSION
ue was considered to reflect the onset of increase in enzyme activity when the rate of increase between the baseline value and the first elevated value was steeper than the increase between the first and second elevated values (Figure 1A). When this rate of increase was less steep, the point at which the line plotted through the first and second elevated value crossed the baseline was considered to most closely approximate the onset of rapid enzyme increase (Figure 1B). Statistical analysis: Differences between the rates of increase in CK and CK-MB activity in patients with and without reperfusion were analyzed using Student t test for unpaired data. The data are expressed as mean f standard deviation. A p value of <0.05 is considered significant. RESULTS Absolute rates of increase in plasma creatine kinase and creatine kinase-MB activity in the first hour after reperfusion: Figure 2B shows individual data on
absolute increase of CK and CK-MB activity in patients with and without reperfusion. In 41 of the 50 patients receiving intracoronary streptokinase, the totally occluded artery of infarction was recanalized with TIM1 grade 3 perfusion. In these patients, plasma CK activity increased by 54 to 1,440 II-l/liter, 480 f 345 II-l/liter on the average during the first hour following angiographic documentation of reperfusion (Figure 2A). The plasma CK-MB activity increased by 10 to 144 II-l/liter, 48 f 36 III/liter on the average over the same period (Figure 2B). Creatine kinase and creative kinase-MB changes in the absence of reperfusion: In 9 of the 50 patients re-
perfusion was not achieved. In these patients, the l-hour increase in plasma CK activity measured 1.5 to 2.5 hours after the start of treatment was 2 to 30 IU/liter,
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Creatine kinase and creatine kinase-MB changes in the absence of reperfusion: In 4 of the 9 patients in
whom reperfusion was not achieved, the peak of the plasma CK and CK-MB activity was not reached because of early bypass surgery. In the remaining 5 patients, the plasma CK activity increased in the last hour of the 2!&hour observation period by 1 to 6%, 3 f 2% on the average. The CK-MB activity increased by 1 to 6%, 4 f 1% on the average over the same period. The difference between patients with and without reperfusion was significant for both the increase in CK (p
onset of rapid increase in enzyme activity occurred an average of 4 f 9 minutes before the angiographic documentation of reperfusion, with a range from 23 minutes before to 17 minutes after. CK and CK-MB activity usually began to increase simultaneously.
11
DISCUSSION
NO REPERFUSION
flGURE 3. The relative first-hour rates croatins klnase (CK) activity and CK-MB tients with repehnion (REPERFUSION) without reperfusion (NO REPERFUSION). 22
on relative rise of CK and CK-MB activity in 35 patients with reperfusion and 5 patients without it. In 6 of the 41 patients in whom the absolute first hour enzyme increase was determined, the peak of the CK and CKMB time activity curve was not reached due to early coronary bypass surgery or death and, therefore, the relative rate of CK and CK-MB increase could not be measured. In the remaining 35 patients, the plasma CK activity increased in the first hour following reperfusion by 13 to 67% of the peak increase, 34 f 18% on the average. The plasma CK-MB activity increased by 13 to 57%, 27 f 13% on the average over the same period.
Temporal relations between the onset of rapid increase in creatine kinase and creatine kinase-MB activity and the angiographic documentation of reperfusiom In the 41 patients in the intracoronary group the
;
0
Relative rates of increase in plasma creative kinase and creatine kinase-MB activity in the first hour following reperfusion: Figure 3 presents individual data
patient, reperfusion was initially incomplete with TIM1 grade 2 perfusion. At that time the l-hour rate of increase in CK-MB activity was 7 II-J/liter or 4% of the peak rise, but, when perfusion improved to TIMI grade 3, there was an acceleration of the rate of increase to 32 II-J/liter/hour or 18% of the peak increase per hour (Figure 5). In 1 patient with initial TIM1 grade 1 perfusion there was no rise in CK or CK-MB activity.
. . .
60
15 f 9 II-l/liter on the average (Figure 2A). The CKMB activity increased by 1 to 4 IU/liter, 2 f 1 IU/liter on the average over the same period (Figure 2B). The difference between patients with and without reperfusion was significant for both the changes in CK (p
of increase in plasma activity in 35 paand in 5 patients
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The rapid initial increase in plasma creatine kinase and creatine kinase-MB activity as a marker of reperfusion: Data from the intracoronary thrombolysis study
indicate that reperfusion of a totally occluded coronary artery with TIM1 grade 3 perfusion is followed by an
The abrupt increase in plasma enzyme activity after immediate rapid increase in plasma CK and CK-MB activity or by an immediate acceleration of the rate of reperfusion is due to the abrupt washout of enzymes increase when the activity was already on the rise. In released from the irreversibly damaged cells and accumost patients the CK activity was steady before the on- mulated in the poorly perfused myocardium. In experiset of rapid increase, giving this rise an appearance of mental studies, the washout of enzymes was detected in abruptness. The CK activity increased in the first hour the coronary sinus and in the systemic blood within secfollowing reperfusion by 34% of the peak increase on onds of the release of coronary artery occlusion.‘2-14 the average, by not less than 13%. When reperfusion The abrupt washout also explains why the rate of enwas not achieved or was incomplete with TIM1 grade 1 zyme increase is highest immediately after reperfusion perfusion, the rise was much smaller, not more than 6% and decreases thereafter, giving the time activity curve of the peak rise in the last hour of the 2M-hour observa- an upward convex shape. In contrast, in the absence of tion period. In the first hour following reperfusion, CK- reperfusion, the appearance of myocardial enzymes in MB activity increased by a mean of 21% of the peak the blood is initially the slowest but accelerates progresrise, by not less than 13%. In the absence of reperfusion sively, as both the amount of irreversibly damaged myothe l-hour increase did not exceed 6%. cardium and its perfusion by collateral blood flow inMeasuring relative rates of increase has the disad- crease, giving the initial portion of the time activity vantage that it requires knowledge of the peak increase, curve an upward concave shape. The onset of rapid enzyme increase as a marker of which becomes available only several hours later. The While the rapid initial increase relative rates of increase have therefore more a confir- the time of reperfusion: matory role and are not helpful during the administrain plasma enzyme activity suggests reperfusion, the ontion of the thrombolytic therapy itself. Accordingly, we set of the rapid increase marks the time of reopening of explored the potential utility of the absolute changes in the artery of infarction. That conclusion is based on the CK and CK-MB activity immediately following reper- close proximity between the time of angiographic docufusion not related to the peak increase. The absolute mentation of reperfusion and the time of the onset of increases in CK and CK-MB activity after reperfusion rapid enzyme increase. These findings are also in agreewere much higher than those seen in the absence of re- ment with experimental studies showing abrupt increase perfusion and completely separated the patients with re- in enzyme activity seconds after the release of an occluded coronary artery. I *-I4 perfusion from the patients without it. The relative rate of increase takes into account the Conclusions: The results of this study indicate that total magnitude of the increase and provides therefore a important information on the status of the artery of inbetter separation between reperfusion and no reperfu- farction can be obtained by observing the time course of sion than the absolute rate of increase, particularly in plasma CK or CK-MB activity during the conduction patients with small infarcts. When the amount of necro- of thrombolytic therapy. Sampling of blood for determisis is small and the total increase in enzyme activity is nation of either CK or CK-MB at intervals of 30 minlow, the absolute first-hour rate of increase will also be utes and immediate analysis of samples over a period of low and may approach the values seen in patients with- up to 2M-hours after initiation of treatment should alout reperfusion. low recognition of reperfusion or its absence. The folWhen patients are treated more than 5 hours after lowing stages of coronary artery patency can be recogthe onset of infarct symptoms, the CK and CK-MB ac- nized from changes in CK or CK-MB activity: (1) the tivity may already be rising spontaneously as a manifes- artery of infarction remains totally occluded. There is tation of the natural history and do so at an accelerating 180 rate reaching values usually associated with reperfusion. However, following reperfusion the rate of increase is highest initially and decreases thereafter.
FfGURE 4. lime activity curve from a patient without reperfusion. There is no abrupt initial increase. CK-MB activity increases by 2 ItJMer in the last hour of the 2lAour period. The rate of increase accelerates giving the initial portion of the curve an upward concave shape,
FIGURE 5. Time activity curve from a patient in whom the totally occluded atery of infarction (first arrow) was initially incompletely reperfused with TM grade 2 perfusion (second arrow) and later completely reperfused with TIMI grade 3 perfusion (fhird arrow). THE AMERICAN
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RAPID
CK RISE
A MARKER
OF REPERFUSION
either no increase in CK and CK-MB activity during 2M-hours following the start of thrombolytic therapy or the absolute rate of increase is 130 II-J/liter/hour in CK and 55 IU/liter/hour in CK-MB activity, and the relative rate of increase does not exceed 6% of the peak increase; (2) the totally occluded artery of infarction is recanalized with TIMI grade 3fzow. There is an abrupt initial increase in CK activity by at least 50 IU/liter/ hour (but usually >lOO IU/liter/hour) or an increase in CK-MB activity by 110 II-J/liter/hour, or both, or by 113% of the peak increase; (3) the artery of infarction is patent prior to treatment with TZMI grade 3 flow.
The first CK and CK-MB activity values are already elevated and the activity continues to increase at a rapid but decreasing rate characteristic of reperfusion. In this way, the time course of CK or CK-MB activity may provide an additional tool for the nonangiographic recognition of reperfusion or the failure to reperfuse during the conduction of thrombolytic therapy in acute myocardial infarction. Acknowledgment: We wish to express our gratitude to Juliana Yano for excellent technical and clinical assistance and to Mira L. Aronovici for valuable assistance in the preparation of the manuscript.
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JOURNAL
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