The prevalence of non–ST-elevation acute coronary syndromes (NSTEACS) is increasing. The major pathophysiologic mechanism is plaque rupture or fissuring with superimposed thrombus. Risk profiling should be performed at admission and repeated on several subsequent occasions to incorporate new information regarding the patient’s response to therapy and risk factors. Treatment should be tailored according to individual patient characteristics and risk.

Patients should initially receive intensive antithrombotic therapy to passivate the thrombotic activity of the culprit unstable plaque. The optimal antithrombotic regimen has not yet been defined. Aspirin reduces the risk of cardiac events by 20%. In comparison with unfractionated heparin (UFH), enoxaparin has been shown to reduce the combined incidence of death and myocardial infarction (MI) by 9% at 30 days, and may be favored for patients being managed conservatively because of its ease of use. In patients managed invasively, enoxaparin and UFH produce similar outcomes, although enoxaparin is associated with a modest increase in bleeding. In patients not selected for early percutaneous coronary intervention (PCI), glycoprotein (GP) IIb/IIIa antagonists have been shown to reduce 30-day death/MI rates by 9% overall and by 18% in patients with elevated troponin levels, although there was no benefit in patients
without elevated troponin levels. Adjunctive use of clopidogrel with aspirin has a synergistic effect, reducing cardiovascular death/MI/stroke by 20% in patients with and patients without elevated troponin levels.

β-Blockers, nitrates, and calcium channel antagonists relieve angina, but have no significant effect on intracoronary thrombus and do not necessarily reduce the risk of death/MI. The risk of cardiac events is decreased by reduction of low-density lipoprotein cholesterol (LDL-C) levels to below 62 mg/dL (1.6 mmol/L) using early aggressive statin therapy.

Early angiography and revascularization are integral to the management of NSTEACS. When compared with conservative medical treatment, early revascularization reduces the risk of death/MI in high-risk patients, decreases the need for antianginal medications, allows a shorter hospital stay, and results in fewer readmissions. This approach is cost effective in many healthcare settings. Patients selected for early revascularization should have the procedure within 48 hours of admission; the optimal timing of intervention has not yet been established. Intermediate-risk patients should be admitted to a coronary care or chest pain unit, monitored closely, and given intensive antithrombotic therapy. If patients become high-risk (i.e., they have recent ischemia or their troponin levels rise), they should have early angiography and revascularization if appropriate. If symptoms settle and troponin levels are not elevated, patients should be managed according to whether or not they have inducible ischemia. Low-risk patients should be discharged early with appropriate arrangements for follow-up and review.

The risk of ischemic events remains high in patients with NSTEACS, and management continues to pose a major clinical challenge. Better treatments and new therapeutic strategies are needed. It is important that evidence-based therapies be used and that primary and secondary preventative measures be instituted to reduce the community burden of acute coronary syndromes (ACS).

The first documented description of a patient with an acute ischemic syndrome is in the Ebers papyrus from 2,600 BCE, which states, “If you find a man with heart discomfort, with pain in his arms, at the side of his heart, death is near.” This description remains apt, but the prognosis has changed over the centuries. Today, unstable angina is one of the commonest causes of hospitalization (1). Each year, more than 1.4 million patients in the United States (2) and more than 4 million worldwide (3) are hospitalized with NSTEACS. These numbers will continue to rise as the prevalence of patients with obesity and diabetes increases (3).

The syndromes of unstable angina, non–ST-elevation MI (NSTEMI) and ST-elevation MI (STEMI) are a continuum, and the pathophysiology is heterogeneous and dynamic. Clinical presentation depends on the severity of the arterial injury, the size and type of thrombus formed, the extent and duration of ischemia, and the amount of previous myocardial necrosis. The extent of ischemia depends on the myocardial distribution of the ischemia-producing artery, the severity of the ischemia-producing stenosis, the absence or presence of collateral circulation, and factors that affect the supply of oxygenated blood or that increase myocardial demands, such as the heart rate, blood pressure, and contractility. Patients may die or may develop MI, recurrent ischemia, heart failure, arrhythmia, or a stroke.

Acute coronary syndromes describes a spectrum of clinical syndromes ranging from unstable angina to NSTEMI and STEMI. Patients presenting with ACS are divided into those with ST elevation (lasting ≥20 minutes) or new left bundle branch block, and those with NSTEACS which includes transient ST elevation (lasting <20 minutes), unstable angina, and NSTEMI (4).

Unstable angina is a syndrome intermediate between chronic stable angina and MI. It is a clinical diagnosis based on a history of chest pain and exclusion of the diagnosis of MI by electrocardiography (ECG) and biomarker testing for myocardial necrosis. The chest pain may be prolonged at rest or of new onset, may represent accelerating symptoms of previously stable angina, or may occur after MI. Patients presenting without ST elevation on the ECG are diagnosed as having either NSTEMI or unstable angina based on whether or not their troponin or creatine kinase (CK)-MB levels are elevated (5). Between 2% and 15% of patients diagnosed with unstable angina subsequently develop Q-wave MI.

The unstable angina classification developed by Braunwald (6) is based on the severity of symptoms, their clinical context, and the intensity of medical treatment. The classification has been validated clinically (7), has been shown to correlate with coronary angiographic findings (8), and has now been updated to include troponin levels (Table 18.1) (9). Prinzmetal angina (recurrent rest angina accompanied by ST elevation on the ECG owing to coronary artery spasm) is considered a separate entity (10).

The five major causes of ACS are thrombus, mechanical obstruction, dynamic obstruction, inflammation, and increased oxygen demand (11). The major pathophysiologic mechanism is rupture or fissuring of an atheromatous plaque with superimposed thrombus (12,13,14,15). Other mechanisms include superficial erosion (which is more common in women), intraplaque hemorrhage, and erosion of a calcified nodule (16). Patients with ACS often have more than one ulcerated plaque, as shown by angiography (17), intravascular ultrasound (18), angioscopy (19), and release of inflammatory markers such as myeloperoxidase across nonculprit coronary vascular beds (20). Multiple plaque ruptures are more common in patients with increased C-reactive protein (CRP) levels (21).

In some patients, thrombogenicity of the blood (sometimes referred to as “vulnerable blood” leading to the concept of “vulnerable patients”) is implicated, with alterations in circulatory prothrombotic or antifibrinolytic mechanisms. Levels of
plasminogen activator inhibitor-1 are increased in patients with obesity or diabetes (22).

Superficial fissuring of a plaque usually results in platelet deposition. There is less superimposed thrombus formation in patients with NSTEACS than in those with STEMI, which is usually associated with deep arterial injury and occlusive thrombus (Fig. 18.1) (14,15). Angioscopic findings show that the thrombus associated with unstable angina is white or gray and consists mostly of platelets, whereas the thrombus associated with STEMI consists mostly of red blood cells (23).

Inflammation plays a major role in atherosclerosis (24,25), and activation of macrophages triggers inflammatory processes that lead to plaque instability, procoagulation, and clinical events. Plaque rupture or fissuring can be triggered by increased shear forces with sudden changes in pressure or tone. Rupture most often occurs on minor plaques (26,27,28,29,30,31) that are eccentric (32) and have a large lipid core with a thin fibrous cap (33), increased concentrations of macrophages (34), and local expression of tissue factor. Macrophages produce metalloproteases such as collagenase, elastases, and stromelysins, which digest extracellular matrix (25). Macrophage-rich areas are more commonly found in atherectomy specimens from patients with unstable angina than from those with stable angina (35). Activated T lymphocytes are present at sites of plaque rupture (36) and they release various cytokines which activate macrophages and promote smooth muscle cell proliferation (25). Mast cells are found on plaque edges at sites that are likely to rupture (37). Increased levels of CRP (38) and its major inducer, interleukin-6 (39), have been found in patients with unstable angina, and are associated with higher rates of death/MI at hospital discharge and at 1 year (40,41,42).

The inflammatory stimulus for triggering expression of soluble cell adhesion molecules has been shown to persist for 6 months after presentation with NSTEACS (43). The inflammatory nature of the cells at the site of plaque rupture and shared T-cell receptor sequences in clonotypes from different patients (43,44) have led to speculation that chronic stimulation by a common antigen or certain bacterial infections, such as Chlamydia pneumoniae or Helicobacter pylori, may be associated with an increased risk of plaque rupture (45,46,47).
The T-cell response in patients with unstable angina is antigen-driven and directed toward antigens carried in culprit coronary atherosclerotic plaques (48). Cytomegalovirus has been found in atheromatous plaque specimens, but active replication of the virus is not thought to be a major cause of plaque instability (49).

After plaque rupture or fissuring, subendothelial adhesive proteins, collagen tissue factor, and von Willebrand factor are exposed, and tissue factor is released. Platelets adhere to GP Ia and Ib, change their shape, and release serotonin, thromboxane A₂, and adenosine diphosphate (ADP). In animal models, episodic platelet aggregation at sites of coronary stenosis has been shown to cause cyclic coronary blood flow (50). Platelet emboli have been found downstream from atheromatous plaques in small intramyocardial vessels from patients who have died suddenly (51). Platelet activation may manifest in anginal episodes associated with increased urinary levels of thromboxane B₂ (52).

Released tissue factor combines with factor VII, stimulating the extrinsic coagulation cascade to form thrombin, a very potent stimulus of platelet aggregation. At the platelet surface, factors V and X are activated to form the prothrombinase complex, which generates more thrombin. Damage to endothelium without plaque rupture may also result in thrombus formation (53). Evidence of a hypercoagulable state has been found in patients with unstable angina (54). During anginal episodes, increases occur in the plasma concentrations of prothrombin fragments 1 and 2 (signifying increased activity of factor X_a and thrombin formation) and fibrinopeptide A (a sign of increased thrombin activity and fibrin formation). These markers remain elevated for at least 6 months after ACS (55), and platelets remain activated for at least 28 days (56). Intracoronary thrombus is visualized in 35% to 52% of patients having coronary angiography for unstable angina (8,57,58,59); the detection rate rises to 70% to 93% when angioscopy is performed (23,58,60,61,62). The presence of thrombus at angiography denotes an increased risk of recurrent ischemia and MI (57). Another potential mechanism of ACS is increased narrowing of a coronary artery due to progression of atherosclerosis or plaque rupture (63).

Cocaine is toxic to the heart, and its use may be associated with ACS, even in patients with angiographically normal coronary arteries (64). There is a circadian variation in the onset of ACS (65). Platelet aggregation increases in the morning, elevating the risk of MI or sudden death (66). Activities such as heavy exertion, which produces acute physiologic effects, may also trigger ischemic events (67).

Risk profiling is critical because it determines the choice of treatment strategy and provides prognostic information for the patient and relatives. It also enhances the cost effectiveness of patient care by allowing evidence-based treatments to be targeted at patients most likely to benefit from them. Risk profiling should take into account clinical factors, ECG features, cardiac marker levels, evidence of spontaneous or inducible ischemia, measures of left ventricular function, and coronary anatomy (Table 18.2) (1,146,147). Certain clinical features are not included in risk profiling models, and the clinical assessment should always be regarded as paramount. For instance, a patient who is gray, sweating, and anxious is likely to be at higher risk than one who is relaxed and appears well. Patients should be assessed fully at presentation and then reviewed at 6 to 8 hours for recurrence of ischemia, response to treatment, and the results of cardiac marker tests, particularly the troponins. Further risk profiling should be done at 12 and 24 hours and again before discharge.

Low-risk patients should be discharged early, advised to report any changes in symptoms (e.g., recurring discomfort at rest or at night), and reviewed subsequently at an outpatient clinic. Intermediate-risk patients should receive intensive antithrombotic therapy and close monitoring. If recurrent ischemia occurs or troponin levels rise, early angiography should be performed with a view to revascularization. If symptoms settle and troponin levels do not rise, tests for inducible ischemia should be performed. If the tests show ischemia at a low workload, angiography should be performed with revascularization as appropriate; otherwise, the patient can be managed medically.
High-risk patients should receive intensive antithrombotic therapy and have early angiography and revascularization if their coronary anatomy is suitable.

Various risk models have been developed for NSTEACS (Table 18.3) (148,149,150,151,152). The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) investigators (149) found that most of the prognostic information was provided by seven variables: age, gender, Canadian Cardiovascular Society angina classification, heart rate, blood pressure, presence of rales, and presence of ST depression. Different models were developed for the endpoints of death and death/MI, and for NSTEMI and NSTEACS without MI.

The TIMI-11B risk model is based on seven readily quantifiable variables: age 65 years or older, three or more risk factors for coronary artery disease (CAD), prior coronary stenosis of 50% or more, ST-segment changes at presentation, two or more anginal events within the previous 24 hours, use of aspirin within the previous 7 days, and elevated serum cardiac marker levels (150). The advantage of this model is its simplicity. An electronic version of the model is available for palmtop computers (153).

The FRISC risk score includes seven risk factors: age over 70 years, male gender, diabetes, previous MI, ST depression, increased troponin levels, and inflammatory markers (CRP or interleukin-6) (152). In FRISC-II (113), invasive treatment was most beneficial in patients with five or more of these factors who had a 12-month relative risk (RR) for death/MI of 0.34 (95% confidence interval [CI] 0.15–0.78) versus 0.69 (95% CI 0.50–0.94) in patients with three or four risk factors (152). Invasive treatment had no benefit in patients with two or more risk factors. The Global Registry of Acute Coronary Events (GRACE) risk algorithm (151) was developed from an international registry. It includes renal function, and may perform slightly better than trial-based risk scores (154,155).

The findings at coronary angiography depend on the population studied. Angiography outlines only the arterial lumen, and may not detect large plaques within the arterial wall (163). In the TIMI-IIIB trial (166), 19% of patients had no coronary stenoses of more than 60% narrowing, and 4% had a left main coronary stenosis of more than 50%. Single-vessel disease was found in 38%, double-vessel disease in 29%, and triple-vessel disease in 15%. Eccentric plaques and complex plaques (Fig. 18.6) are more common in patients with unstable angina than in those with chronic stable angina (8). Coronary artery thrombi may be detected in 40% of patients having angiography soon after an episode of rest pain (57). Impaired coronary flow is common (167,168).

Left ventriculography may detect abnormalities of regional wall motion caused by previous MI or “hibernation” owing to prolonged or recurrent ischemia. Wall motion abnormalities and changes in ventricular volumes may occur during episodes of acute ischemia (169). The presence of mitral regurgitation can be detected and its severity assessed.

The prognosis is worse in patients with NSTEACS than in patients with STEMI (83). Within 1 month, 2% to 5% die and 5% to 16% have an MI (91,170,171). Within 1 year, 26% to 35% require readmission to hospital for recurrent symptoms (172) and 4% to 15% die (166,172,173,174,175,176). Patients with unstable angina and a normal coronary angiogram have good short- (177) and long-term prognoses (178).

In a TACTICS–TIMI-18 substudy of patients without stenoses of 50% or more (179), the 6-month death/MI rate was 3.1% in those with elevated troponin I levels versus 0% in those without elevated troponin I levels. These patients may have had elevated troponin levels for another reason, or they may have had coronary atherothrombosis undetected by angiography. Coronary artery spasm may also have played a role (117).