Unstable Angina 

Chest pain is a nonspecific symptom that can have cardiac or noncardiac causes (see Differentials). The term angina is typically reserved for pain syndromes arising from presumed myocardial ischemia.

The traditional term of unstable angina was first used 3 decades ago and was meant to signify the intermediate state between myocardial infarction and the more chronic state of stable angina. The old term, preinfarction angina, conveys the clinical intent of intervening to attenuate the risk of myocardial infarction or death. Patients with this condition have also been categorized according to their presentation, diagnostic test results, or course over time; these categories include new-onset angina, accelerating angina, rest angina, early postinfarct angina, and early postrevascularization angina.

Unstable angina belongs to the spectrum of clinical presentations referred to collectively as acute coronary syndromes, which range from ST-segment elevation myocardial infarction (STEMI) to non–ST-segment elevation myocardial infarction (NSTEMI). Unstable angina is considered to be an acute coronary syndrome in which there is no release of the enzymes and biomarkers of myocardial necrosis.

For practical purposes in this article, the term unstable angina includes non–Q-wave myocardial infarction (NQMI), because this cannot be confirmed or excluded during the initial contact with the patient. (Unstable angina shares the pathophysiology and evaluation of, as well as treatments for, NQMI and Q-wave myocardial infarction.)

Although the etiology and definition of unstable angina can be broad, interplay between disrupted atherosclerotic plaque and overlaid thrombi is present in many cases of unstable angina, with consequent hemodynamic deficit or microembolization. This is distinct from stable angina, in which the typical underlying cause is a fixed coronary stenosis with compromised blood flow and slow, progressive plaque growth that allows for the occasional development of collateral flow.

Other causes of angina, such as hypertrophic obstructive cardiomyopathy (HOCM) or microvascular disease (syndrome X), cause ischemia by means of different mechanisms and are considered separate entities.

Factors involved in the etiology of unstable angina include the following:

• Supply-demand mismatch
• Plaque disruption or rupture
• Thrombosis
• Vasoconstriction
• Cyclical flow

Supply-demand mismatch

The myocardial ischemia of unstable angina, like all tissue ischemia, results from excessive demand or inadequate supply of oxygen, glucose, and free fatty acids.

Increased myocardial oxygen demand may be caused by the following:

• Fever
• Tachyarrhythmias (eg, atrial fibrillation or flutter)
• Malignant hypertension
• Thyrotoxicosis
• Pheochromocytoma
• Cocaine use
• Amphetamine use
• Aortic stenosis
• Supravalvular aortic stenosis
• Obstructive cardiomyopathy
• Aortovenous shunts
• High output states
• Congestive failure

Decreased oxygen supply may be caused by the following:

• Anemia
• Hypoxemia
• Polycythemia
• Hypotension

The above causes must be investigated because a number of them are reversible. For instance, anemia from chronic GI bleeding is not uncommon in elderly patients. This can coexist with coronary artery disease. However, patients may not benefit or may be harmed by treatments such as anticoagulants and antiplatelet drugs. Avoidance or treatment of the underlying condition is paramount.

Excess demand from increased myocardial workload (heart rate–systolic pressure product) or wall stress is responsible for nearly all cases of stable angina and perhaps one third of all episodes of unstable angina.

Plaque disruption

Accumulation of lipid-laden macrophages and smooth muscle cells, so-called foam cells, occurs within atherosclerotic plaques. The oxidized low-density lipoprotein cholesterol (LDL-C) in foam cells is cytotoxic, procoagulant, and chemotactic. As the atherosclerotic plaque grows, production of macrophage proteases and neutrophil elastases within the plaque can cause thinning of the fibromuscular cap that covers the lipid core. Increasing plaque instability coupled with blood-flow shear and circumferential wall stress lead to plaque fissuring or rupture, especially at the junction of the cap and the vessel wall.

The pathogenesis of acute coronary syndrome is shown in the image below.

The degree and consequence of plaque disruption covers a wide spectrum. Minor fissuring is typically nonocclusive and hence clinically silent, and repeat occult episodes of plaque ulceration and healing with a gradual growth of plaque volume have been histologically documented. Moderate to large plaque disruptions commonly result in unstable angina or acute infarction.

As many as one half of myocardial infarctions are due to lesions that are angiographically insignificant.^[1] Moreover, recurrent major adverse cardiovascular events (MACE) are not caused by the original culprit coronary site in as many as one half of cases (ie, a different lesion is the cause). Hence, angiographically mild lesions can still be dangerous because they have an unstable thin-cap fibroatheroma (TCFA) or because they actually overlie a large amount of vessel wall plaque burden that can occlude or rupture. This means that focal treatments such as percutaneous coronary intervention (PCI) is incomplete and that medical therapy to protect the entire vascular tree is complementary and crucial, particularly in patients with a history of ACS.

Vasoconstriction and thrombosis

Most patients with acute coronary syndrome have recurrent transient reduction in coronary blood supply because of vasoconstriction and thrombus formation at the site of atherosclerotic plaque rupture. These events occur because of episodic platelet aggregation and complex interactions among the vascular wall, leukocytes, platelets, and atherogenic lipoproteins.

Exposure of subendothelial components provokes platelet adhesion and activation. Platelets then aggregate in response to exposed vessel wall collagen or local aggregates (eg, thromboxane, adenosine diphosphate). Platelets also release substances that promote vasoconstriction and production of thrombin. In a reciprocating fashion, thrombin is a potent agonist for further platelet activation, and it stabilizes thrombi by converting fibrinogen to fibrin.

The nonocclusive thrombus of unstable angina can become transiently or persistently occlusive. Depending on the duration of occlusion, the presence of collateral vessels, and the area of myocardium perfused, recurrent unstable angina, NQMI, or Q-wave infarction can result.

Vasospasm and cyclic flow variation

Vasospasm, provoked by either ergonovine or acetylcholine, is a common finding in patients with acute coronary syndrome, particularly in Taiwanese and Japanese patients. Although correlated with chest pain, whether this coronary hyperreactivity causes acute coronary syndrome or is simply an associated finding is not known.^[2]

Acute coronary syndromes may involve a clot in flux (ie, forming and enlarging, chipping-off and embolizing). This dynamic clot formation and/or lysis, over time, in conjunction with coronary vasoreactivity and resistance in the microvascular bed, causes intermittent and alternating (or cyclical) occlusion and flow.

In the United States, the incidence of unstable angina is increasing, and nearly 1 million hospitalized patients each year have a primary diagnosis of unstable angina.

A similar number of unstable angina episodes likely occur outside the hospital and are unrecognized or managed in the outpatient setting. With heightened public awareness, improved survival after myocardial infarction, and aging of the population, this number should continue to rise despite primary and secondary prevention measures.

US demographics for unstable angina

Reasonably representative statistical estimates for unstable angina can be obtained from 2 registries, the Global Unstable Angina Registry and Treatment Evaluation (GUARANTEE) registry^[3] or the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA (CRUSADE) registry.

GUARANTEE involved 3000 consecutive hospital admissions for unstable angina in 35 US hospitals in 6 geographic regions (Northeastern, Mideastern, Midwestern, Southeastern, Southwestern, Northwestern) from September 1995 to August 1996.

CRUSADE registered more than 180,000 patients with NSTEMI in the US from 2001-2006, targeting high-risk patients with unstable angina or NSTEMI using the following inclusion criteria, either separately or in combination:

• Chest pain or anginal equivalent at rest, more than 10 minutes in duration
• Ischemic electrocardiographic changes (ST-segment depression >0.5 mm, transient ST-segment elevation 0.5–1.0 mm lasting for< 10min); and/or
• Elevated markers of myocardial necrosis (CK-MB and/or troponin I or T > the upper limit of normal for the local laboratory assay used at each institution)

The demographics and characteristics of patients in the GUARANTEE registry compared with the CRUSADE registry are shown in Table 1.

Table 1. Patient Characteristics, GUARANTEE Versus CRUSADE (Open Table in a new window)

International demographics for unstable angina

The best international demographic data available are from the Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) registry. Table 2 lists characteristics for 7987 patients, from 95 hospitals across 6 countries, with acute myocardial ischemia without ST elevation.

Table 2. Demographic Characteristics of Patients in the International OASIS-2 Registry (Open Table in a new window)

Because unstable angina is intimately linked to the incidence of coronary events, an approximation of international trends might be found in the Monitoring Trends and Determinants in Cardiovascular Diseases (MONICA) Registry sponsored by the World Health Organization (WHO). This large project monitored more than 7 million people aged 35-64 years from 30 populations in 21 countries from the mid 1980s.

In the study, the highest average rates of heart disease were found in Glasgow and Belfast, United Kingdom; North Karelia and Kuopio, Finland; Newcastle, Australia; and Warsaw, Poland. The lowest average myocardial infarction rates, and presumably unstable angina rates, were observed in Beijing, China; Toulouse, France; Catalonia, Spain; Vaud-Fribourg, Switzerland; and Brianza, Italy.

The GRACE registry is prospectively tracking contemporary acute coronary syndrome treatment and outcome across 30 countries, now accumulating more than 100,000 patients.^[4]

Disparities in unstable angina between black and white populations

Disparities in outcomes and the prevalence of risk factors among different ethnic groups have been widely reported. For instance, as a group, blacks exhibit a higher prevalence of atherosclerotic risk factors (eg, hypertension, diabetes mellitus, smoking), greater left ventricular mass, and decreased peripheral vasodilatory response. Relative to whites, myocardial infarction more frequently results in death in blacks at young ages.

Fewer myocardial events but more cerebral complications have been observed in black patients with unstable angina in randomized clinical trials of heparin versus hirudin (the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries II [GUSTO II] trial) or eptifibatide versus placebo (the Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy [PURSUIT] trial). This may be due to the enhanced fibrinolytic activity and higher prevalence of hypertension in this population.

Differences also exist in the delivery and response to medical care. Whites have a higher rate of catheterization, angioplasty, and bypass surgery than other racial groups.

Studies have shown equivalent short-term (30-day) mortality rates from unstable angina (including NQMI) for blacks, but over the long term, persistent worse outcomes have been demonstrated.

Sex trends in unstable angina

Women with unstable angina are older and have a higher prevalence of hypertension, diabetes mellitus, congestive heart failure, and family history of coronary artery disease than men. Men tend to have a higher previous incidence of myocardial infarction and revascularization, a higher proportion of positive cardiac enzymes on admission, and higher rates of catheterization and revascularization. However, outcome is related more to the severity of the illness than to sex.

Age trends in unstable angina

The mean age of presentation with unstable angina is 62 years, with an age range of 23-100 years. To put this in perspective, the mean age is 60 years for patients in clinical trials for myocardial infarction, about 67 years for carotid artery stenosis, and 63 years for congestive heart failure. On average, women with unstable angina are 5 years older than men on presentation, with approximately half of women older than 65 years, as opposed to only about a third of men. Blacks tend to present at a slightly younger age than do people of other races.

The risk of myocardial infarction, complications, and death in unstable angina varies because of the broad clinical spectrum that is covered by the term unstable angina. The aggressiveness of the therapeutic approach should be commensurate with the individualized estimated risk.

Patients who present with new ST-segment deviation (1 mm or greater) have a 1-year death or myocardial infarction rate of 11%, compared with a rate of only 6.8% in patients with isolated T-wave inversion.

Older studies showed the incidence of death in the early weeks after hospitalization to be approximately 4% and the incidence of myocardial infarction to be approximately 10%.

Thirty-day event rates are the current standard for cross-comparing studies. The aggregate data for the more than 40,000 patients with acute coronary syndromes, as derived from studies using contemporary treatments (albeit in varying degrees), indicate improving outcomes (see Table 3 below). The myocardial infarction and 30-day death rates are currently around 8.5% and 3.5%, respectively, despite increased disease complexity and an aging cohort.

The Recursos Empleados en el Sindrome Coronario Agudo y Tiempos de Espera (RESCATE) investigators from Spain reported a 1.8% mortality rate and a 5.1% myocardial infarction rate at 28 days (n = 791, consecutive series between 1992 and 1994, early revascularization rate about 6%) in patients with unstable angina.^[5] In comparison with the therapeutically aggressive and predominantly North American studies listed in Table 2 (see Epidemiology), these adverse event rates seem lower, probably because of the healthier case-mix, which illustrates the difficulties of direct outcome comparisons between institutions and countries, as well as across different trials.

Table 3. Thirty-Day Clinical Outcome in Patients With Acute Coronary Syndromes in Clinical Trials (Open Table in a new window)

Prognostic indicators

Of note, studies have shown that the following are significant prognosticators for poor outcome:

• Ongoing congestive heart failure
• Presence/history of poor left ventricular ejection fraction (LVEF)
• Hemodynamic instability
• Recurrent angina despite intensive anti-ischemic therapy
• New or worsening mitral regurgitation
• Sustained ventricular tachycardia

Although these factors were not evaluated in the TIMI Risk Score model (see Physical Examination), they should be taken into consideration when the level of care is decided.

Other predictors of worse long-term outcome in unstable angina include underlying left ventricular systolic dysfunction and a more widespread extent of coronary artery disease.

The level of troponin positivity correlates with intermediate-term death in a dose-dependent fashion (ranging from 1.0-7.5% at 6 wk) independent of age, CK-MB levels, and ST-segment deviation.

Before hospital discharge, patients and their family members should be educated about the manifestations of myocardial infarction and actions that need to be taken in that eventuality. They should also receive cardiopulmonary resuscitation (CPR) training.

For excellent patient education resources, visit eMedicine's Cholesterol FAQs, Circulatory Problems Center, and Heart Center.

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