CHAPTER 36: DEFINITIONS OF ACUTE CORONARY SYNDROMES

Coronary artery disease (CAD) accounts for 30% of all global deaths, representing the single most common cause of adult mortality and equivalent to the combined number of deaths caused by nutritional deficiencies, infectious diseases, and maternal/perinatal complications.^1,2 Recent growth in the global burden of cardiovascular disease (CVD) is primary attributable to the rising incidence across low- and middle-income countries.³ Among European member states of the World Health Organization (WHO), for example, CVD death rates for men and women were highest in the Russian Federation and Uzbekistan, respectively, whereas risk was lowest in France and Israel.⁴ Conversely, in the United States, over 15 million Americans, or 6.2% of the adult population, have coronary heart disease (CHD), with a myocardial infarction (MI) occurring once every 43 seconds.⁵ Health care resource utilization as a result of CHD is significant, as over 1.1 million hospital discharges in 2010 listed MI or unstable angina (UA) as a primary or secondary diagnosis.⁵ Health care expenditures are also substantial; costs for MI and CHD were approximately $11 billion and $10 billion, respectively, in 2011.⁶ These diagnoses constitute two of the most expensive discharge diagnoses and are expected to increase by 100% by 2030.

Despite these sobering statistics, important strides in the diagnosis, prevention, and management of CHD have occurred over the past 50 years. In the United States, for example, several population-based studies have shown a reduction in both the incidence and case fatality rate associated with MI.^7,8 These favorable trends have been attributed to greater utilization of evidence-based therapies and improvements in control and burden of risk factors.⁹ Concordant changes in the epidemiology of acute coronary syndromes (ACS) have occurred over the past 10 years as a result of changing demographics and updated definitions of MI. In this chapter, we focus primarily on the definition and diagnostic criteria for ACS.

The term ACS is a unifying construct representing a pathophysiologic and clinical spectrum culminating in acute myocardial ischemia. This is usually, but not always, caused by atherosclerotic plaque rupture, fissuring, erosion, or a combination with superimposed intracoronary thrombosis and is associated with an increased risk of myonecrosis and cardiac death.¹⁰ ACS encompasses UA and ST-segment elevation MI (STEMI) or acute non–ST-segment elevation MI (NSTEMI). Distinguishing these presentations is predicated on the presence or absence of myocyte necrosis coupled with the electrocardiographic tracing at the time of symptoms. ACS without myocardial necrosis is defined as UA, whereas myocardial necrosis is a necessary, but not sufficient, component of either STEMI or NSTEMI, respectively. Recognizing a patient with ACS is important because the diagnosis triggers both triage and management. Those deemed to have an ACS in the emergency department should be triaged immediately to an area with continuous electrocardiographic monitoring and defibrillation capability. Patients with suspected ACS should be managed immediately with antiplatelet and anticoagulant therapies and considered for immediate mechanical or pharmacologic revascularization if new ST-segment elevation is noted.¹¹

The diagnosis of ACS relies on integrating clinical information from the patient history with the initial electrocardiogram (ECG) and laboratory results. In the initial hours after presentation, distinguishing between STEMI, NSTEMI, and UA may be difficult, because biomarkers of myonecrosis can initially be normal. However, as a result of the life-threatening nature of ACS, it is prudent to have a low threshold in suspecting this diagnosis, and therefore, diagnostic sensitivity is usually favored over specificity. Additional details surrounding the pathophysiology and diagnosis of ACS are provided in Chap. 37.

Initial triage of patients suspected of having acute coronary ischemia should identify patients as having (1) ACS; (2) a non-ACS cardiovascular condition such as myocarditis/myopericarditis, stress-related cardiomyopathy, aortic dissection, or pulmonary embolism; (3) a noncardiac cause of chest pain such as gastroesophageal reflux; or (4) a noncardiac condition that is yet undefined, such as sepsis.¹² ACS patients with new ST-segment elevation on the presenting ECG are labeled as having STEMI and should be considered for immediate reperfusion therapy by thrombolytics or percutaneous coronary intervention (PCI); those without ST-segment elevation but with evidence of myonecrosis are deemed to have an NSTEMI; and those without any evidence of myonecrosis are diagnosed with UA (Fig. 36–1). Further details on the management of different types of ACS are provided in Chaps. 39, 40, 41.

Unstable Angina

UA is usually secondary to abrupt reduction in myocardial perfusion as a result of nonocclusive coronary thrombosis. In this event, however, the nonocclusive thrombus that developed on a disrupted atherosclerotic plaque does not result in biochemical evidence of myocardial necrosis. Accordingly, UA and NSTEMI can be viewed as very closely related clinical conditions with similar presentations and pathogenesis but variable clinical severity. Nevertheless, given the increased reliance on highly sensitive biomarkers of myocyte necrosis, the incidence of troponin-negative ACS or UA is decreasing.¹³ This shift in ACS epidemiology was illustrated in a report from the US Nationwide Inpatient Sample, which demonstrated an 87% decline in the prevalence of UA between 1998 and 2001 but an increase in NSTEMI.¹⁴

As a result of the lack of objective criteria used to define this condition, UA must be diagnosed from the clinical history and is thus the most subjective of the ACS diagnoses. There are three principal clinical presentations of UA: (1) rest angina or angina with minimal exertion usually lasting at least 20 minutes; (2) new-onset severe angina (Canadian Cardiovascular Society grade III or higher; Table 36–1); and (3) crescendo angina, defined as previously diagnosed angina that has become distinctly more frequent, precipitated by less severe degrees of exertion, or more severe.^15,16 Despite a clear and consistent definition for UA, the subjective nature of these criteria may compromise diagnostic accuracy, thereby leading to misclassification. In one report, for example, 20% of patients diagnosed with UA and referred for coronary angiography did not have any angiographically apparent obstructive epicardial CAD.¹⁷

Non–ST-Segment Elevation Myocardial Infarction

For many years, the diagnosis of an acute MI was defined by the WHO based on two of the following three criteria: (1) typical ischemic chest pain; (2) typical ECG pattern including the development of Q waves; and (3) typical rise and fall in serum markers of myocardial injury, usually creatine kinase myocardial band (CK-MB).¹⁸ If the patient did not have ST-segment elevation or Q waves and the CK-MB was elevated, the patient was diagnosed with an NSTEMI. Patients with acute ischemic chest pain without ST-segment elevation or Q waves and who had negative CK-MB levels were classified as having UA.

With the introduction of serum troponin levels, which were much more sensitive and specific for myonecrosis than CK-MB levels, a joint European Society of Cardiology and American College of Cardiology committee in 2000 proposed the following definition of an acute, evolving, or recent MI: typical rise and gradual fall of serum troponin levels or a more rapid rise and fall of serum CK-MB levels in addition to presenting with ischemic symptoms, development of pathologic Q waves on ECG, ST-segment changes indicative of ischemia, or coronary artery intervention (eg, PCI).¹⁹ This has since been replaced with the currently accepted Universal Definition of MI, which relies on biomarker evidence of myocardial necrosis (preferably troponin), in the clinical context of myocardial ischemia.²⁰

Although greater use of troponin measurements has led to a reduction in the diagnosis of UA, an opposite trend has been observed with respect to the epidemiology of NSTEMI. Data from the National Registry of Myocardial Infarction demonstrate an increase in the proportion of patients diagnosed with NSTEMI, from 14% to 59% between 1990 and 2006⁷ (Fig. 36–2). This change occurred with a concordant increase in the proportion of patients in whom a troponin assay was performed, from 67% in 1998 to 96% in 2008.⁷ Nevertheless, the increasing incidence of NSTEMI was apparent before widespread use of troponin assays, suggesting that changes in population demographics or increasing use of preventive medications may also be contributory.^21,22

Non–ST-Segment Elevation Acute Coronary Syndrome Risk Stratification

As articulated by Braunwald et al²³ and subsequently embedded within clinical practice guidelines, the initial steps in the evaluation of patients presenting with chest pain is to first determine the likelihood of CAD as the underlying etiology followed by an assessment of short-term risk. With respect to the former, the following parameters (ranked in order of importance) are most strongly linked with CAD, representing the pathologic substrate for chest pain symptoms: nature of anginal symptoms, prior history of CAD, male sex, older age, and number of traditional risk factors (Table 36–2).^24,25 The need to accurately and rapidly triage chest pain patients into those with versus without symptomatic CAD is highlighted by the fact that although over 7 million patients present to the emergency department with chest pain annually, 20% to 25% are ultimately diagnosed with non–ST-segment elevation ACS (NSTE-ACS). Among those with noncardiac chest pain, the most common etiologies appear to be gastrointestinal, musculoskeletal, or psychiatric in nature.^26,27 As a result, the differential diagnosis for chest pain must incorporate noncardiac, vascular, and nonatherosclerotic coronary pathology. Focal coronary spasm or Prinzmetal angina, for example, is caused by exaggerated coronary vasomotor tone and/or endothelial dysfunction. In addition, patients with chronic stable CAD may present with chest pain as a result of noncoronary conditions that increase myocardial oxygen demand, such as fever or tachycardia, reduce coronary blood flow, or decrease myocardial oxygen content, such as hypoxemia or anemia. In such settings, the magnitude of ischemia might even result in myonecrosis, classified as type 2 MI according to the Universal Definition.

Once CAD has been established as the likely cause of chest pain, it is necessary to estimate, or stratify, risk for adverse events using qualitative or quantitative methods. As shown in Table 36–3, the tempo and severity of chest pain, extent of electrical abnormality, and magnitude of serum biomarker elevation all portend a higher risk for adverse events. Among these, biomarker evidence of myocyte necrosis is the strongest and most consistent correlate of risk. Quantitative risk scores provide an alternative and more precise approach to risk stratification. Perhaps the most widely used is the integer-based Thrombolysis in Myocardial Infarction (TIMI) risk score, which allots a single point for each of the following in patients with chest pain: age > 65 years; aspirin use within 7 days prior to presentation; ST-segment deviation > 0.5 mm; severe angina; at least three risk factors for CAD; raised cardiac biomarker; and known coronary stenosis.²⁸ Short-term risk of all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization within 14 days varied from 1.4% for patients with very low scores (0-1) to 40% for those with the highest scores. Other scores with a greater number of variables and computational complexity have been developed, some of which have online calculators to facilitate ease of use and point-of-care application, as shown in Table 36–4.²⁹ Not only do these scores provide important information on prognosis, but they also dictate clinical management. Patients at higher risk benefit more from aggressive interventions than those with lower scores. This allows for more rational and cost-effective allocation of health care resources. The importance of this principle is reflected in clinical practice guidelines, which provide a class I recommendation for the use of validated algorithms to stratify risk during the initial evaluation of patients presenting with chest pain.¹¹

Biomarkers of Myonecrosis

Serum biomarkers indicating myocardial injury and/or necrosis are critical elements in the diagnostic evaluation of a patient with presumed cardiac chest pain and are essential to distinguish between UA and overt infarction. Ideally, such biomarkers would be specific to cardiac muscle, absent from nonmyocardial tissue, released quickly into the peripheral blood after onset of injury, and reflect the magnitude of necrosis. Moreover, the marker should be easy to use, quick and inexpensive to measure, and stable in vitro. Historically, myoglobin, creatine kinase, and the cardiac-specific CK-MB isoform have served this purpose in the diagnosis of MI. The main limitation of these markers is the lack of cardiac specificity, as each may also be variably released from skeletal muscle and other tissues, such as the tongue, small intestine, uterus, and prostate. As a result, earlier definitions of MI did not require the presence of these cardiac biomarkers for diagnosis but rather considered their elevation along with clinical symptoms and electrical signs of myocardial ischemia.¹⁸

The introduction of monoclonal antibody–based immunoassays in the late 1980s and early 1990s capable of detecting cardiac-specific troponins (troponin I [TnI] and troponin T [TnT]) represented a major advance in the diagnostic armamentarium.^30,31 The troponin complex consists of three subunits that regulate contraction of cardiac muscle. TnI binds to actin and inhibits the actin-myosin interaction, whereas TnT binds to tropomyosin, which attaches the troponin complex to the thin filament. In the early phases of myocyte necrosis, troponin present in cytosolic pools is released rapidly into the bloodstream, whereas a more protracted release occurs over several days as actin is degraded.³² Because TnI and TnT are found only in myocardial tissue, elevated levels of either marker reflect myocyte injury and, therefore, represent the sine qua non of MI as articulated in the Universal Definition.²⁰

The approval and widespread availability of troponin assays in clinical practice has substantial implications for the classification, prognosis, and management of ACS patients. With respect to classification, several studies have shown that approximately 25% to 30% of patients diagnosed as having UA based on normal CK-MB levels manifest elevations in cardiac troponin (cTn), increasing the number of patients with NSTEMI at the expense of a diagnosis of UA.³³ Whether or not the diagnosis of UA will persist as a distinct clinical entity with the ongoing evolution of high-sensitivity cTn assays has been questioned¹³ and remains controversial.

From a prognostic perspective, cTns demonstrate a graded, dose-dependent association with increasing cardiovascular risk. Antman et al³³ illustrated this relationship in a post hoc analysis of a randomized trial evaluating various pharmacologic approaches in patients with ACS, demonstrating that unadjusted mortality at 42 days increased from 1.0% to 7.5% among those with the lowest versus highest levels of cTn. In addition, changes in cTn confer an independent and stronger impact on subsequent risk than clinical symptoms, ECG signs, or other biomarkers.³⁴

In terms of treatment, randomized trials have shown the beneficial impact of managing patients with elevated levels of cTn in an aggressive fashion using potent antiplatelet, anticoagulant, and invasive approaches. These findings form the foundation for current guideline recommendations that support the routine measurement of cTn in diagnostic and therapeutic algorithms for ACS patients. Similar findings were also reported in an observational study evaluating the impact of implementing a sensitive troponin assay on the classification and management of ACS patients in clinical practice.³⁵ In this study, lowering the diagnostic threshold for MI increased the frequency of diagnosis by 29%. In addition, patients diagnosed with MI under the more sensitive criteria were more likely to receive aggressive therapy, translating to a significant reduction in adverse events at 6 months. Given these benefits of assessing and formulating clinical decisions based on detecting cTn, the Universal Definition of MI considers this biomarker preferentially over CK-MB. In addition, American College of Cardiology/American Heart Association guidelines no longer consider the routine measurement of CK-MB as necessary for diagnosis of MI, providing a class III recommendation against routine use of this test.¹²

The advantages to cTn testing notwithstanding, as with any diagnostic test, gains in sensitivity occur at the expense of specificity. This paradigm also extends to measuring troponin and is particularly relevant given the iterative evolution of even more sensitive troponin assays. Several studies have shown that troponin elevations may occur in non-ACS clinical settings, such as heart failure, renal dysfunction, and pulmonary embolism. Troponin may even be detected in apparently healthy community-dwelling adults, as shown in the Dallas Heart Study.³⁶ In that report, investigators found the following clinical conditions independently associated with detectable levels of cTn: left ventricular hypertrophy, diabetes mellitus, chronic kidney disease, and heart failure. Newby et al³⁷ introduced a conceptual model to delineate the various possible scenarios in which elevated levels of serum troponin might be detected, as shown in Fig. 36–3. Embedded within this framework is the principle that not all elevated troponin represents an MI and that not all myonecrosis reflects an ACS event, even when ischemic in etiology. As a result, the diagnosis of type 1 MI requires not only the presence of elevated cTn, but also a clinical context supporting an ischemic etiology. The underlying pathophysiology of elevations in serum troponin outside the ACS context remains unclear. Postulated mechanisms surround normal cellular turnover, which might be accelerated by age, exercise, or other factors, and increases in myocyte cellular permeability as a result of transient episodes of ischemia.^38,39

In summary, cTns have emerged as the biochemical marker of choice in the evaluation of myonecrosis and diagnosis of MI. Their greater sensitivity and specificity for cardiac muscle damage and proven prognostic value have established their current clinical position. Gains in troponin assay sensitivity may continue to decrease the incidence of troponin-negative ACS or UA, while increasing the number of patients diagnosed with NSTEMI.

ST-Segment Elevation Myocardial Infarction

STEMI represents the most lethal form of ACS, in which a completely occlusive thrombus typically results in total cessation of coronary blood flow, manifested electrically as elevation of the ST segment on the ECG. Pathologic Q waves may evolve because of full- or nearly full-thickness necrosis of the ventricular wall segment supplied by the occluded artery. Accurate diagnosis of STEMI is of paramount importance because it mandates immediate consideration of reperfusion therapy, either by typically mechanical approaches or, less frequently, by infusion of one of several thrombolytic agents. In the absence of contraindications, thrombolytic therapy is favored for patients with very early presentations or substantial delays in accessing a facility capable of performing primary PCI (pPCI). In addition, thrombolytics remain the only therapeutic option for less developed medical systems without pPCI facilities. In contrast, patients presenting with shock, older age, or several hours after symptom onset should be referred for PCI if available.

Although widespread adoption of troponin measurements in the diagnostic evaluation of ACS has influenced the detection of UA and NSTEMI, the diagnosis of STEMI is less sensitive to changes in biomarkers of cardiac injury. Indeed, the incidence of STEMI has continued to decline, even after the introduction of sensitive troponin assays.⁸ In addition, case fatality rates associated with STEMI have also improved.⁷ Several factors may account for these trends. First, as the population ages, presentation with NSTEMI versus STEMI is the more common manifestation of MI.²¹ Second, increased use of preventive therapies in the population at large, such as aspirin and statins, increases the probability of nonocclusive rather than occlusive thrombus at the site of plaque rupture culminating in NSTEMI rather than STEMI.²² Third, reductions in the overall burden and improved control of risk factors may reduce the propensity to thrombotic complications of atherosclerosis.⁹

Criteria for diagnosis of MI have evolved substantially over the past 50 years. Classically, as articulated by the WHO in 1971, the diagnosis of MI required a consensus of at least two of the following three parameters: clinical presentation, ECG changes, and temporal changes in serum biomarkers.¹⁸ The need for consensus in these historical definitions was a result of the variability in clinical presentation of patients with acute MI and reliance on nonspecific biomarkers that might indicate either cardiac or noncardiac injury, such as creatine kinase, lactate dehydrogenase, serum glutamic oxaloacetic transaminase (or aspartate aminotransferase), or myoglobin. The introduction of novel assays sensitive to very low levels of highly specific cardiac enzymes, however, allowed clinicians to identify patients sustaining myocyte necrosis with nearly 100% certainty. Nevertheless, elevations in cardiac-specific biomarkers do not provide insight into the underlying mechanism of injury, highlighting the need for a more refined definition incorporating both clinical context and pathobiology. Accordingly, in 2007, the World Heart Federation, in concert with major European and American cardiovascular societies, convened a global task force to introduce the Universal Definition of MI. The result was a clinicopathologic classification of MI that considers five different MI types, each representing a distinct clinical and pathologic entity culminating in myocyte necrosis. The Universal Definition has been updated twice, with the most recent iteration published in 2012.²⁰

There are several important advantages to standardized diagnostic criteria for MI. First, the prevalence and incidence of coronary events can be estimated accurately, a necessary process to examine trends and overall burden of disease. Second, assessing the effects of therapeutic interventions, pharmacologic or device based, requires end points that are clearly defined, reproducible, and reflect the pathologic substrate that the intervention is intended to modify. Third, a lack of standardized definitions precludes comparative inferences across trials, populations, or time.

The new accepted universal criteria for diagnosing an acute MI state that one of the following criteria must be present in the proper clinical setting leading to evidence of myocardial necrosis:

• Detection of rise and/or fall of an acceptable cardiac biomarker (preferably troponin, but CK-MB mass method is an alternative) with at least one value above the 99th percentile of the upper reference limit (URL), in addition to evidence of myocardial ischemia by one of following:

  1. Symptoms of ischemia

  2. ECG changes indicative of new ischemia (new ST/T-wave changes or new left bundle branch block [LBBB])

  3. Development of new pathologic Q waves on ECG

  4. Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality

• Sudden or unexpected cardiac death, involving cardiac arrest, often preceded by symptoms of coronary ischemia and accompanied by new ST-segment elevation or new LBBB with evidence of fresh intracoronary thrombus detected by angiography or autopsy when death occurred before blood was obtained or an expected rise in serum biomarkers could occur.

• For patients with normal baseline biomarker levels undergoing PCI, a periprocedural increase of cardiac biomarkers above the 99th percentile URL is deemed abnormal. An increase of a biomarker greater than five times the 99th percentile URL is defined as a PCI-related MI.

• For patients undergoing coronary artery bypass graft (CABG) with normal baseline biomarker levels, increases greater than five times the 99th percentile URL accompanied by either new pathologic Q waves or new LBBB, angiographically documented graft or native artery occlusion, or new imaging evidence of loss of viable myocardium is labeled as a CABG-related MI.

• Pathologic evidence of MI.

In addition to revising the criteria for MI diagnosis, the Global Task Force added a clinical classification of MI encompassing most of the common etiologies leading to myocardial necrosis.

Each etiology of MI differs with respect to short- and long-term mortality.

• Type 1 MI occurs as a result of a primary coronary event such as plaque erosion and/or rupture, fissuring, or dissection.

• Type 2 MI occurs secondary to ischemia from either increased oxygen demand or decreased supply, for example, coronary artery spasm, embolism, anemia, arrhythmias, hypertension, or hypotension.

• Type 3 MI occurs in the setting of sudden cardiac death, including cardiac arrest, that may be preceded by ischemic symptoms, accompanied by new ST-segment elevation, new LBBB, or evidence of fresh thrombus by coronary arteriography or autopsy. Death could occur before blood samples are obtained or before cardiac biomarkers appear in the blood.

• Type 4 MI is associated with PCI and is further classified as Type 4a or 4b.

  1. Type 4a MI is associated with PCI.

  2. Type 4b MI is associated with stent thrombosis as documented by angiography or at autopsy.

• Type 5 MI is associated with CABG.

The universal MI document stressed the role of imaging in the diagnosis of MI, both in the acute and chronic phases.²⁰ Because regional hypoperfusion and ischemia lead to myocardial dysfunction, cell death, healing, and fibrosis, imaging techniques that evaluate myocardial perfusion, myocyte viability, myocardial thickness, thickening and motion, and the effects of fibrosis are valuable tools aiding diagnosis of MI. Echocardiography, radionuclide ventriculography, myocardial perfusion scintigraphy, and magnetic resonance imaging (MRI) are commonly used modalities. Positron emission tomography and x-ray computed tomography (CT) are less common.

Echocardiography can help in diagnosis of both acute and prior MI.⁴⁰ Because of its wide availability and mobility, it has become a highly valuable tool in distinguishing true myocardial ischemia from common nonischemic causes of chest pain, such as myopericarditis, valvular heart disease, cardiomyopathy, pulmonary embolism, or aortic dissection. It can help detect mechanical complications of acute infarction, such as free wall rupture, acute ventricular septal defect, and mitral regurgitation. Furthermore, regional myocardial hypocontractility with thinned walls implies not an acute MI but subacute or remote MI.

Radionuclide tracers such as thallium-201, technetium-99m methoxyisobutyl isonitrile, tetrofosmin, and ¹⁸F-fluorodeoxyglucose allow viable myocytes to be imaged directly, the only technique to do so.⁴¹ Furthermore, the common single-photon–emitting tracers also detect myocardial perfusion in addition to infarction.

MRI is well validated for assessment of myocardial function and therefore similar to echocardiography in diagnosis of MI, except in the realms of availability and mobility. Paramagnetic contrast agents can assess myocardial perfusion and the increase in extracellular space associated with the fibrosis of chronic infarction.⁴²

CT imaging can detect infarcted myocardium as a focal area of left ventricular enhancement, and later imaging shows hyperenhancement similar to late gadolinium imaging by MRI.^43,44 This is relevant to distinguish acute MI from pulmonary embolism or aortic dissection.

Several in vivo imaging modalities, such as virtual histology intravascular ultrasound (VH-IVUS) and optical coherence tomography (OCT), complement coronary angiography and provide insight into the natural history, prognosis, and determinants of risk in ACS patients. In the Providing Regional Observations to Study Predictors of Events in the Coronary Tree (PROSPECT) study, VH-IVUS defined thin cap fibroatheroma as an independent nonculprit lesion-based predictor of adverse events in patients presenting with NSTE-ACS undergoing PCI.⁴⁵ The relevance of these findings is highlighted by the fact that most of these lesions were angiographically mild, with a mean diameter stenosis of only 32%. Compared to other imaging modalities, the detailed resolution of OCT allows microstructural characterization of plaque morphology, such as cap thickness, thrombus, and calcific nodules. In a study of 126 ACS patients, the NSTE-ACS presentation was most common with underlying OCT erosion, whereas plaque rupture was most frequently observed in patients with STEMI, consistent with prior autopsy data.^46,47 Whether these findings can guide clinical decision making at the time of angiography requires further study.

Myocardial injury culminating in necrosis may result from embolization of thrombotic or plaque debris during PCI or as a consequence of periprocedural events, such as coronary dissection, slow flow/no reflow, or side branch occlusion. Strategies to prevent injury using adjunctive filters have not yet been effective. Moreover, the optimal threshold and prognostic relevance of such infarction remain controversial.⁴⁸ In a post hoc analysis of randomized trials evaluating different pharmacologic strategies in NSTE-ACS patients, there was no significant association between postprocedural MI (PPMI) and 6-month mortality.⁴⁹ This notwithstanding, the third universal MI definition defines PPMI (type 4a) as cTn elevations greater than five times the 99th percentile URL occurring within 48 hours of the procedure with other manifestations of ischemia or angiographic evidence of a flow-limiting complication. For patients with a baseline elevation of cTn, an increase > 20% compared to baseline is required. The diagnosis of MI following CABG (type 5) requires cTn elevations > 10 times the 99th percentile URL during the first 48 hours after CABG with other manifestations of ischemia or angiographic evidence of a new occlusion within a bypass graft or native coronary artery.

In 2013, the Society for Cardiovascular Angiography and Interventions proposed an alternative set of criteria to define “clinically relevant” PPMI.⁵⁰ In contrast to the universal approach, the Society for Cardiovascular Angiography and Interventions document advocates the use of CK-MB over cTn and a common threshold for CK-MB elevation (≥ 10 times upper limit of normal) to diagnose MI following either PCI or CABG. In the setting of pathologic Q waves or persistent LBBB, a lower threshold of CK-MB elevation ≥ 5 times the upper limit of normal is allowed to diagnose PPMI. These varying taxonomies reflect inconsistencies across studies in linking periprocedural myonecrosis with cardiac risk⁵¹ and the lack of clear and reproducible diagnostic thresholds above which either CK-MB or cTn may be considered harmful.^52,53 Longitudinal studies with long-term follow-up are required to examine the relative merits of either definition on prognosis following coronary revascularization.

The definitions of ACS have become more important as more effective therapies have been developed to treat patients with thrombotic manifestations of coronary atherosclerosis, with or without myocardial necrosis. Assessing a patient's symptoms, ECG pattern, and serum biomarker levels are critical components of the diagnostic evaluation and have remained remarkably constant for approximately 50 years. A false-negative diagnosis may deprive a patient of beneficial treatment, whereas false-positive results expose patients to unnecessary risk and cost. As a result, the current paradigm for the diagnosis of MI centers on measuring very sensitive and specific biomarkers of myocyte necrosis in a clinical scenario consistent with ischemia. Integration of increasingly sophisticated imaging modalities complements other parameters in distinguishing coronary from noncoronary etiologies of chest pain. Changes in the performance of diagnostic tests will continue to impact the number of patients classified as having ACS, with important implications for both prognosis and treatment.

We would like to thank Dr. Michael C. Kim and Dr. Annapoorna S. Kini, who contributed to the previous version of this chapter in the 13th edition.