An MI was once defined according to symptoms, ECG abnormalities, and serum cardiac enzyme levels. The advent of more sensitive and specific cardiac biomarkers and imaging studies has led to an ability to detect smaller amounts of myocardial necrosis and, in turn, a need for a more precise definition of MI. While myocardial injury, defined as an elevation in serum cardiac troponin, is a prerequisite for the diagnosis of MI, there must also be clinical evidence of myocardial ischemia to distinguish MI from cardiac troponin elevation caused by nonischemic myocardial injury (e.g., myocarditis, sepsis, chronic kidney disease). The European Society of Cardiology (ESC), the American College of Cardiology Foundation (ACCF), the AHA, and the World Heart Federation jointly developed a Universal Definition of MI Consensus Document, last updated in 2018, which states: "the clinical definition of MI denotes the presence of acute myocardial injury detected by abnormal cardiac biomarkers in the setting of evidence of acute myocardial ischemia" [31]. Detection of an elevated cardiac troponin value above the 99th percentile of the upper reference limit is the preferred diagnostic indicator of myocardial injury. The injury is considered acute if there is a rise and/or fall of troponin value. Myocardial ischemia in a clinical setting is most often determined from the patient's history, the EKG, or cardiac imaging studies, as evidenced by any one of the following [31]:

A comprehensive comparison of CABG and PCI was carried out in the Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (SYNTAX) study, and the findings were considered in the formulation of the 2011 ACC/AHA/Society for Cardiac Angiography and Interventions (SCAI) guideline recommendations for PCI [5]. In a meta-analysis (31 trials, 15,004 patients) published after the guideline, among patients eligible for either PCI or CABG, the latter procedure was associated with lower rates of repeat revascularization, and death; the rate of MI was similar, and the rate of stroke was higher with CABG [204]. Class I recommendations for the use of PCI include patients who have refractory angina or hemodynamic or electrical instability (without comorbidities or contraindications), and initially stabilized patients who have an elevated risk for clinical events [5]. PCI is preferred for patients with discrete lesions, in large-caliber vessels, or one or two vessels, whereas CABG is recommended for more extensive CHD, including left main disease, three-vessel disease, or two-vessel disease with severe involvement of the proximal left anterior descending coronary artery [6]. For patients with multivessel disease, CABG has been associated with higher adjusted rates of long-term survival and lower rates of MI and repeat vascularization compared with PCI with stenting [205,206]. CABG is also recommended for patients with left ventricular systolic dysfunction [6].

The 2013 ACCF/AHA guideline indicates that PCI is preferred over fibrinolytic therapy for patients with STEMI when it can be performed in a timely manner by experienced operators [2]. PCI should be done within less than 90 minutes after the patient's first medical contact [2]. If PCI cannot be done within 90 minutes, fibrinolytic therapy should be initiated as the reperfusion strategy within 120 minutes of the first medical contact.

The most significant factor in achieving an optimal outcome from PCI is timing. Findings from hospitals reporting to the Centers for Medicare and Medicaid Services have shown an improvement in the number of patients treated with primary PCI within the recommended 90-minute window, from 44.2% in 2005 to 91.4% in 2010 [210]. In addition, the median door-to-balloon or door-to-device time declined from 96 minutes in 2005 to 64 minutes in 2010 [210].

Specific strategies that have improved the door-to-device time interval focus on three key components: door-to-ECG time, ECG-to-catheterization laboratory time, and laboratory arrival-to-device time. The ACCF/AHA provides the following steps as a general protocol in improving door-to-device times [2]:

Class I indications for primary PCI include the following [5]:

The use of coronary stents during PCI reduces the rates of adverse events such as re-occlusion, restenosis, and target-vessel revascularization [5,209,211]. Drug-eluting stents have been associated with lower long-term rates of target-vessel revascularization and restenosis compared with bare-metal stents, but the reduction has varied among the many types of drug-eluting stents and stent thrombosis was originally a complication [213,214]. Subsequent-generation drug-eluting stents were developed to overcome this complication, and thin-strut fluoropolymer-coated cobalt chromium everolimus-eluting stents have been associated with rates of stent thrombosis that are lower than those for other types of drug-eluting stents or bare-metal stents [214]. One small study that included 372 patients compared the efficacy of drug-eluting stents with drug-coated balloons for use during PCI [215]. The primary outcome was a composite of major adverse cardiovascular events (e.g., cardiac death, MI, target lesion revascularization) at one year [215]. Major adverse events occurred in 10 patients (12%) in the drug-coated balloon group and in 50 patients (13.4%) in the drug-eluting stent group. Other studies have confirmed the potential benefit of using drug-coated balloons during PCI [216,217].

The aspirin dose before PCI should be 325 mg for patients who had not been taking aspirin therapy and 81 mg to 325 mg for patients who had already been taking daily aspirin [5]. If stents are to be implanted during PCI, a loading dose of a P2Y12 inhibitor should be given (clopidogrel, 600 mg; prasugrel, 60 mg; or ticagrelor, 180 mg) [5]. For clopidogrel, a 300-mg loading dose is recommended for patients who have PCI within 24 hours after receiving fibrinolytic therapy; a 600-mg loading dose is recommended for patients who have PCI more than 24 hours after receiving fibrinolytic therapy [5]. This recommendation is based on the results of several investigations to explore various loading doses of clopidogrel before or during PCI. A meta-analysis of seven studies demonstrated that a 600 mg loading of clopidogrel reduces the rate of adverse cardiovascular events without an increase in major bleeding compared with 300 mg [5]. The findings of another study suggested that a 600-mg loading dose (compared with a 300-mg dose) is associated with improvements in procedural angiographic endpoints and one-year clinical outcomes in patients with STEMI who undergo primary PCI [5]. No benefit is derived from increasing the loading dose to 900 mg compared with 600 mg [5]. The guideline acknowledges that the safety and efficacy of pretreatment with clopidogrel remains controversial [5].

When compared with clopidogrel, prasugrel was associated with a 2.2% reduction in a composite endpoint of cardiovascular-related death, nonfatal reinfarction, or nonfatal stroke [5]. Prasugrel is contraindicated in patients with active pathologic bleeding or history of transient ischemic attack or stroke. Its use is not recommended for patients older than 75 years of age because of increased risk of fatal intracranial bleeding [5].

The most common complication of fibrinolytic therapy is major bleeding, which occurs in approximately 5% to 6% of patients [208]. Adverse outcomes after fibrinolytic therapy are generally more common among women and older patients [228,229]. Many instances of bleeding can be traced to incorrect dosing, particularly with weight-based agents [222]. In addition, patients who receive an improperly high dose of fibrinolytic agents have increased 30-day mortality.

Although PCI is performed more frequently, several situations call for the use of CABG. The ACCF/AHA guideline for STEMI and the ACC/AHA guideline for CABG surgery recommend emergent or urgent CABG when PCI has failed, for coronary anatomy not amenable to PCI, and at the time of surgical repair of a mechanical defect (e.g., ventricular septal, papillary muscle, free-wall rupture) [2,6].

The 2013 ACCF/AHA guideline for the management of STEMI recommends aspirin at a dose of 162–325 mg as a loading dose before either PCI or fibrinolytic therapy [2]. A P2Y12 inhibitor is used along with aspirin as dual-antiplatelet therapy. For patients treated with PCI, clopidogrel (600 mg), prasugrel (60 mg), or ticagrelor (180 mg) should be given as a loading dose as early as possible or at the time of the PCI [2]. Treatment with a P2Y12 inhibitor is continued for one year. Clopidogrel is the recommended P2Y12 inhibitor to support fibrinolytic therapy; a loading dose of 300 mg is used for patients 75 years of age or younger, and no loading dose is used for patients older than 75 years of age [2]. Treatment with clopidogrel is continued for at least 14 days and up to one year.

Obesity is another well-documented risk factor for CHD, and weight management programs and information on healthy eating/caloric intake should be promoted as appropriate [260]. The patient's body mass index and waist circumference should be measured at each visit. The goal is to attain a body mass index of 18.5–24.9 and a waist circumference of 35 inches (women) or 40 inches (men) [260]. When weight reduction is needed, the initial goal is weight loss of 5% to 10% from baseline [260].

The recommended antiplatelet therapy after discharge is a combination of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, or ticagrelor) [2,260,264]. The findings of studies have suggested that low-dose aspirin is as effective as higher doses but has a better safety profile [170,266,267]. The recommended daily dose of aspirin is 75–162 mg for all patients, and the ACC/AHA guidelines for the management of STEMI and NSTE-ACS state that it is reasonable to a use an 81-mg dose [2,3,264,267]. However, despite the better safety profile of low-dose aspirin, data have indicated that 325 mg is the most common dose, prescribed for 55.7% of patients with UA/NSTEMI [268].

An ACS event can be distressing for many patients, leading to a heightened fear of dying and anxiety about adjusting to life with cardiac disease [281]. These emotions can substantially affect a patient's psychosocial status and lead to depression [282,283]. Some degree of clinically significant depression has been reported to occur in up to half of patients with ACS, with major depression occurring in 15% to 20% of patients [282]. Depression has been found more often in women compared with men and in men with a history of MI [284]. In addition to the negative effect on the patient's quality of life, depression has also been shown to be associated with lack of adherence to secondary prevention measures and with increased mortality [283,285,286].

Lack of patient compliance with medications is also a serious problem and has been referred to as an unrecognized risk factor for CHD, because of its association with significant increases in adverse events and health costs [305,306]. Among individuals with CHD (many of whom had experienced a recent ACS event), compliance with guideline-recommended medications has ranged from 18% to 55%. Approximately 54% of individuals have been compliant with all of their initial medications, and compliance decreases over time [305,307,308]. One study showed that compliance was 60.3% at one year, 53.7% at two years, and 48.8% at five years [309]. Individuals who discontinue medications are more likely to be older, female, unmarried, and less educated [307]. Several other factors have been found to be associated with noncompliance with medications [305,307,308]:

The most common cause of ACS is atherosclerotic CAD, a multi-decade process augmented by aging and acquired factors that impact the degree of atherosclerosis. Atherogenesis proceeds by sequential pathologic change within the vessel wall that leads to formation of an atheromatous plaque. Further progression of the atheroma results in a necrotic core beneath a fibrous cap, accompanied by some degree of plaque instability. ACS is most often precipitated by plaque rupture (especially in men) and acute thrombosis as vascular endothelium is exposed to highly thrombogenic necrotic core material [32,41]. Plaque erosion or fissuring may also lead to ACS [41]. The mechanisms underlying plaque erosion are not as well understood as those for plaque rupture, but inflammation plays a central role in both [41,42,43].

A system for classifying the severity of atherosclerotic plaques (lesions) was developed in the 1990s, with lesions categorized into several types according to their histologic composition and structure [45,46,47,48]. A simpler classification, based on morphologic characteristics, was later introduced [49]. According to this system, lesions are defined in seven categories: intimal xanthoma (so-called fatty streak), intimal thickening, pathologic intimal thickening, fibrous cap atheroma, thin-cap fibroatheroma (TCFA), calcified nodule, and fibrocalcific plaque [49]. Pathologic intimal thickening or a thick-cap fibroatheroma is usually involved in plaque erosion [43]. Erosion is often the cause of thrombosis in young patients, particularly women younger than 50 years of age [34,43]. The least often cause of thrombosis is a calcified nodule, which is usually found in older patients with substantially calcified and tortuous arteries [43].

The stability of plaque is a crucial factor in the potential for rupture. Plaque that is at high risk of rupture is referred to as vulnerable plaque [50]. Vulnerable plaque has the following hallmark characteristics [41,51]:

The Framingham Heart Study identified the first risk factors, and these factors were integrated into a risk-assessment tool, the Framingham Risk Score [62]. The factors in the Framingham Risk Score include age, total cholesterol level, HDL level, systolic blood pressure, treatment for hypertension, and cigarette smoking, and the score is used to determine the 10-year risk of so-called hard CHD (defined as MI or coronary-related death) among asymptomatic adults. The Framingham risk score is one of several scores that involve several traditional risk factors for assessing risk; other scores recommended include the Systematic Coronary Risk Evaluation (SCORE), PROCAM (men) and Reynolds (separate scores for men and women) [63]. The use of one of these risk calculators is a class IB recommendation from the American College of Cardiology Foundation and American Heart Association [63]. It is important to consider the populations on which these risk scores are based. For example, the Framingham Risk Score was developed on the basis of risk factors identified in the Framingham Heart Study, which involved a primarily White, middle-aged population. When the risk score has been evaluated in other populations, it has been found to underestimate the risk of CHD among older (mean age: 73.5 years) Black and White individuals, especially women [64]. ACC/AHA guidelines published in 2013 recommend that race- and sex-specific Pooled Cohort Equations be used to predict 10-year risk of a first hard atherosclerotic cardiovascular disease event in non-Hispanic Black and non-Hispanic White individuals (class IB) [65]. These equations were developed on the basis of data on participants from several large racially and geographically diverse studies [65]. The guidelines also note that the sex-specific pooled cohort equations for non-Hispanic White individuals may be considered to estimate risk for people other than Black and non-Hispanic White individuals (class IB) [65].

The 2010 ACCF/AHA guideline and the ACP screening guideline note that stress echocardiography is not indicated for asymptomatic adults at low or intermediate risk [63,79]. Transthoracic echocardiography (to detect left ventricular hypertrophy) is not recommended for asymptomatic adults but "may be considered" for asymptomatic adults with hypertension. Coronary CT angiography is not recommended for asymptomatic adults. Stress myocardial perfusion imaging is not indicated for asymptomatic adults at low or intermediate risk but "may be considered" for assessment of advanced cardiovascular risk in asymptomatic adults with diabetes or with a strong family history of CHD [63,79].

Most emergency department clinicians err on the side of caution when evaluating patients with chest pain because of the serious consequences of a missed diagnosis of ACS, in terms of adverse patient outcome as well as threat of medical malpractice [105]. As a result, fewer than 10% of patients who are evaluated for chest pain are ultimately found to have ACS [106].

So-called classic ACS-related chest pain has been described as diffuse pain or pressure in the substernal or epigastric area that frequently radiates to the neck, throat, jaw, back, shoulder, and left arm [123]. Chest pain related to ACS usually begins abruptly and lasts at least 15 to 20 minutes; however, the duration of pain varies among patients [123,124]. The intensity of classic ACS chest pain increases over time, reaching maximal intensity after a few minutes [123]. Pain is usually worse with activity and improves with rest.

The classic presentation of ACS includes some symptoms in addition to chest pain, primarily dyspnea, diaphoresis, nausea, abdominal pain, or syncope [2,3]. Again, there is wide variation in the symptoms reported by patients with ACS, as well as differences in subgroups of patients. Patients with STEMI more commonly report nausea, cold sweats, and vomiting [134]. Diaphoresis occurs more often in men with ACS compared with women [128]. In contrast, the likelihood of nonspecific symptoms is greater for women with ACS, with higher rates of fatigue, nausea and/or vomiting, indigestion, palpitations, dyspnea, and dizziness, and lightheadedness [128,129,133,134,135,136]. Among older individuals, dyspnea and fatigue have been noted to be the most common symptoms and diaphoresis has been reported less often [11,125,126].

The five most important history-related factors that relate to the likelihood of ischemia due to CHD are (in order of importance) [139]:

Cardiac biomarkers are detectable intracellular macromolecules released into the circulation after cardiomyocyte injury and death. The biomarkers once used—creatinine kinase (CK)-MB and myoglobin—have been replaced by cardiac-specific troponin (troponin I or T) because of the latter's high concentration in myocardium, near-absolute specificity for myocardial tissue, absence in the blood of healthy individuals, and high clinical sensitivity [2,3,31]. Measurement of CK-MB or myoglobin levels was not useful or cost-effective [145].

As noted, cardiac troponin I and T are sensitive and specific biomarkers of myocardial injury, and serum measurements are used to identify whether patients with ACS have had an MI. A variety of troponin assays are in use. Contemporary ("sensitive") troponin assays have been in use for many years, while "highly sensitive" assays were only approved in 2017 for use in the United States. The Fourth Universal Definition of MI recommends using highly sensitive troponin assays when available [31]. The time to initial elevation of cardiac troponin levels following MI is 2 to 12 hours when measured by sensitive assays, with peak elevation at 24 hours (troponin I) and 12 to 48 hours (troponin T) [3,146]. Levels may remain elevated for 5 to 10 days (troponin I) or up to 14 days (troponin T) after an MI [146]. Highly sensitive assays detect significant elevations of cardiac troponin within one hour, which has the advantage of more rapid diagnosis and triage. The sensitivity of cardiac troponin for the diagnosis of MI is relatively low during the first six hours, especially in patients who present shortly after symptom onset [146]. However, for most patients with ACS, MI can be ruled out or confirmed within six hours, in part because of the high rate of delayed presentation associated with chest pain [3].

The ACC/AHA guideline for UA/NSTEMI states that troponin levels should be measured at the time of presentation and three to six hours after the onset of symptoms in all patients suspected of having ACS [3]. If the time of symptom onset is unclear, the time of presentation should be used instead. When initial serial troponin levels are normal but ECG changes and/or clinical features increase the suspicion for ACS, additional troponin levels should be measured beyond six hours [3]. The lack of elevated troponin levels at the time of presentation should not rule out an MI, as the initial level is normal in as many as 23% of patients with MI [148]. Troponin levels appear to have value in ruling out an MI; the negative predictive value of undetectable troponin levels has been reported to be 99% to 100%.

The TIMI risk score is based on seven independent risk factors [151]:

One point is given for each factor, and the total score corresponds to the risk of all-cause mortality, new or recurrent MI, or severe recurrent ischemia requiring urgent revascularization through 14 days [151]. That risk ranges from 4.7% for a TIMI risk score of 0 or 1 to 40.9% for a score of 6 or 7. Patients with a higher TIMI score will derive greater benefit from an invasive strategy [3]. The TIMI risk calculator can be accessed online at https://timi.org.

The GRACE risk model includes eight variables [152]:

The general care of patients with UA/NSTEMI is directed at the severity of symptoms. Bed rest is recommended while patients have ischemic pain. After symptoms have subsided, patients may move to a chair. The ACC/AHA guideline notes that there is no benefit to the routine use of supplemental oxygen, and it may, in fact, even be harmful [3]. Instead, supplemental oxygen should be given only to patients who have an arterial oxygen saturation of less than 90%, respiratory distress, or other high-risk features of hypoxemia. Continuous ECG monitoring should also be carried out, not only to detect ECG changes that may provide additional diagnostic and prognostic information but also because sudden ventricular fibrillation is the primary preventable cause of death during this initial period [3].

The inhibition of beta-1 adrenergic receptors by beta blockers acts to decrease cardiac work and myocardial oxygen demand. Beta blockers also slow the heart rate, which helps enhance coronary blood flow. A beta blocker should be given orally to all patients (unless contraindicated) within 24 hours after presentation [3]. This use of beta blocker therapy has been associated with significantly lower in-hospital mortality [159]. The evidence for the benefit of beta-blocker therapy is well established, but it diminishes as the time from the index cardiac event elapses [160]. Contraindications include signs of heart failure, low-output state, increased risk of cardiogenic shock, or other relative contraindications to beta blockade.