Electrocardiographic signs of reperfusion. How should they be used in the clinical setting?

Y. Birnbaum¹, D. Ware^1
1University of Texas Medical Branch, 5,106 John Sealy Annex, 301 University Blvd., Galveston, Texas, 77555-0553, USA

The standard 12-lead electrocardiogram (ECG) gives us crucial information concerning myocardial perfusion and the success and completeness of reperfusion therapy for ST elevation acute myocardial infarction. Continuous monitoring has advantages over repeated snapshot recordings. There are four electrocardiographic markers for prediction of the perfusion status of the ischemic myocardium: 1) ST-segment changes (either sum of ST elevation/deviation in all leads or the lead(s) with maximal ST deviation at the beginning of recording; 2) T-wave configuration; 3) QRS changes; and 4) reperfusion arrhythmias. Complete and stable (≥ 70%) resolution of ST-segment elevation is associated with better outcome and preservation of left ventricular function than partial (30 to 70%) or no (<30%) ST segment resolution. Although negative T waves in the leads with ST elevation before initiation of reperfusion therapy may be a poor prognostic sign and associated with reduced rates of successful reperfusion, early inversion of the T waves after initiation of reperfusion therapy is another marker of myocardial reperfusion and a good prognostic sign. It is unclear whether inversion of the terminal portion of the T wave and complete T wave inversion have the same underlying mechanisms and prognostic implications. Using standard 12-lead ECG, dynamic changes in Q-wave number, amplitude, and width; R-wave amplitude; and S-wave appearance are detected during reperfusion therapy. However, the significance of these changes has not been studied. Reperfusion arrhythmias, especially bradycardia and accelerated idioventricular rhythm, are detected occasionally during reperfusion therapy, but the value of reperfusion arrhythmias as a marker of coronary artery patency is still debatable. Dynamic changes in the QRS complexes, ST segments and T waves occur during reperfusion therapy and the days after. Whereas changes in ST-segment amplitude have been extensively studied, the significance of QRS-complex and T-wave changes is less clear, and especially whether changes in the QRS complex and T wave may be complementary and additive to ST-segment monitoring.  It has remained unclear how electrocardiographic signs of ischemia and reperfusion should be used for therapeutic decision making in the clinical setting.

INTRODUCTION

Acute myocardial infarction (AMI) in humans is a dynamic process with frequently repeated episodes of coronary artery reperfusion and reocclusion, both before, after initiation of thrombolytic therapy and even several days after reperfusion therapy. While the extent of myocardium involved can be estimated by clinical signs (presence of heart failure, tachycardia, hypotension, etc.), and various imaging techniques (echocardiography, radionuclid imaging, or ventriculography), currently there is no alternative to electrocardiography in assessing online over extended periods of time the status of myocardial perfusion.

The primary goal in the acute management of AMI is to halt the progression of myocardial necrosis by prompt and complete restoration of blood flow to the ischemic myocardium. Reperfusion may occur spontaneously, after aspirin administration or after the use of thrombolytic therapy or percutaneous coronary interventions (PCI). Reliable assessment whether stable and complete reperfusion has occurred is crucial. Absence of signs of reperfusion after infusion of a thrombolytic agent may lead to performance of rescue PCI, since lack of reperfusion is associated with adverse outcome. Identifying the earliest sign of reperfusion or reocclusion by noninvasive tests is challenging. This paper reviews the role of bedside 12-leads electrocardiogram in identifying and monitoring the perfusion state of the myocardium in ST-elevation AMI.

There are 4 EKG markers for prediction of the perfusion status of the ischemic myocardium.

1) ST-segment recovery

Several studies showed that recanalization of the infarct-related artery, is accompanied by rapid resolution (≥50%) of ST-segment elevation. This ST recovery was obtained from serial EKG performed on arrival of the patient to the hospital and at various times after initiation of therapy. Unfortunately these studies were not unified regarding the definition of ST-segment recovery or in the timing of coronary angiography and the final EKG assessment. Some of the studies followed a single lead with maximal ST elevation whereas some have followed the reduction in the sum of ST elevation in all leads. It seems that the latter method is more useful in patients with mild ST deviation whereas in cases of large ST deviation, following the reduction in the single worst lead is preferable.

Since reperfusion is a dynamic process, in which the infarct related artery might recanalized and reoccluded intermittently, serial EKG recording is limited in predicting reperfusion. One third of episodes of recurrent ST elevation are silent. Thus, unless recorded continuously, these EKG changes may be completely missed by serial intermittent EKG recordings or misinterpreted as sign of improvement, should the re-elevation in ST be lesser than that in the initial EKG recording. Moreover, since the EKG criteria for reperfusion is ≥50% ST reduction compared to maximal ST elevation at any time-point (not necessarily the enrollment EKG), without continuous monitoring starting immediately upon admission, interpretation of ST resolution relative to the enrollment EKG may be misleading.

A proper alternative to continuous 12-lead recording would be EKG monitoring that engage computer-assisted ST-segment analysis and continuous 12-lead recording (using either the single lead or the summed ST segment deviation). Another technique is the continuous vectrocardiographic monitoring that assesses online both vectrocardiographic QRS complex and ST deviation simultaneously.

The amount of ST elevation present during recording is a major determinant of the accuracy of patency prediction. The lesser ST deviation at enrollment and during the subsequent recordings there is less accuracy in prediction infarct related artery patency. In order to detect ST recovery, the recording must be started early (preferably before the start of thrombolytic therapy). Otherwise, the first episode of ≥50% ST recovery may not be properly recorded, and that may result in false assessment of infarct related artery status.

However, myocardial reperfusion is not dichotomous phenomenon. Epicardial coronary flow is graded by the TIMI flow classification and myocardial perfusion may be complete, partial or absent irrespective of the epicedial coronary flow. Analysis of ST-segment deviation may give us better estimation of myocardial perfusion over time. Complete (≥70%) resolution of ST elevation is associated with better outcome and preservation of left ventricular function than partial (30% to 70%) or no (<30%) ST-segment resolution. Thus, whereas ≥50% resolution of ST-segment elevation is a reliable indicator of patency of the infarct related artery, only complete (≥70%) ST elevation resolution is an indicator of restoration of myocardial tissue perfusion. Even in patients with successful recanalization of the epicardial coronary artery by primary PCI, patients with early resolution of ST-segment elevation have better outcome than patients with incomplete or no resolution of ST elevation. It seems that ST-segment monitoring gives us better information on the status of myocardial perfusion and hence, prediction of prognosis and left ventricular function, than the coronary angiographic findings.

2) T-wave configuration

Early inversion of the terminal portion of the T waves after initiation of reperfusion therapy is another indicator of reperfusion. Moreover, recent analysis showed that T-wave inversion was associated with the lowest in-hospital mortality rate (odds ratio 0.25, confidence interval 0. 10- 0.56). When all markers of coronary artery reperfusion (Resolution of chest pain; STt elevation >50% resolution at 90 min; abrupt creatine kinase rise before 12 hours; and T-wave inversion) were included in a regression model, T-wave inversion (odds ratio 0.29, confidence interval 0.11-0.68) and abrupt creatine kinase rise (odds ratio 0.36, confidence interval 0.16-0.77) continued to be significantly associated with better outcome, whereas ST-segment resolution was not.

Only a few studies have investigated the significance of T-wave direction in leads with ST elevation. It was found that before initiation of thrombolytic therapy, negative T-waves in leads with STt elevation were associated with better prognosis among patients enrolled within 2 h of symptoms onset, whereas among those enrolled 2-6 h after initiation of symptoms negative T-waves were associated with increased mortality. At 90 minutes after initiation of streptokinase therapy, TIMI grade 3 flow in the infarct related artery was more commonly seen in patients without T-wave inversion (50%) than in those with T-wave inversion (30%; p 0.002). Among patients treated within 3 h of onset of symptoms, TIMI grade 3 flow was seen in 62% of those without versus 43% of those with T-wave inversion (p = 0.06). Among patients treated after 3 h, TIMI grade 3 flow was seen in 38% of those without versus 23% of those with T-wave inversion (p 0.05). In contrast, after initiation of thrombolytic therapy, early inversion of the T waves may be a sign of reperfusion. Negative T-waves on the predischarge ECG of patients with anterior AMI, especially if associated with complete resolution of the ST elevation, is a sign of a relatively small infarct size with preserved left ventricular ejection fraction. However, during the following months, spontaneous normalization of the T-waves in the involved leads may be associated with better outcome and preservation of left ventricular function. Therefore, the configuration of the T-waves may bear different meanings at different stages after AMI. Moreover, it is unclear whether partial inversion of the terminal portion of the T waves has the same significance of complete or giant T-wave inversion. Furthermore, the exact underlying mechanisms and significance of various patterns of ST-segment resolution and T-wave inversion have not been studied. It is well known that the amplitude of the ST-segment is mostly influenced by epicardial ischemia and is less influenced by the degree of subendocardial ischemia. Thus, resolution of ST elevation may be a better correlated with amelioration of epicardial ischemia due to restoration of flow through the infarct related artery or by recruitment of collaterals and less with the status of the subendocardial zones. It might be that the configuration of the T-waves is more related to the subendocardial perfusion status. Since myocardial necrosis starts from the subendocardium and expands towards the epicardium, the configuration of the T-waves after reperfusion therapy may better correlate with recovery of left ventricular function and prognosis.

3) QRS changes during ischemia and reperfusion

Dynamic changes in the QRS complex are detected during reperfusion therapy for AMI. These changes have been investigated mainly by vectrocardiography. It seems that the QRS-vector changes are less specific than the ST-vector changes for predicting reperfusion. Using standard 12-lead EKG, dynamic changes in Q-wave number, amplitude and width, R-wave amplitude and S-wave appearance are detected. Some have reported that early pathologic Q-waves develop especially after reperfusion, however, others have found these to be associated with larger ischemic zone and ultimate necrotic area. It has been reported that early Q waves (< 6 hours) do not signify irreversible damage, and do not preclude myocardial salvage by thrombolytic therapy, however, Q-waves on admission is associated with worse prognosis. It is unclear whether dynamic changes in Q-waves early after initiation of reperfusion therapy have additive prognostic significance to ST-segment monitoring and T-wave configuration. Acute myocardial ischemia causes a transient increase in R-wave amplitude, followed later by Q-wave appearance with loss of R-wave amplitude. Absence of S-waves in leads V1-V3 in the enrollment ECG of patients with anterior acute myocardial infarction is associated with increased mortality, larger final infarct size, higher rates of no-reflow or no ST resolution and less benefit from thrombolytic therapy. During thrombolytic therapy, S-waves in these leads may increase or decrease in size and even disappear. It is unclear whether decrease in S-wave amplitude is a marker of more severe ischemia and whether re-appearance of S-wave is a sign of reperfusion.

It is generally accepted that loss of R waves and appearance of new Q wave in the following days after AMI represent myocardial necrosis. However, during the first 48 hours of AMI a recovery of R wave and disappearance of new Q waves can be detected even in patients not undergoing reperfusion therapy. This phenomenon is usually confined to small AMIs.

4) Reperfusion arrhythmias

Clinical trials confirmed a 5 to 22% incidence of ventricular fibrillation or ventricular tachycardia during reperfusion in patients with AMI who were treated with thrombolysis. The mechanism of reperfusion tachyarrhythmias seems to be multofactorial. Although heterogeneous electrical activity of previously ischemic myocardium may create a milieu for reentrant tachyarrhythmias, the suppression of increased idioventricular rate in the reperfused tissue by overdrive atrial pacing indicates the role of enhanced automaticity.

The value of reperfusion arrhythmias as a marker of coronary artery patency is still debatable. Accelarated idioventricular rhythm, considered to be the most common reperfusion arrhythmia has a low predictive value for reperfusion.

DISCUSSION

The standard 12-lead EKG gives us crucial information concerning myocardial perfusion and the success of reperfusion therapy. Continuous monitoring has advantages over repeated snapshot recordings. Dynamic changes in the QRS complexes, ST-segments and T-waves occur during reperfusion therapy and the days after. While changes in ST-segment amplitude have been extensively studied, the significance of QRS-complex and T-wave changes are less clear, and especially whether changes in the QRS-complex and T-wave may be complementary and additive to ST-segment monitoring.

It has remained unclear whether EKG signs of reperfusion and re-ischemia can be used for therapeutic decision-making in the clinical setting. For example:

1) The AHA/ACC guidelines for acute myocardial infarction states that class I indications for thrombolysis are: ST elevation (> 0.1 mV, ≥2 contiguous leads), time to therapy <12 hours or less, and history suggesting AMI. Do we need to give reperfusion therapy for patients with ST elevation but with EKG evidence of reperfusion (≥50% reduction in ST elevation compared with EKG done earlier after initiation of symptoms? This question could be extended to patients admitted with ST elevation, but with negative T-waves in whom pain subsided before initiation of therapy (with or without administration of narcotics) and there is no previous EKG to verify whether ≥50% ST resolution has occurred before admission. Should infusion of thrombolytic agent be stopped immediately after ST resolution had occurred, or should infusion be completed according to the recommended protocol?

2)   Do we need to routinely refer patients with less than complete ST elevation resolution and/or T-wave inversion to rescue angiography and PCI? There are no data showing that rescue PCI at 90 minutes or more after initiation of thrombolytic therapy without complete ST resolution changes clinical endpoints.

3)   Will newer thrombolytic agents and/or combination of thrombolytics and glycoprotein IIb/IIIa inhibitors result in more complete ST resolution and T-wave inversion than the current available therapy? Should we add glycoprotein IIb/IIIa inhibitors to patients who do not show complete electrocardiographic signs of reperfusion?

4)   Should patients with asymptomatic ST re-elevation after initial resolution or abrupt T-wave normalization during the first few hours or even days after reperfusion therapy be referred for coronary angiography with a suspicion of infarct related artery reocclusion?

All these questions should be answered in prospective clinical trials in order to improve our understanding of the EKG changes early after AMI and to improve patient care, using an inexpensive and widely available ancillary tool- the electrocardiogram.

REFERENCES

 [1] M. Vaturi, Y. Birnbaum. “The use of the electrocardiogram to identify epicardial coronary and tissue reperfusion in acute myocardial infarction”. Journal of Thrombosis and Thrombolysis. Vol. 10, pp. 137-147; 2000.