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.
Clinical, pathologic, electrical, and biochemical correlates of acute coronary syndrome. ACS, acute coronary syndrome; Dx, diagnosis; ECG, electrocardiogram; NQMI, non–Q-wave myocardial infarction; NSTE, non–ST-segment elevation; NSTEMI, non–ST-segment elevation myocardial infarction; QwMI, Q-wave myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina. Reproduced with permission from Amsterdam EA, Wenger NK, Brindis RG, et al: 2014 AHA/ACC Guideline for the Management of Patients with Non-ST-Elevation Acute Coronary Syndromes: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2014 Dec 23;64(24):e139-e228.
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
TABLE 36–1.Canadian Cardiovascular Society Grading of Angina ||Download (.pdf) TABLE 36–1. Canadian Cardiovascular Society Grading of Angina
|Class ||Description of Stage |
|I ||Angina occurs with strenuous, rapid, or prolonged exertion at work or recreation |
|II ||Angina occurs on walking > 2 level blocks and climbing > 1 flight of ordinary stairs at normal pace and under normal conditions |
|III ||Angina occurs on walking 1-2 level blocks and climbing 1 flight of ordinary stairs under normal conditions and at normal pace. |
|IV ||Anginal symptoms may be present at rest. |
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
Prevalence of ST-segment elevation myocardial infarction (STEMI) and non–ST-segment myocardial infarction (NSTEMI) in the National Registry of Myocardial Infarction from 1990 to 2006 and proportion of patients in whom a troponin assay was used to diagnose myocardial infarction. Reproduced with permission from Rogers WJ, Frederick PD, Stoehr E, et al: Trends in presenting characteristics and hospital mortality among patients with ST elevation and non-ST elevation myocardial infarction in the National Registry of Myocardial Infarction from 1990 to 2006. Am Heart J. 2008 Dec;156(6):1026-1034.
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.
TABLE 36–2.Likelihood That Signs and Symptoms Represent an Acute Coronary Syndrome Secondary to Coronary Artery Disease ||Download (.pdf) TABLE 36–2. Likelihood That Signs and Symptoms Represent an Acute Coronary Syndrome Secondary to Coronary Artery Disease
|Feature ||High Likelihood: Any of the Following ||Intermediate Likelihood: Absence of High-Likelihood Features and Presence of Any of the Following ||Low Likelihood: Absence of High- or Intermediate-Likelihood Features But May Have the Following |
|History ||Chest or left arm pain or discomfort as chief symptom reproducing documented angina; known history of CAD, including MI ||Chest or left arm pain or discomfort as chief symptom; age > 70 years; male sex; diabetes mellitus ||Probable ischemic symptoms in absence of any of the intermediate-likelihood characteristics; recent cocaine use |
|Examination ||Transient MR, hypotension, diaphoresis, pulmonary edema, or rales ||Extracardiac vascular disease ||Chest discomfort reproduced by palpation |
|ECG ||New, or presumably new, transient ST-segment deviation (≥ 0.05 mV), or T-wave inversion (≥ 0.2 mV) with symptoms ||Fixed Q waves; abnormal ST segments or T waves not documented to be new ||T-wave flattening or inversion in leads with dominant R waves; normal ECG |
|Cardiac markers ||Elevated cardiac TnI, TnT, or CK-MB ||Normal ||Normal |
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
TABLE 36–3.Short-Term Risk of Death or Nonfatal MI in Patients With Unstable Angina/NSTEMI ||Download (.pdf) TABLE 36–3. Short-Term Risk of Death or Nonfatal MI in Patients With Unstable Angina/NSTEMI
|Feature ||High Risk: At Least 1 of the Following Features Must Be Present ||Intermediate Risk: No High-Risk Feature But Must Have 1 of the Following ||Low Risk: No High- or Intermediate-Risk Feature But May Have Any of the Following |
|History ||Accelerating tempo of ischemic symptoms in preceding 48 h ||Prior MI, peripheral or cerebrovascular disease or CABG, prior aspirin use || |
|Character of pain ||Prolonged ongoing (> 20 min) rest pain ||Prolonged (> 20 min) rest angina, now resolved, with moderate or high likelihood of CAD; rest angina (< 20 min) or relieved with rest or sublingual nitroglycerin ||New-onset or progressive CCS class III or IV angina within the past 2 wk without prolonged (> 20 min) rest pain but with moderate or high likelihood of CAD |
|Clinical findings ||Pulmonary edema, most likely caused by ischemia; new or worsening MR murmur; S3 or new/worsening rales; hypotension, bradycardia, tachycardia; age > 75 y ||Age > 70 y || |
|ECG ||Angina at rest with transient ST-segment changes > 0.05 mV; bundle branch block, new or presumed new; sustained ventricular tachycardia ||T-wave inversions >0.2 mV; pathologic Q waves ||Normal or unchanged ECG during an episode of chest discomfort |
|Cardiac markers ||Elevated (eg, TnT or TnI > 0.1 ng/mL) ||Slightly elevated (eg, TnT > 0.01 but < 0.1 ng/mL) ||Normal |
TABLE 36–4.Quantitative Risk Scores to Predict Outcomes in Patients with Acute Coronary Syndrome ||Download (.pdf) TABLE 36–4. Quantitative Risk Scores to Predict Outcomes in Patients with Acute Coronary Syndrome
|Risk Score ||Outcome ||Time Point ||Components ||Website |
|GRACE || |
Death or MI
|6 months to 3 years ||Age; heart rate; systolic blood pressure; CHF or diuretic use; serum creatinine or renal failure; ST-segment deviation; cardiac arrest at admission; elevated troponin ||http://gracescore.org/WebSite/WebVersion.aspx |
|TIMI ||All-cause mortality, new or recurrent MI, severe ischemia requiring urgent revascularization ||14 days ||Age ≥ 65; ≥ 3 CAD risk factors; known CAD (stenosis ≥ 50%); aspirin use in past 7 days; severe angina in last 24 hours; ECG ST-segment deviation ≥ 0.5 mm; positive cardiac marker ||http://www.mdcalc.com/timi-risk-score-for-uanstemi/ |
|PREDICT ||Death ||30 days; 2 years; 6 years ||Age; shock; CHF; ECG severity; renal function; Charlson index; prior MI; hypertension; stroke; CABG; pre-MI angina ||N/A |
|PURSUIT || |
Death or MI
|30 days ||Age; sex; CCS class in prior 2 weeks; CHF; ST-segment depression ||N/A |
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
Conceptual model for clinical distribution of elevated troponin. ACS, acute coronary syndrome; AMI, acute myocardial infarction; CAD, coronary artery disease; CHF, congestive heart failure; CM, cardiomyopathy; CT, cardiothoracic; MI, myocardial infarction; PCI, percutaneous coronary intervention; PE, pulmonary embolism; STEMI, ST-segment elevation myocardial infarction. Reproduced with permission from Newby LK, Jesse RL, Babb JD, et al: ACCF 2012 expert consensus document on practical clinical considerations in the interpretation of troponin elevations: a report of the American College of Cardiology Foundation task force on Clinical Expert Consensus Documents. J Am Coll Cardiol. 2012 Dec 11;60(23):2427-2463.
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