European Heart Journal

European Heart Journal Advance Access originally published online on March 16, 2006
European Heart Journal 2006 27(8):901-904; doi:10.1093/eurheartj/ehi829

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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Aborted myocardial infarction: a new target for reperfusion therapy

Freek W.A. Verheugt^1,*, Bernard J. Gersh² and Paul W. Armstrong³

¹Heartcenter, Department of Cardiology, University Medical Center, St Radboud, Nijmegen, The Netherlands
²Cardiovascular Diseases and Internal Medicine, Mayo Clinic and Mayo Foundation, Rochester, MN, USA
³Division of Cardiology, University of Alberta, Edmonton, Canada

Received 3 November 2005; revised 9 February 2006; accepted 16 February 2006; online publish-ahead-of-print 16 March 2006.

^* Corresponding author. Tel: +31 24 3614220; fax: +31 24 3540537. E-mail address: f.verheugt{at}cardio.umcn.nl

Abstract

Reperfusion therapy for ST-elevation acute coronary syndromes aims at early and complete recanalization of the infarct-related artery in order to salvage myocardium and improve both early and late clinical outcomes. Myocardial necrosis is usually confirmed and quantified by myocardial enzyme release in plasma. However, over 10% of patients treated with reperfusion therapy fail to develop an enzyme rise, but do exhibit transient ECG changes, which are consistent with an aborted myocardial infarction. The earlier the reperfusion therapy is instituted, the higher the incidence of aborted infarction. Treatment within an hour after symptom onset may result in 25% of aborted infarction and is in combination with complete (70%) ST-segment resolution associated with better survival. This endpoint is easy to define and occurs promptly in time. The faster that effective treatment is initiated, the more likely aborted infarction will occur. Given that mortality, re-infarction, and stroke are declining in incidence, we suggest the introduction of aborted infarction as an endpoint in clinical trials of ST-elevation acute coronary syndromes.

Key Words: Myocardial infarction • Reperfusion therapy • Creatine kinase • Abortion

Introduction

Reperfusion therapy has become the indisputable gold standard for the early management of acute ST-segment elevation coronary syndromes. The benefit of this strategy rises exponentially, if the therapy is initiated earlier. The highest number of lives saved by reperfusion therapy is within the first hour after symptom onset: thus, creating a window of opportunity aptly termed the golden hour.¹ Clearly and logically, the mechanism of this benefit relates to maximizing myocardial salvage by early restoration of adequate coronary blood flow, resulting in preservation of left ventricular function, thereby enhancing both early and long-term survival.

According to the principle of the infarct wave front initially postulated by Reimer et al.,² a brief interruption of blood flow is associated with a small infarct size. The temporal dependence of the beneficial effect of coronary reperfusion has also been characterized by multiple metrics including positron emission tomography.³ Irrespective of the methodology, however, the relationship between duration of symptoms and infarct size remains consistent.

The exponential form of the curve illustrating the benefit of reperfusion therapy upon mortality and myocardial salvage has major implications for the timing of treatment. The impact of delay in time to treatment lessens as the duration of ischaemia lengthens. Consequently, reducing delays will have a much more positive return in patients presenting early than those presenting late.⁴ These considerations have provided strong incentive for the initiation of very early reperfusion therapy including the use of pre-hospital fibrinolysis.⁵

Pre-hospital and early in-hospital reperfusion therapy

In 1985, Gotsman and co-workers⁶ implemented pre-hospital triage and treatment of patients with ST-segment elevation myocardial infarction in Jerusalem, Israel. They demonstrated the presence of minimal myocardial damage after the early administration of streptokinase. Nine years later, in a larger and randomized study, pre-hospital treatment resulted in significantly less Q-wave infarctions, which may be correlated with a greater number of smaller infarctions.⁷ The same trial also demonstrated accelerated and more extensive ST-segment resolution with pre-hospital treatment, suggesting enhanced myocardial perfusion.⁸ Subsequently, the large In-TIME-2 study demonstrated that with each additional hour of symptom onset to the start of fibrinolytic reperfusion therapy, the likelihood of achieving complete (>70%) ST-segment resolution decreases by 6%.⁹ In an ASSENT-2 substudy, including 13 100 patients, the earlier lytic therapy was initiated if the likelihood of ST-segment resolution on the ECG is higher. Moreover, earlier therapy was inversely related to 1-year mortality.¹⁰

Hence, the ultimate objective of reperfusion therapy is early and effective treatment, which limits or even averts clinically detectable myocardial necrosis, resulting in aborted myocardial infarction, a term first used by Weaver when reporting the pre-hospital MITI trial.¹¹

Pathophysiology of aborted myocardial infarction

Abortion of myocardial infarction is thought to follow rapid early reperfusion of a thrombotic occlusion of an epicardial coronary artery such that myocardial necrosis cannot be detected by classical plasma enzyme analyses. However, aborted infarction may also occur in the absence of reperfusion as a spontaneous variant of ‘stuttering’ infarction.¹² It has been postulated that in some patients with suspected ST-segment elevation acute coronary syndromes, there is a subtle balance between coronary thrombosis and endogenous fibrinolysis, sometimes modulated by vasoconstriction, resulting in intermittent occlusion and spontaneous reperfusion. Yet, reperfusion therapy in such patients may be warranted. In prior studies, aborted infarction was strongly related to a shorter time-to-fibrinolytic,^13,14 despite the fact that other baseline characteristics and the number of diseased coronary vessels appeared to be similar to that in patients with an overt myocardial infarction.^15,16

Definition, diagnosis, and incidence of aborted myocardial infarction

Aborted myocardial infarction is defined by major, i.e. over 50%, ST-segment resolution of the initial ST-segment elevation on the presenting ECG indicative of transmural myocardial ischaemia and a lack of a subsequent enzyme rise more than twice the upper normal limit of creatine kinase.^13,14 In prior studies addressing the issue, CK-MB was not used in the diagnosis. Aborted infarction has been observed in 13–17% of patients after fibrinolysis.^13,14,16 This rises to 25% of patients treated within 1 h after symptom onset¹³ (Figure 1). Pre-hospital initiation of fibrinolysis results in a four-fold higher rate of aborted infarction than in-hospital fibrinolysis.¹⁶ The rate of aborted infarction after primary angioplasty is unknown. Angioplasty early after symptom onset is also presumed to lead to abortion of infarction in many cases, but this has not been studied systematically. Myocardial salvage after primary angioplasty has been extensively evaluated in the STOPAMI studies^17–19 using myocardial perfusion scintigraphy before and after intervention, which method, however, is distinctively different from myocardial enzyme release studies. Furthermore, a time interval from symptom onset to balloon inflation within 2 h, the golden window for myocardial salvage,⁴ was only achieved in very few patients in those studies. Finally, it is possible that primary angioplasty, especially if it is performed early, may result in distal embolization of atherothrombotic material sufficient to cause significant enzyme rise precluding a diagnosis of abortion of myocardial infarction.

View larger version (27K): [in this window] [in a new window]   Figure 1 Relationship between time to fibrinolytic therapy for acute ST-elevation myocardial infarction and the incidence of aborted myocardial infarction.13 With permission of the author. Reprinted from J Am Coll Cardiol, 44, Taher T, Fu Y, Wagner GS, Goodman SG, Fresco C, Granger CB, Wallentin L, Van de Werf F, Verheugt F, Armstrong PW. Aborted myocardial infarction in patients with ST-segment elevation: insights from the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen-3 Trial Electrocardiographic Substudy, pp. 38–43, 2004, with permission from the American College of Cardiology Foundation.

 
It is uncertain whether the use of the troponins as a more sensitive marker of myocardial necrosis may change the definition of aborted infarction. The studies on aborted infarction originate from a time period when troponin measurements were not included in the trial designs. Moreover, even in the present era, troponin levels are not routinely used as a risk stratifier in ST-segment elevation acute coronary syndromes, as they are in non-ST-segment elevation coronary syndromes.

Not all patients with presumed ST-segment elevation myocardial infarction without significant rise of cardiac enzymes have subsequent evolutionary ECG changes during or after lytic treatment. This leads to a potentially false diagnosis of aborted myocardial infarction (masquerading myocardial infarction) and occurs in 2% of patients treated with fibrinolysis.¹³ Thus, the lack of an enzyme rise does not necessarily indicate aborted myocardial infarction: the evolutionary ECG changes at presentation should be compared with subsequent ECGs made during and after treatment and are an essential component of the diagnosis. The most common differential diagnoses of patients with masquerading myocardial infarction are given in Table 1.

View this table: [in this window] [in a new window]   Table 1 Differential diagnoses of chest pain with persistent ST-segment elevation without significant CK enzyme rise (masquerading myocardial infarction)

 
The differentiation from aborted myocardial infarction is important. If patients with masquerading myocardial infarction have been treated with fibrinolytic therapy, treatment must be classified as inappropriate fibrinolysis: a judgment that can only be made retrospectively after serial enzyme measurements and serial ECGs. Inappropriate fibrinolysis may result in unnecessary bleeding and, in the case of therapy with non-fibrin-specific lytics, allergic reactions. Inappropriate fibrinolytic therapy has been previously documented.²⁰ On the basis of anecdotal observations from large trials, the frequency of masquerading infarction is between 1 and 3% and occurs in both the pre-hospital and in-hospital settings irrespective of the use of computer diagnosis.²⁰ The most dramatic complication of lytic therapy for masquerading myocardial infarction may occur in the setting of aortic dissection. In the large ASSET trial, inappropriate lytic therapy in the case of dissecting aortic aneurysm resulted in a 6-month mortality (6/11 or 54%) than in patients treated with placebo (3/9 or 33%).²¹

One of the major advantages of primary angioplasty for ST-segment elevation acute coronary syndromes is the immediate angiographic diagnosis of coronary occlusion and, thus, can accurately and quickly differentiates between masquerading and true acute myocardial infarction. Other imaging techniques for the diagnosis of aborted myocardial infarction and differential diagnosis of masquerading infarction have not been tested, but will likely yield additional insights.

Subsequent treatment of aborted myocardial infarction

In evaluating aborted myocardial infarction, it is relevant to ascertain the magnitude of the myocardial territory at risk. The discrepancy of the extent of the initial ST-segment elevation, on one hand, and the lack of myocardial enzyme rise, on the other, point to the likelihood of myocardial viability in the ischaemic zone after reperfusion therapy. This in turn might increase the frequency of ‘recurrent’ myocardial infarction. Nonetheless, this has not been substantiated by an analysis of the 727 aborted infarctions from the ASSENT-3 trial, which did not demonstrate a higher risk of recurrent infarction at 30 days in patients with an aborted infarction.¹³ Only those with >70% ST-segment resolution at 60 min needed more non-urgent angioplasty and tended to have more recurrent infarction than those who had aborted infarctions but with <70% ST-segment resolution. In two smaller analyses of aborted myocardial infarction, recurrent infarction was more common, but overall the 1-year prognosis of aborted myocardial infarction was excellent.^14,16 Also in the ASSENT-3 trial patients with aborted myocardial infarction, long-term mortality was 30% lower than that with established myocardial infarction after correction for baseline differences.¹³ In a subset of 300 patients (<5%), who had aborted infarction ánd >70% ST-segment resolution, 1-year mortality was very low, i.e. 2.7%.

It is currently uncertain as to how to best approach patients with aborted myocardial infarction. A strong case for coronary angiography with a view to coronary intervention seems intuitive,¹⁶ especially if there is a large initial territory at risk. Failure to intervene could attenuate the initial prognostic benefit. This is supported by the new European Society of Cardiology guidelines on percutaneous coronary intervention, which advocate early angiography following successful lytic therapy for ST-segment elevation acute coronary syndromes.²² Future strategies aimed at optimizing pre- and post-discharge management and defining indications for coronary revascularization in patients with aborted myocardial infarction are worthy of study.

Aborted myocardial infarction as a novel therapeutic target

The ultimate goal in reperfusion therapy is early and effective treatment that actually averts myocardial infarction: i.e. aborted myocardial infarction. The premise is pathophysiologically sound and the outcomes are logical and clinically satisfying. As future trials are designed to evaluate treatment of ST-segment elevation myocardial infarction, it is appreciated that the traditional endpoints of mortality and re-infarction are declining in incidence. Although aborted infarction has never been prospectively studied, it can be defined very early in time and with reasonable frequency. Hence, we propose that its prognostic relevance be validated prospectively with the intent that it could be ultimately included as a meaningful endpoint and therapeutic target in future studies.

Conflict of interest: none declared.

Footnotes

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

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