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Acute Ischemic Heart Disease ’

A comparison of electrocardiographic changes during reperfusion of acute myocardial infarction by thrombolysis or percutaneous transluminal coronary angioplasty Xander H.T. Wehrens, MSc, Pieter A. Doevendans, MD, PhD, Ton J. Oude Ophuis, MD, PhD, and Hein J.J. Wellens, MD, PhD, FACC Maastricht, The Netherlands

Background D’ff I erent electrocardiographic changes have been described during thrombolytic therapy for acute myocar-

dial infarction to indicate successful reperfusion. The occluded coronary artery also can be reopened by percutaneous translumi-

nal coronary angioplasty (PTCA). This study was performed to compare electrocardiographic changes during primary or rescue

PTCA and thrombolytic therapy. The electrocardiographic changes were studied directly at the moment of reperfusion during PTCA.

Methods and Results c on muous t’ 12-lead electrocardiographic monitoring was performed in 1 10 patients with

acute myocardial infarction undergoing a reperfusion intervention (thrombolytic therapy or primary or rescue PTCA) to

assess electrocardiographic changes during reperfusion. Patency and Thrombolysis In Myocardial Infarction flow in the

infarct-related artery were assessed by coronary angiography. During reperfusion of the infarct-related coronary artery,

early signs of reperfusion were an increase of ST-segment deviation (30%), ST-segment normalization (70%), and terminal T-

wave inversion (60%); only 1 1% of patients showed no ST-segment changes. Thrombolytic therapy was significantly more

often accompanied by a transient increase in ST-segment deviation compared with primary PTCA. Accelerated idioventricu-

lar rhythm was documented in 5 1%, an increase in the number of ventricular premature complexes in 42%, nonsustained

ventricular tachycardia in 7%, and bradycardia in 18% of all patients.

Conclusions This study confirms the occurrence of specific electrocardiographic changes at the time of reperfusion.

The pattern of ST-segment change upon reperfusion relates to the type of treatment. Awareness of electrocardiographic

changes at the moment of reperfusion will help to select patients for rescue PTCA and can be used to assess the effect of

future pharmacologic interventions to limit reperfusion damage (Am Heart J 2000; 139:430-6.)

See related Editorial on page 390.

Previous studies described the clinical and electrocardiographic signs of reperfusion during thrombolytic therapy for an acute myocardial infarction. Decrease or disappearance of chest pain was an important indicator of reperfusion. 1 The most important electrocardiographic signs of reperfusion were rapid normalization of ST-segment deviation,” development of terminal T-wave inversion,-’ an increase in the number of ventricular premature beats,‘,3 and the occurrence of accelerated idioventricular rhythm (AIVR).* The temporal relation between these

From the Deportment of Cordlology, Unwersky Hospttol Maortrtchi, Cordtovosculor

Research fnshrute.

Submttted June I, 1999; accepted August I, 1999

Reprinl requests- Pefer A. Doevendans, MD, PhD, Deportment of Cordrology, Unl-

verrdy Hosp~tol Moostncht, PO Box 5800, 6202 Ai! Moosrnchr, The Nerherlonds

E-mall. [email protected]

Copyright 0 2000 by Mosby, fnc

0002.8703/2000/$12.00+ 0 4/I/103222

electrocardiographic changes and the exact moment of reperfusion, however, has never been documented. New pharmacologic approaches to reduce myocardial infarct size and to limit reperfusion damage are being evaluated in clinical trials (free radical scavengers, Na+/H+Txchanger blockers).5 The electrocardiographic changes during reopening of the infarct-related artery may provide an excellent tool to evaluate the effects of these drugs in individual patients. We documented the incidence, magnitude, and time course of the electrocardiographic changes in relation to reperfusion during primary percutaneous transluminal coronary angioplasty (PTCA) or after thrombolytic therapy. Reperfusion was documented by coronary angiography in all patients. This study provides a baseline to evaluate protective measures against reperfusion damage in future studies.

Most recent studies on reperfusion-associated ST-segment changes and arrhythmias have been performed in the setting of thrombolytic therapy to define electrocardiographic criteria to predict reopening of the occluded

A,,,er,con Hem Journo~ volume 139, Number 3 Wehrens et al 431

coronary artery noninvasively. However, the incidence and patterns of electrocardiographic changes occurring in patients treated with a primary FTCA, a rescue FTCA, or thrombolytic therapy have never been compared before. These differences might provide additional insight into the relation between the mode of vessel reopening and reperfusion injury.

Methods Patients

In total, 110 consecutive patients with acute myocardial infarction (symptoms lasting <6 hours) were included in the study. Acute myocardial infarction was diagnosed by the pres- ence of typical chest pain lasting >45 minutes, together with ST-segment elevation >O. 1 mV in at least 2 extremity leads or >0.2 mV in at least 2 precordial leads. Two patients were excluded because of continuous atrial fibrillation (n = 2). Conventional antianginal treatment was used as needed.

In total, 44 patients were treated with prourokinase intra- venously (Satuplase. GrunenthaI, Aachen, Germany), with reperfusion status confirmed by subsequent coronary angiography (group A). Prourokinase was given as a bolus injection of 20 mg followed by infusion of 60 mg in the subsequent hour. In addition, patients studied were referred to the catheterization laboratory for either primary PTCA (group B; n = 42) or rescue PTCA (group C; n = 22). A rescue PTCA was performed if thrombolytic therapy did not lead to reperfusion (Throm- bolysis In MyocardiaI Infarction [TlMI] flow grade 0 or 1).

Electrocardiographic evaluation All patients were connected to a Marquette CASE 12 electro-

cardiograph (Marquette Electronics, Milwaukee, Wis) before administration of prourokinase or transfer to the catheterization laboratory, allowing continuous 12-lead electrocardiographic monitoring. During catheterization the patients were connected to a Siemens electrocardiograph, and the leads selected were dependent on the infarct localization. In the setting of an anterior waII myocardial infarction, leads I, V,, Vs, and aVR were used and in inferior myocardial infarction, leads I, II, III, and aVF were recorded continuously. The leads were adapted in case the maximal ST-segment deviation before angiography was observed in any of the remaining leads. The tracings were analyzed by 2 blinded, experienced investigators.

ST segment In patients of group A, ST segments were measured every 5

minutes throughout the entire monitoring period, starting 15 minutes before administration of prourokinase. ST segments were measured 60 ms after the J-point.6 and this score was used for determining the changes in the ST segment that occurred. Compared with baseline ST-segment deviation, a change of 25% in 1 lead was considered significant and scored as either a decrease or increase of ST-segment deviation. Ter- minal T-wave inversion was considered present if the terminal part of the T wave changed direction from positive to negative or vice versa. In patients undergoing a PTCA (groups B and C), the electrocardiogram was continuously monitored, starting approximately 10 minutes before and up to 10 minutes after angiographically documented reperfusion. The ST-

segment changes and arrhythmias registered directly after contrast injection were excluded, resulting in a blanking period of 60 seconds after each contrast injection.

Arrhythmia monitoring In group A, the number of ventricular premature beats was

counted during every 5mInute interval. The number of ventricular premature beats during 15 minutes before thrombolytic therapy divided by 3 was used as a baseline count. A 2-fold increase during a 5minute interval was considered as a positive result. In groups B and C, the number of ventricular premature complexes was counted during a lOminute period before and after documented reperfusion. When after reperfusion the number of ventricuIar premature complexes increased 2-fold or more per minute, this was considered a positive result. When the baseline count was II per minute, an increase to t2 per minute was considered a positive score.

For arrhythmias, the following criteria were used. Acceler- ated idioventricular rhythm was defined as a run of >3 consecutive ventricular beats, with a rate between 60 and 120 beats/n-tin; nonsustained ventricular tachycardia, ventricular rhythm > 120 beats/min lasting ~30 seconds; and bradycardia, rate 150 beats/mIn.

Coronary angiography Patency and flow in the infarct-related coronary artery were

assessed by 2 interventional cardiologists who did not partici- pate in the procedure and were not informed about the electrocardiographic changes that occurred during the procedure. For the classification of the coronary flow, the TIM1 trial trite- ria were used.7 In group A, coronary angiography was performed between 60 and 90 minutes after the start of thrombolytic therapy in ail patients Irrespective of the clinical findIngs to assess infarct-related coronary artery patency. In patients undergoing a PTCA (groups B and C), the moment of reperht- sion was defined by the fmt visualization of TIM1 flow grade 2 or 3. Flow could be restored during the coronary angiography, after passage of a guide wire, or after PTCA. Only when TIMI 2 or 3 flow was obtained, 20 minutes of the electrocardio graphic tracings were analyzed starting 10 minutes before the moment of angiographicaIly documented reperfusion.

Statistical analysis Results are expressed as mean value f SD. Data were analyzed

with the use of the Statistical Package for the Social Sciences program for Windows, version 7.5. The Student f test was used to compare groups with continuous variables with a normal distribution, the Mann-Whitney U test for those with a non- normal distribution, and the cl-&square test for groups with dis Crete variables. A value of P < .05 was considered significant.

Results Clinical data

In total, 108 patients with a mean age of 59 years admitted for an acute myocardial infarction were included in this study. All patients are characterized by documented successful reperfusion therapy of the infarct-related coronary artery, achieved by throm-

432 Wehrens et al Americans Heart Journal

March 2000

Table I. Characteristics of patients with documented’reperfusion (n = 108) ft a er th rombolytic therapy, primory PTCA, ond rescue PTCA

Thrombolytic therapy Primary PTCA Rescue PTCA (group A) (group W (group Cl

No. of patients Men Mean (y) age History of angina pectoris >l mo

Prior myocordial infarction Infarct localization

Anterior Inferior

Posterior Later01

Mean duration of pain before reperfusion Enzyme release

Maximal serum glutamic oxaloacetic transominase (U/l) Time to peak level (h)

Coronary angiagraphy

1 -Vessel disease 2-Vessel disease J-Vessel diseose left main stem

Coronary artery flow

TIMI 2 TIMI 3

44 42 22 37 (84) 32 (73) 16 (73) 60+ 10 59f 12 58f 11

9 120) 12 (27) 4 (18) 4 (91 7 (16) 4 (18)

24 (55) 21 (50) 8 (361 14 (32) 18 (41) 12 (55)

4 (9) 3 (7) 2 19) 2 (5) 0 PI 0 (01

2.0 * 1 .o* 3.8f 1.5 4.3 f 1.4

325&220 305+220 270f 148 13?6t 17f6 16+8

22 (50) 16 (36) 7 (32) 14 (32) 14 (32) 6 127)

5 (111 9 (20) 8 (36) 3 (7) 3 (7) 1 (5)

10 (23) 8 1191 6 (27) 34 (77) 34 (81) 16 (73)

Values are expressed 01 number (%.) or meon + SD ‘PC ,001, A VI B and A vs C. ~P<.OI,AvsB.

bolytic therapy (A), primary PTCA (B), or a combina- tion of both (rescue F’TCA; C). All 3 groups were com- parable with respect to mean age, sex, and cardiac history and did not differ significantly in infarct localization and enzyme release, the severity of coronary artery disease, and TIM1 flow after reperfusion. However, the mean duration of pain from onset of symptoms until reperfusion was significantly shorter in patients receiving only thrombolytic therapy (group A) compared with patients undergoing primary (B) and rescue FTCA (C) (P < .OOl). Excluding the 20 patients referred to our institute for primary F’TCA, the difference in time interval was still statistically significant (3.5 f 1.4 vs 2.0 f 1.0 hours; P < .Ol). The time interval from onset of symptoms until peak of the serum glutamic oxaloacetic transaminase levels was significantly longer in group B compared with group A. No differences were noted in the use of anticoagulant therapy (aspirin and heparin; data not shown). The baseline clinical characteristics of the patients are listed in Table I.

ST-segment analysis Illustrative electrocardiographic tracings at the moment

of reperfusion are shown in Figure 1, A through C. Typically, ST-segment deviation was the first electrocardiographic change after coronary artery reperfusion. ST-segment normalization was documented in 84% (A),

61% (B), and 64% (C) of patients after reperfusion (Table II). In patients undergoing a PICA, it was observed that normalization of the ST segment typically took <5 minutes after the moment of reperfusion. Interestingly, an increase (temporary) in ST-segment deviation was seen significantly more often in patients receiving thrombolytic therapy (59%) compared with patients undergo ing a primary or rescue FTCA (12% and 5%, respectively; P < .05). Terminal T-wave inversion was seen in 57% vs 64% of the tracings. Only 12 (11%) of 108 patients showed no ST-segment changes upon reperfusion of the infarct-related artery. Comparing patients in whom reperfusion was achieved within or after 3 hours of ischemia, ST-segment normalization occurred significantly more often in patients with fast reperfusion (75% vs 45%; P < .05). In Table III, electrocardiographic changes after reperfusion are compared for TIM1 grades 2 and 3 flow in the infarct-related coronary artery. ST- segment changes occurred significantly more often in conjunction with TIM1 grade 3 flow after reperfusion (94% vs 71%; P c .05; Table III).

Reperfusion arrhythmias In most patients with reperfusion arrhythmias, an

increase in the number of ventricular premature complexes was the first arrhythmic event to occur. A 2-fold increase in the number of ventricular premature complexes after reperfusion of the infarct-related artery was

American Heart Journal Volume 139, Number 3

Figure 1

Wehrens et cd 433

“6

C I

A, Typical electrocardiographic changes indicating reperfusion during thrombolytic therapy. Alteration intervals (time from start therapy)

show acute anterior myocardial infarction, increase of ST-segment deviation, terminal negative T waves, AIVR, and electrocardiogram dur-

ing coronary angiography. 6, Reperfusion in inferior wall myocardial infarction induced by contrast injection. Note development of AIVR

ST-segment normalization and terminal negative T waves. C, Reperfusion during rescue PTCA. Note ST-segment normalization, terminal T-

wave inversion, and appearance of ventricular premature complexes.

434 Wehrens et al American Heart Journal

March 2000

Table II. Electrocardiographic changes after reperftiion of the infarct-related artery after thrombolytic therapy, primary PTCA, and rescue PTCAPTCA

Thrombolytic therapy (group Al

Primary PTCA (group B)

Rescue PTCA (group Cl

No. of patients ST segment

Temporarily increased deviation Decreased deviation Terminal T-wave inversion

No changes Arrhythmia

Increased No. of ventricular premature complexes AIVR Nonsustained ventricular tachycardia

Atriai fibrillation Bradycardio Ventricular fibrillation No arrhythmias

Values are expressed OS No. (%) l P < .05, A VI B. ~Pc.Ol,AvsC.

AA A2 22

26 (59)'t 5 (121 1 (5) 37(84) 25 (61) 1 A (64) 25 (57) 27(64) 13 (60)

5 (111 5 (12) 2 (9)

24(55) 22 (52) 9(411 20(45) 1 A(33) 11 (50)

A (9) 2 15) 2 (91 1 PI 4 (101 1 (5) 9 (20) 7(17) 3 (141 0 (01 1 PI 2 (91 2 I51 10 (24) 2 (9)

observed in 55% (A), 52% (B), and 41% (C) of patients (Table 11). In addition, AIVR developed in 45 (42%) patients and nonsustained ventricular tachycardia developed in 8 (7%). Atria1 (6%) and ventricular (3%) fibrillation occurred less frequently. Transient slow heart rate was observed in 19 (18%) patients; sinus bradycardia was seen most often (n = 15). In 14 patients, no arrhythmias occurred after reperfusion. In a comparison of patients with TIM1 grades 2 and 3 flow through the infarct-related artery after reperfusion, no differences were observed in the occurrence of arrhythmias (Table III). In patients in whom reperfusion arrhythmias developed, serum creatine kinase (CK) levels were significantly higher compared with patients without arrhythmias (3145 f 2032 vs 2090 f 1138 U/L; P < .05). This difference in serum CK levels could not be explained by preexisting differences in ST-segment deviations before reperfusion.

Influence of infarct location The ST-segment changes and arrhythmias were not

dependent on the location of myocardial infarction, with bradycardia being the only exception. Transient slow heart rates occurred significantly more often in the setting of an inferoposterior (31%) than in anterior (4%) myocardial infarction (P < .Ol).

Discussion Although some of the bedside markers of reperfusion,

such as rapid relief of chest pain,’ early peak of serum CK levels,* rapid decrease in ST-segment elevation,*,9 early inversion of T waves, 1 33 and reperfusion arrhythmias* have been shown to predict reperfusion after thrombolytic therapy, the reliability of these markers is

still controversial. We sought to relate the temporal relation of electrocardiographic changes and angiographically documented reperfusion. The main finding was that in a group of patients with documented successful reperfusion therapy and TIMI grade 2 or 3 flow through the infarct-related coronary artery, ST-segment alterations (89%) and reperfusion arrhythmias (87%) frequently occur. The timing of these electrocardiographic changes is directly related to the moment of reperfusion. Because 97% of patients undergoing a PTCA showed either ST- segment normalization or reperfusion arrhythmias, the 12-lead electrocardiogram provides a reliable tool for early bedside recognition. The occurrence of reperfusion-related electrocardiographic changes does not enable the clinician to distinguish noninvasively between TIM1 grades 2 and 3 flow after thrombolytic therapy. However, we found a difference in the pattern of ST- segment behavior in relation to the reperfusion strategy.

ST-segment analysis Continuous ST-segment monitoring has been estab-

lished as a valuable method to assess reperfusion after thrombolytic therapy.tJ~ia In a previous study we found ST-segment normalization in the hrst hour after thomboly- sis to be a very important indicator for reperfusion (sensi- tivity 95%, specificity 94%) l whereas terminal T-wave inversion was a less sensitive but very specific (94%) sign of reperfusion. A similar study approach was applied by Shah et al,” who reported a rapid decrease in ST-segment elevation and pain in all patients with TIMI grade 3 flow within 90 minutes. However, all aforementioned studies described retrospectively the relation between changes on the electrocardiogram after the start of thrombolytic therapy and patency of the infarct-related artery at

American Heart Journal Volume 139, Number 3 Wehrens et al 435

Table III. Coronary artery flow-dependent electrocardiographic changes after reperfusion of the infarct-related coronary artery

TIM1 2 flow (n = 24) TIM1 3 flow (n = 84) P value

ST segment Temporarily increased deviation Decreased deviation Terminal T-wave inversion No changes

Arrhythmia Increased No. of ventricular premature complexes AIVR Nonsustained ventricular tachycardia Atrial fibrillation Bradycardia Ventricular fibrillation No arrhythmias

5 (21) 15 (63) 11 (46)

7 (291

12 (50)

7 (29) 2 (8) 2 (81 5 (21) 0 (0) 2 P31

27 (32) 61 (73) 54 (64)

5 (6)

43 (51) 38 (45)

6 (71 4 (5)

14 (17)

3 (4) 12 (14)

NS NS NS

PC.05

NS NS NS NS NS NS NS

NS, Not significant. Values are expressed os No. (%I.

follow-up.*.2,‘“,‘2,1~ In the current study, electrocardiographic changes were registered in relation to the documented moment of reperfusion in patients undergoing PICA (groups B and C). In these patients, rapid ST-segment normalization was found in 61% and terminal T- wave inversion in 63% of all patients. Only 11% of alI patients did not show any ST-segment alterations during the first 10 minutes after opening of the coronary artery. ST-segment normalization is therefore most likely a direct consequence of restoration of myocardial blood flow. In addition, ST-segment normalization occurred significantly more often in patients with short-term (~3 hours) compared with long-term (>3 hours) ischemia, which suggests that ST-segment normalization is a direct consequence of reperfusion. The importance of ST-segment normalization has been illustrated by the study performed by van? Hoff et al,13 who demonstrated a direct correlation with clinical outcome and mortality rate.

Reperfusion arrhythmias In the current study, arrhythmias were assessed

prospectively during angiographically documented reperfusion in patients undergoing PTCA (groups B and C). There was a high incidence of reperfusion arrhythmias (78%) during the first 10 minutes after reperfusion, with an increase in ventricular extrasystolic complexes occurring in 48%, AIVR in 39%, and bradycardia in 16%. This provides evidence that these arrhythmias are the direct consequence of restoration of coronary blood flow after a short-term occlusion. Only 14 of 108 patients did not have arrhythmias after reperfusion. Patients in whom reperfusion arrhythmias developed had significantly higher peak serum CK levels than patients without, which suggests that there is a direct relation between myocardial ischemia-reperfusion injury and reperfusion arrhythmias.

Reperfusion arrhythmias have been recognized since Goldberg et al-’ registered AIVR during intracoronary

thrombolytic therapy. The value of AIVR as a marker of reperfusion was further established by several groups.i~“~ia~ta Gressin et ali* showed that especially the early occurrence (~6 hours) of AIVR was a specific (76%) sign for a patent infarct-related coronary artery after thrombolytic therapy. Other arrhythmias during reperfusion occur in lower frequencies and are found in 33% to 89% of patients after thrombolysisinduced reperfusion with Holter monitoring. 12+ls The increased number of ventricular premature complexes is of limited value, with a specificity of 71%.‘* Nonsustalned ventricular tachycardia, 14.15 ventricular fibrillation,is and sinus bradycardial have been described to be of less lmpor- tance because of their infrequent appearance.

Contrast medium Selective coronary injection of contrast medium may

be associated with electrocardiographic alterations. Since the introduction of nonionic media, contrast injection is rarely complicated by life-threatening arrhythmias such as ventricular flbrillation.16 However, injection of contrast medium may be associated with a transient widening of the QRS complex and QT time, usually not lasting >lO seconds.16,17 ST-segment depression of up to 0.3 mm not lasting >5 seconds without associated T-wave inversion was observed in a study by Gertz et al. l7 Temporary (~60 seconds) occurrence of ventricular extrasystolic beats was reported in 70% of all patients after lntracoronary injection of nonionic contrast medium.18 Because all reported contrast-related electrocardiographic changes occur within seconds after intracoronary injection, they can easily be distinguished from reperfusion-related electrocardiographic changes by introducing a blanking period of 1 minute after contrast medium injection.

Reperfusion strategy In our study, a temporary increase preceding a decrease

of ST-segment deviation was observed significantly more

436 Wehrens et al

American Heart Journal March 2000

often in patients receiving thrombolytic therapy compared with those who had FICA. This increase in ST- segment deviation could be a sign of additional damage caused by incomplete or gradual reopening of the occluded vessel achieved by thrombolysis. This suggests that a more aggressive restoration of coronary blood flow by means of a PICA might prevent reperfusion- related myocardial injury to some extent. Successful sal- vage angioplasty, angioplasty performed on arteries that remain occluded after thrombolytic therapy, appears to achieve the same low in-hospital and long-term mortality rates as successful thrombolytic therapy.19 On the other hand, it became clear that immediate angioplasty of patent but stenotic arteries with good flow after thrombolytic therapy is of no value and probably is harmful.*0 An alternative explanation of reperfusion damage could be the interaction of a thrombolytic drug with damaged myocardial tissue. However, during rescue FTCA, an increase of ST-segment deviation was not observed frequently (5%).

Study limitations The number of patients studied was limited to 110,

with only 22 patients in the TIM1 grade 2 group. These numbers were too small to be conclusive about the possibility to use noninvasive parameters to distinguish between TIMI 2 and 3 flow grades. Another limitation of this study was that clinical features such as resolution of chest pain and the temporal course of cardiac enzymes were not considered in relation to the electrocardiographic findings.

This study allowed accurate correlation of electrocardiographic changes with the exact moment of coronary reperfusion. Because of the short period of electrocardiographic follow-up (10 minutes after reperfusion), only immediate reperfusion-related electrocardiographic changes are described in groups A, B, and C. Compared with other studies with longer observation times, the fre- quency of ST-segment normalization and arrhythmias is lower.

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