In total, ACS presentations account for over 2 million annual hospital admissions in the United States. Almost 1.4 million people suffer an ACS each year, of which 55% are new events, 31% are recurrent events, and 14% are silent events. Of all diagnosed MIs, approximately three fourths are NSTE-ACS events and the remaining are STEMI events. Despite recent declines in associated mortality, coronary artery disease causes one out of every five deaths in the United States. Notably, half of MI-related deaths occur within the first hour, primarily due to ventricular dysrhythmias. Therefore, the presentation of ACS challenges the clinician to rapidly integrate key aspects of the history, physical examination, and diagnostic tests in order to diagnose correctly and manage effectively this potentially life-threatening condition.

PATHOPHYSIOLOGY

The pathophysiology underlying virtually all ACS is rupture or erosion of a vulnerable coronary atherosclerotic plaque. Vulnerable plaques usually cause only a mild or moderate degree of stenosis, contain a soft atherogenic lipid core, and are covered by a thin cap that can easily rupture. Conversely, stable plaques tend to be larger, less lipid laden, and covered by a thick fibrous cap. Numerous factors contribute to plaque vulnerability, including inflammation and sheer stress. When a vulnerable plaque ruptures, the inner lipid-laden core is exposed to the bloodstream and activates multiple pathways leading to the rapid formation of a superimposed platelet- and fibrin-rich thrombus. This thrombus interrupts coronary blood flow, causing regional myocardial ischemia and, eventually if severe enough, infarction if not promptly treated with reperfusion therapies. Subtotal arterial occlusion typically manifests as NSTE-ACS, whereas total occlusion of a coronary artery often manifests as STEMI (table 78.1).

DIAGNOSIS

ACS is diagnosed by integrating key aspects of the history, examination, ECG, and cardiac biomarkers (table 78.2). During the evaluation of a patient with possible ACS, alternative cardiovascular and noncardiovascular causes of chest discomfort should always be entertained. In particular, conditions that can mimic ACS by presenting with chest pain and potentially ECG changes include aortic dissection (with or without coronary involvement), acute pericarditis, and pulmonary embolism.

CLINICAL PRESENTATION

ACS can occur at any time of day and may be triggered by physiological, physical, or emotional stress—or even the simple act of early morning awakening. Typical ACS symptoms include a substernal or left-sided chest discomfort, pain, or pressure that can radiate to the left arm, neck, or jaw. Accompanying symptoms may include dyspnea, nausea, vomiting, diaphoresis, lightheadedness, and palpitations. Women, older individuals, and diabetics are more likely to present with atypical symptoms as well as silent coronary attacks.

PHYSICAL EXAMINATION

At baseline, coronary artery disease may be accompanied by signs of vascular disease in more accessible carotid or peripheral arterial beds with concomitant vascular bruits. At the time of an ACS, additional physical findings will vary depending on disease severity and associated complications. There can be an audible S4 due to impaired left ventricular (LV) compliance in the setting of myocardial ischemia. In an extensive MI, severe LV systolic dysfunction may be reflected by a palpable apical dyskinesis, soft S1, paradoxically split S2, and audible S3 in addition to classic signs of heart failure (jugular venous distension, rales, and edema). Frank cardiogenic shock can present with small volume pulses and a narrow pulse pressure in addition to classic signs of shock. Importantly, the degree of heart failure (HF) on examination portends a worse prognosis (see table 78.3).

    Many ACS patients are hypertensive due to increased adrenergic stimulation. Conversely, hypotension suggests the presence of peri-MI complications, in which case the examination should focus on detecting the murmurs of mitral regurgitation or ventricular septal defect (often accompanied by a palpable thrill). Severe hypotension may also be part of the specific but insensitive triad for right ventricular (RV) infarct, which includes elevated jugular venous pressure (JVP) and clear lungs in addition to hypotension.

ELECTROCARDIOGRAM

The critical diagnostic test is the 12-lead ECG which allows the clinician to differentiate between NSTE-ACS and STEMI (or equivalent entities) and then to determine the most appropriate management (Figure 78.1).

    In NSTE-ACS, a number of ECG patterns can be seen: ST-segment depressions, T-wave inversions, nonspecific ST- and T-wave changes, and occasionally no changes at all (table 78.1). Any ECG changes that come and go in timing with chest discomfort are often called “dynamic” and are highly suggestive of ischemia. The regionality of ECG changes in NSTE-ACS may correspond to but are not specific for the location of a coronary lesion.

    In STEMI, the classic defining criteria include acute ST-segment elevations of new ST elevation in two contiguous ECG leads: ≥2 mm (men) or ≥1.5 mm (women) in leads V2-V3, or ≥1 mm in other leads. These criteria are not only specific for the location of a coronary lesion and the area of myocardium at risk (table 78.4), but they are also specific for the presence of an acute coronary occlusion in need of emergent reperfusion.

    When there is clinical concern for a possible STEMI or STEMI-equivalent, a few situations benefit from more than the standard 12-lead ECG. For example, the suggestion of ST-segment elevations in the inferior leads (II, III, aVF) should prompt the placement of a right-sided lead (R-V4), which can show findings more specific for an RV infarct. The suggestion of ST-segment elevations in the inferior or high lateral leads (I, aVL) or reciprocal ST-segment depressions isolated to the right-sided precordial leads (V1, V2) should prompt the placement of posterior leads (V7, V8, V9), which can reveal findings more specific for a posterior infarction. Because of its posterior location, the left circumflex artery is the one coronary territory that may suffer a total occlusion despite a “silent” or apparently normal ECG.

    A new left-bundle branch block (LBBB) is considered equivalent to a STEMI. The presence of an old LBBB typically interferes with the assessment of ST-segment changes. However, many would also consider an old LBBB with new ST deviations that are 1 mm concordant (in the same direction as the QRS) or 5 mm discordant (in the opposite direction from the QRS) as equivalent to STEMI.

    Whereas ST-segment elevations typically represent injured myocardium, Q waves typically represent infarcted myocardium. Historically, the presence of pathologic Q waves in the distribution of a coronary territory on ECG was considered to reflect the presence of an old or recent transmural infarction. We now know that Q waves do not necessarily reflect the transmurality of an infarct. However, the development of Q waves still suggests the presence of less prominent collaterals, a larger infarct, a lower ejection fraction, and increased mortality.

CARDIAC BIOMARKERS

The diagnosis of MI can be made when cardiac biomarkers are elevated in combination with any of the following: ischemic symptoms, ECG evidence of ischemia or recent infarct, and/or a new occlusive thrombus seen by coronary angiography. Moreover, the specific timing and pattern of cardiac biomarker elevation following the onset of myocardial ischemia offer prognostic as well as diagnostic information (Figure 78.2). Notably, the absolute peak as well as the combination of time to peak and duration of elevation (“area under the curve”) of cardiac-specific markers correspond to the extent of myocardial injury, subsequent myocardial dysfunction, and overall 1-year mortality.

Cardiac-Specific Markers

Detecting abnormally elevated cardiac-specific markers can facilitate early diagnosis of an acute MI and expedite management. Cardiac troponin I and T are proteins that originate from the cardiomyocyte apparatus and, therefore, are highly specific for cardiac injury when detected in the systemic circulation. Troponins start to rise within 3 hours of chest pain onset, peak within 24–48 hours, and return to baseline within 7–14 days (Figure 78.2). Notably, troponin levels can be elevated in the setting of renal dysfunction; thus, interpretation must take this factor into account. However, in the appropriate clinical context, an elevated troponin in a patient with renal dysfunction remains a marker of poor prognosis.

    Although elevations in total creatinine kinase (CK) correlate well with the extent of myocardial injury in ACS, the CK-MB isoenzyme is more specific to cardiac versus extracardiac muscle damage. CK-MB isoenzyme levels rise within 4 hours after acute injury, peak within 24 hours, and return to baseline within 48–72 hours (Figure 78.2). Because CK-MB levels normalize more quickly than do troponins after an acute MI, serial CK-MB measures are more useful for the detection of post-MI ischemia and reinfarction, particularly following percutaneous coronary intervention (PCI).

    Importantly, cardiac biomarkers may be negative very early in ACS (Figure 78.2). However, the advent of highly sensitive cardiac troponin assays has improved the diagnostic accuracy of the troponin, increasing the sensitivity of a single sample at presentation from 70–75% to 90%. Moreover, serial use of highly sensitive assays increases the sensitivity at presentation to as high as 98%. Thus, troponin is now considered the preferred biomarker for diagnosing ACS. Conversely, positive biomarkers may not always represent a typical ACS process. A number of non-ACS cardiac conditions can occasionally lead to myonecrosis and mildly elevated cardiac biomarkers: non-ACS coronary obstruction (e.g., spasm from Prinzmetal angina or cocaine, embolism, dissection, vasculitis); fixed atherosclerotic coronary disease with increased demand or decreased supply (e.g., tachycardia, hypovolemia, anemia, HF, aortic stenosis, or sepsis); and, other causes of myonecrosis (e.g., myocarditis, pulmonary embolism, cardiomyopathy, cardiac trauma, or subarachnoid hemorrhage).

TREATMENT

Early and appropriate risk stratification is essential for managing ACS. The critical decision point is the ECG: if ST-segment elevation (or its equivalent) is present, the patient should be treated with immediate reperfusion in addition to recommended medical therapies; if there is no ST-segment elevation (or equivalent), the patient should receive the same recommended medical therapies and then further risk stratification to decide if reperfusion should be pursued within the next 24–48 hours (Figure 78.1).

BASIC MANAGEMENT

Any patient with suspected ACS should receive bed rest and continuous ECG monitoring to screen for ischemic and rhythm changes. All patients diagnosed with a probable or definite ACS should be treated in a coronary care or step-down unit, depending on the severity of the ACS. Supplemental oxygen is recommended for the first 6 hours of ACS and then as needed to maintain an oxygen saturation >90%. In addition, a number of specific ACC/AHA recommended medications should be promptly administered (Figure 78.1). The general goal of these therapies is (1) to counteract platelet and thrombin activity in the involved coronary artery, and (2) to improve the myocardial oxygen supply-demand mismatch caused by disrupted coronary blood flow.

    Antiplatelet and antithrombin therapies are the foundation of medical treatment in ACS and should be administered at the time of initial evaluation.

• Aspirin will immediately and covalently modify cyclooxygenase-1 by acetylation, resulting in near-totally blocked thromboxane A₂ production by platelets, which halts thromboxane A₂-mediated platelet aggregation. Because aspirin has utility across the entire spectrum of ACS, it should be given immediately to all suspected ACS patients.

• Adenosine diphosphate (ADP) receptor blockers inhibit the P2Y12 platelet ADP receptor, thereby decreasing platelet activation and aggregation, and are indicated for all patients diagnosed with ACS. ADP receptor blockers include clopidogrel (currently the most widely used) and the third-generation agents prasugrel and ticagrelor. Clopidogrel, a prodrug, is typically given with a loading dose (except for patients age >75 receiving fibrinolysis, in whom a loading dose should be avoided) and takes 4–6 hours to reach steady-state platelet inhibition. Because clopidogrel is an irreversible platelet inhibitor, it should be held 5 days prior to coronary artery bypass grafting (CABG) surgery. Prasugrel is also a pro-drug, but is more quickly converted to its active metabolite. It has shown efficacy in the setting of patients with planned PCI and so is typically not given until the coronary anatomy has been defined and PCI is planned. In contrast, ticagrelor has a completely different chemical structure, does not require metabolic activation, and is a reversible ADP receptor blocker. Cangrelor, administered intravenously, is a particularly fast-acting reversible ADP receptor blocker and has been shown to reduce ischemic events following PCI for STEMI or NSTE-ACS; it is not FDA approved.

• Anticoagulant therapy should also be given to all ACS patients. Several rapidly acting options exist including unfractionated heparin (UFH), the low-molecular-weight heparin enoxaparin, the highly selective Xa-inhibitor fondaparinux, and the direct thrombin inhibitor bivalirudin. Long-term oral anticoagulant therapy may also be indicated for concurrent LV thrombus, atrial fibrillation, or deep venous thrombosis.

• Glycoprotein (GP) 2b/3a inhibitors block the final common pathway of platelet aggregation and thereby complement the antiplatelet actions of aspirin and clopidogrel. There are currently three types of GP 2b/3a inhibitors in use: abciximab (fab fragment of a monoclonal antibody directed at the 2b/3a receptor), eptifibatide (a synthetic peptide), and tirofiban (a synthetic nonpeptide molecule). GP 2b/3a agents are reserved for higher-risk patients with MI, particularly in the setting of PCI.

    Several anti-ischemic medications are available to help improve myocardial oxygen supply-demand mismatch:

• Beta blockers reduce heart rate, blood pressure, and contractility, which effectively decrease myocardial oxygen demand while also augmenting supply. In addition to relieving pain, beta blockers also reduce infarct size and prevent serious arrhythmias. Therefore, beta blockers should be started for even suspected ACS unless contraindicated (Figure 78.1). The dosing goal of beta blockers is to control resting heart rate and blood pressure while relieving ischemic signs and symptoms. Nondihydropyridine calcium channel blockers (diltiazem or verapamil) may be considered as an addition or a substitute if beta blocker therapy is inadequate or contraindicated.

• Nitrates are vasodilators that relax coronary arteries and reduce cardiac afterload and preload, which lowers ventricular wall tension and oxygen demand. In addition, they improve blood flow to the subendocardium and through collateral vessels. Therefore, nitrates should be used to treat chest discomfort and or symptoms of HF unless contraindicated (Figure 78.1).

• Morphine is an analgesic with vasodilator properties and is recommended for refractory chest discomfort or the presence of HF unless contraindicated (Figure 78.1). Anxiolytics may be used in addition to morphine to decrease anxiety in the acute setting.

    In addition to the above therapies, certain additional medications can serve to optimize conditions affecting the vasculature and myocardium in the setting of an ACS. These medications effectively improve longer-term outcomes and can begin to offer benefit when started early, even within the first 24 hours:

• Angiotensin-converting enzyme (ACE) inhibitors block renin-angiotensin-aldosterone activity and, in doing so, reduce afterload and also prevent infarct expansion and remodeling. Therefore, ACE inhibitors should be given to all ACS patients with HF, LV dysfunction, or hypertension and considered in all patients without contraindications (Figure 78.1). In this respect, angiotensin receptor blockers (ARBs) are likely equivalent and can be used as a substitute in cases of allergy to ACE inhibitors.

• Statins reduce recurrent events for all MI patients, likely through antiinflammatory as well as lipid-lowering mechanisms. A high-dose statin should be started within the first 24 hours typically regardless of the patient’s baseline lipid profile.

    Medications to avoid in ACS include dihydropyridine calcium channel blockers (e.g., nifedipine) and empirical antiarrhythmics, which can increase mortality in the peri-MI setting.

MANAGEMENT OF STEMI

Rapid recognition of a STEMI is critical. The faster that normal flow can be restored to an occluded artery, the more myocardial necrosis can be prevented, and the more likely that at-risk myocardium will be salvaged, LV function preserved, and MI-related morbidity and mortality decreased. On diagnosing STEMI, therefore, reperfusion therapy should be performed immediately with concurrent administration of key adjunctive medical therapies (Figure 78.1).

Emergent Reperfusion

The most important initial decision point in managing STEMI pertains to which method of emergent reperfusion to pursue. At a PCI-capable hospital, PCI should be performed within 90 minutes of the patient’s first medical contact. PCI is also preferred if rapid transfer to a PCI-capable hospital will allow PCI to be performed within the time-sensitive goal of 120 minutes of first medical contact (Figure 78.1). If PCI cannot be initiated within 120 minutes, and <12 hours have passed since the onset of ischemic symptoms, then fibrinolysis should be administered within 30 minutes of first medical contact unless contraindicated (box 78.1). In the timeframe of 12 to 24 hours since symptom onset, PCI is still reasonable for treating ongoing signs of ischemia. The benefit of fibrinolysis given >12 hours after symptom onset is less clear, but it is reasonable if there are ongoing ischemic symptoms and/or persistent ST-segment elevations without PCI availability.

Box 78.1 CONTRAINDICATIONS TO FIBRINOLYTIC THERAPY

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