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Classification and Diagnosis of Acute Coronary Syndromes
Introduction
Until the beginning of 20th century, it was believed that coronary thrombosis was always immediately fatal. In 1910, two Ukrainian physicians described five patients with acute myocardial infarction (MI), in whom three were found to have coronary thrombosis at autopsy. In 1912, James Herrick articulated the first clear description in English of the clinical syndrome of acute MI in his landmark article, “Certain Clinical Features of Sudden Obstruction of the Coronary Arteries.” Up to that time, although pathologists had made causal connections between thrombotic coronary occlusion and degenerative changes in the myocardium, a clinical syndrome of MI in surviving patients had not been described. The term acute coronary syndrome (ACS) that emerged more than eight decades later is now used to denote any clinical presentation suggestive of acute myocardial ischemia caused by unstable ischemic heart disease. ACS encompasses both unstable angina (UA) and acute MI, in distinction from chronic stable angina. In addition, some clinicians have adapted use of the term ACS to imply acute coronary atherothrombosis, which is differentiated from ischemia caused by increased myocardial oxygen demand in the presence of stable coronary atherosclerotic lesions.
Over the past century, the classification of ACS, its epidemiology, and our understanding of its pathobiology have evolved considerably. The epidemiology and natural history of MI are reviewed in Chapter 2 . The pathobiology of ACS is discussed in Chapter 3 . Both a historical perspective and a summary of emerging concepts regarding mechanisms of myocardial ischemic injury and healing are provided in Chapter 4 . Chapter 7 details the role of cardiac biomarkers of necrosis in the diagnosis of acute MI. In this chapter, we describe the evolution of the clinical classification of ACS, including UA, non–ST-elevation MI (NSTEMI), ST-elevation MI (STEMI), and the additional subclassification of the types of MI as defined in the section on Universal Definition of Myocardial Infarction. This chapter reflects our opinion that in the era of high-sensitivity assays for cardiac troponin (cTn), UA is a disappearing diagnostic entity.
Spectrum of Unstable Ischemic Heart Disease
Stable ischemic heart disease (SIHD) is most commonly caused by atheromatous plaque that obstructs or gradually narrows one or more of the epicardial coronary arteries. Although the clinical manifestations of SIHD are variable, stable angina induced by increased effort, as classically described by Heberden in 1772, is typically the predominant symptom. UA is characterized by an accelerated pattern of increasing frequency and tempo of angina or angina at rest in the absence of MI. MI is defined by evidence of myocardial necrosis in a clinical setting consistent with acute myocardial ischemia. Because of the implications for treatment, including reperfusion therapy, MI is classified clinically into those cases in which the clinical presentation includes ST-segment elevation in 2 contiguous leads on the 12-lead electrocardiogram (ECG) and those cases without ST-elevation at presentation, which are designated as NSTEMI. Moreover, because of their indistinguishable clinical and electrocardiographic features (ST-segment depressions and T-wave inversion) and similar management, patients with UA and NSTEMI are commonly grouped together by the term non–ST-elevation ACS (NSTE-ACS) ( Figure 1-1 ; also see the section on Clinical Classification: Electrocardiography ).
A nomenclature that incorporates the development of pathological Q waves (Q-wave MI) versus their absence (non–Q-wave MI) on the surface ECG is no longer deemed useful as part of initial management of acute MI; however, the presence of Q waves should be recognized as indicative of late presentation of a large MI. In addition to the categories already described, MI can be classified into various types, based on pathological, clinical, and prognostic differences, along with different treatment strategies (see the section on Clinical Classification ).
Unstable Angina: A Historical Perspective
In the days of Herrick’s original clinical description of MI, MI and angina were beginning to be recognized as manifestations of the same underlying disease process. Nevertheless, the conclusions by Russian physicians Obrastzow and Straschesko that “the differential diagnosis of coronary thrombosis from angina pectoris is made by the presence of status angiosus with coronary thrombosis and its absence with isolated attacks of angina pectoris ” reflected the prevailing view at the time that these two diagnoses were quite distinct. This distinction began to blur by 1937, when Sampson and Eliaser and Feil each described several patients with prolonged chest discomfort at rest that differed from stable angina, and appeared sometimes to precede an acute MI. This pattern of symptoms was variously referred to as “pre-infarction angina” or “crescendo angina.” In 1948, Wood proposed that this “intermediate coronary syndrome” between stable angina and MI was caused by “a coronary circulation insufficient to meet the full demands at rest yet sufficient to prevent MI.” He recognized that, just as for acute MI, coronary thrombosis could be playing a role in this coronary insufficiency. Moreover, he observed that MI or death occurred in 12 of 25 patients with this intermediate coronary syndrome, whereas among 33 patients with the same syndrome whom he treated with oral anticoagulants, only 3 patients died or had an MI. It was nearly 25 years later, in 1971, that Fowler and colleagues introduced the term “unstable angina.”
At first, UA was considered to be quite rare, and as late as the 1950s, some experts even questioned its existence. Friedberg, in the leading cardiology textbook at the time, described these patients as “a motley group,” which he recommended should be “best classified clinically as angina pectoris (more or less severe or prolonged) or as MI.” Despite this debate, in the era predating the development of high-sensitivity assays for cTn, it appeared that UA was common. In 1991, the National Center for Health Statistics reported that UA was responsible for 570,000 hospitalizations annually in the United States, making UA one of the most common reasons for hospital admission.
In 1994, in the first published guidelines on its diagnosis and management, UA was defined as “a clinical syndrome falling between stable angina and MI.” Three principal clinical presentations were considered to be typical of UA: (1) angina at rest; (2) new onset of severe exertional angina; and (3) distinct, often sudden, intensification of previously stable angina. Any one of these, in the absence of an acute MI (see the section on Diagnosis of Myocardial Infarction ), was the basis for a diagnosis of UA. UA could be further classified according to its severity, the clinical circumstances in which it occurred, and the presence or absence of electrocardiographic ST-segment deviations ( Table 1-1 ).
TABLE 1-1
Original Braunwald Classification of Unstable Angina
Adapted from Braunwald E: Unstable angina—a classification. Circulation 80:410–414, 1989.
| Severity | Clinical Circumstances | |||
|---|---|---|---|---|
| A | B | C | ||
| Develops in Presence of Extracardiac Condition that Intensifies Myocardial Ischemia (secondary UA) | Develops in the Absence of Extracardiac Condition (primary UA) | Develops within 2 wks after Acute Myocardial Infarction (postinfarction UA) | ||
| I | New onset of severe angina or accelerated angina; no pain at rest | IA | IB | IC |
| II | Angina at rest within past month but not within preceding 48 hr (angina at rest, subacute) | IIA | IIB | IIC |
| III | Angina at rest within 48 hr (angina at rest, acute) | IIIA | IIIB Troponin negative IIIB Troponin positive ∗ |
IIIC |
UA , Unstable angina.
∗ Now defined as myocardial infarction if cardiac troponin is more than the 99th percentile upper reference limit.
By the beginning of the 21st century, UA was firmly established as one possible manifestation of ACS; however, ambiguity had begun to creep into its definition. As an example, the World Health Organization revision of the definition of MI in 2008 to 2009 characterized UA as “new or worsening symptoms of ischemia (or changing symptom pattern) and ischemic ECG changes…with normal biomarkers,” but noted that the “distinction between new angina, worsening angina and unstable angina is notoriously difficult and based on a clinical assessment and a careful and full clinical history.” At the same time, the increasing analytical sensitivity of assays for cTn decreased the proportion of patients with ACS with “normal biomarkers” (see the section on Biomarkers of Myocyte Necrosis ), resulting instead in the diagnosis of MI.
Diagnosis of Myocardial Infarction
In 1971, the World Health Organization proposed that the diagnosis of MI required the presence of at least two of the following: (1) typical symptoms; (2) a typical ECG pattern involving the development of Q waves; and (3) an initial rise and subsequent fall in serum and/or plasma biomarkers of myocardial necrosis. Patients with similar clinical manifestations of myocardial ischemia as UA, but who exhibited a typical pattern of a rise to abnormally elevated level(s) and subsequent fall in serum biomarkers of necrosis were diagnosed with MI. Subsequently, the emergence of both more sensitive and specific serologic biomarkers of myocardial necrosis and precise imaging techniques prompted a reevaluation of this definition of MI. This effort resulted in an evolution of the definition of MI that placed greater emphasis on the detection of ischemic myocardial necrosis, either with sensitive biomarkers or with cardiac imaging.
In 2000, the First Global MI Task Force, which was a collaborative joint committee of the European Society of Cardiology and the American College of Cardiology, articulated a new definition of MI that was founded on the principle that “any amount of myocardial necrosis caused by ischemia should be labeled as a [myocardial] infarct.” In addition, this joint committee confirmed previous guidelines that established the 99th percentile in the distribution of cTn in an apparently healthy population as the upper reference limit (URL) for diagnosis of myocardial injury (see Chapter 7 ). The task force also recognized that as a consequence of this fundamental premise “an individual who was formerly diagnosed as having severe, stable or unstable angina pectoris might be diagnosed today with a small MI.” These principles were refined by the Second Global MI Task Force in 2007, leading to the Universal Definition of Myocardial Infarction, which included a clinical classification of MI that placed emphasis on differentiating the various conditions that might lead to an MI (see the section on Clinical Classification of Myocardial Infarction ). Subsequently, the 2012 Third Universal Definition of Myocardial Infarction responded to the development of even more sensitive assays for markers of myocardial necrosis.
The Third Universal Definition of Myocardial Infarction formulated by the European Society of Cardiology, the American College of Cardiology, the American Heart Association, and the World Heart Federation recommends that patients who are suspected on clinical grounds of having ACS should undergo serial sampling for cTn. An MI is defined by a typical rise and/or fall of cTn, with at least one value above the assay’s URL, accompanied by at least one other feature of ischemia (e.g., typical symptoms or ECG changes) ( Table 1-2 ).
TABLE 1-2
Criteria for Acute Myocardial Infarction
From Thygesen K, Alpert JS, Jaffe AS, et al: Third universal definition of myocardial infarction. J Am Coll Cardiol 60:1581,2012.
The term acute myocardial infarction (MI) should be used when there is evidence of myocardial necrosis in a clinical setting consistent with myocardial ischemia. Under these conditions any one of the following criteria meets the diagnosis for MI:
MI in specific settings:
|
Biomarkers of Myocyte Necrosis
Contemporary assays for cTn, their related important analytical considerations, and their clinical use in the evaluation of patients with suspected MI are discussed in Chapter 7 . This development of progressively more sensitive and precise biomarkers of myocardial necrosis has changed the epidemiology of MI. In the 1980s and 1990s, the myocardial band fraction of creatine kinase (CK-MB) was deemed to be the most sensitive and specific biomarker. Because serial determinations of CK-MB were not part of routine practice at the time in patients with NSTE-ACS, NSTEMI was not adequately excluded in many patients who were given a final diagnosis of UA. Therefore, the high incidence of UA reported in 1991 was likely an overestimate.
The differentiation between UA and NSTEMI has proven to be of considerable prognostic importance. First demonstrated with CK-MB, and subsequently refined with cTn, patients with unstable ischemic symptoms and biomarker evidence of myocardial necrosis (i.e., NSTEMI) are at significantly higher risk of death or recurrent ischemic events compared with patients presenting with UA, in whom, by definition, biomarkers of necrosis are not elevated (see Chapter 11 ).
Although, in the 1970s and 1980s, CK-MB was superior to previously available enzymes used as biomarkers of necrosis (total creatine kinase, aspartate aminotransferase, and alanine aminotransferase), it lacked optimal sensitivity and specificity. In 1987, Cummins and colleagues introduced an assay for cardiac-specific troponin I (cTnI), and shortly thereafter, Katus and colleagues developed an analogous assay for cardiac-specific troponin T (cTnT). Troponin I and T are components of the troponin regulatory complex that is bound to actin and modulates the interaction between actin and myosin in myocytes. In contrast to CK-MB, troponin I and T have cardiac isoforms (cTnI and cTnT) that are unique to cardiac myocytes and may be measured by assays that use monoclonal antibodies specific to epitopes of the cardiac form. Because of this greater tissue specificity, cTn allows detection of a faint signal of release from cardiac myocytes against minimal background noise in the circulation, and delivers considerably higher sensitivity and specificity than CK-MB. For example, in the TIMI 3 trial, 25% of the patients classified with UA, based on the absence of abnormally elevated concentrations of CK-MB, had cTnI ≥0.4 ng/ml (the cutpoint of a relatively insensitive assay from the mid-1990s), and therefore, should be reclassified as having had an NSTEMI. Thus, in retrospect, patients with UA made up a smaller percentage of patients with NSTE-ACS than had previously been believed.
Like the earlier classification of ACS patients based on CK-MB, this second wave of reclassification also appeared to be clinically important. Among patients with normal CK-MB, patients with elevated cTn were at higher risk of adverse cardiac events than those without such elevations. In the TIMI 11B trial, we observed a six-fold increase in death or new MI in patients with normal CK-MB who had elevated cTnI compared with patients without such an elevation. The clinical relevance of such reclassification with cTn was reinforced by evidence that patients with ACS who had elevated cTn benefited more from newer therapies than did patients in whom cTn was not detectable. These therapies included an early invasive strategy (see Chapter 16 ), the addition of platelet glycoprotein IIb/IIIa inhibitors (see Chapter 19 ), and treatment with a low–molecular-weight heparin rather than unfractionated heparin (see Chapter 18 ).
Two critical trends in the clinical applications of cTn have since ushered in what we view as a third wave of reclassification of ACS: (1) a move to lower diagnostic cutoffs for cTn; and (2) progressive improvement in the analytical precision of assays for cTn that has further lowered diagnostic and prognostic decision limits. At initial approval for clinical use, manufacturer-recommended cutpoints for cTn originated from comparative studies with CK-MB. However, this approach was flawed because the derived cutpoints were based on a comparison with a less sensitive test. For this reason, in 1999, laboratory professional guidelines recommended an additional lower cutpoint based on the distribution of cTn in a healthy reference population. This approach of defining an upper limit of normal at the 97.5th or 99th percentile of a reference population is the method used to establish cutpoints for many clinical laboratory tests. In 2000, cardiology and laboratory professional guidelines endorsed a single cutpoint for diagnosis of MI at the 99th percentile URL for each assay (see Chapter 7 ).
However, more than 10 years after publication of the first Universal Definition of Myocardial Infarction, many laboratories have continued to report an inconclusive or suggestive range using two cTn cutpoints based on the outdated initial proposal from laboratory guidelines and some package inserts. This practice is no longer consistent with present guidelines.
The progressive improvement in analytical precision of assays for cTn during the past 25 years had driven both the limit of detection and the URL downwards. This trend is illustrated by the data from clinical studies that revealed the proportion of patients with NSTE-ACS with a positive cTn result, and hence, a diagnosis of NSTEMI. In 1996, in the TIMI 3 trial, 25% of patients with UA had elevated cTnI (≥0.4 ng/mL). A decade later, in NSTE-ACS patients enrolled into the MERLIN-TIMI 36 trial, which used a widely available current generation sensitive assay for cTnI (URL 0.04 ng/mL), we observed that 65% of patients with NSTE-ACS had a positive cTnI result, approximately 50% of whom would not have been identified with CK-MB. Importantly, the subgroup of patients who had low-level elevations in cTnI that would not have been detected with the previous generation cTn assay turned out to be at similar heightened risk of death or recurrent ischemic events. Using the earlier assay, these patients did not have detectable elevations of cTn and would therefore have been considered to have UA, but were later classified as NSTEMI and were found to have a commensurately increased risk.
With yet another decade of evolution, high-sensitivity assays with improved analytical precision have progressively lowered the URL and enabled detection limits as low as 0.0002 ng/ml (0.2 ng/L) with consequent detection of cTn above the URL in 82% to 99% of patients with putative UA; again, data demonstrate a graded rise in the rate of adverse outcomes. Such clinical studies have established that most patients with clinical manifestations of myocardial ischemia, with pain at rest, but without elevated cTnI by a previous generation assay, have detectable dynamic concentrations of circulating cTnI measured by a high-sensitivity assay, and therefore, would be reclassified from UA to NSTEMI. Clinically, there is a need to distinguish acute increases in cTn that occur in MI from chronic, relatively stable, low-level concentrations that can exist in patients with SIHD or other structural heart disease, but which are not necessarily indicative of ACS (see Chapter 7, Table 7-2 ).
Classication of Myocardial Infarction
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