Official reprint from UpToDate®

www.uptodate.com
© 2021 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Angina pectoris: Chest pain caused by fixed epicardial

coronary artery obstruction
Author: Simon A Mahler, MD, MS
Section Editor: Juan Carlos Kaski, DSc, MD, DM (Hons), FRCP, FESC, FACC, FAHA
Deputy Editor: Nisha Parikh, MD, MPH

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Sep 2021. | This topic last updated: Feb 09, 2021.

INTRODUCTION

Myocardial ischemia is one of the more common causes of chest pain (also termed "chest
discomfort") in adults. Angina pectoris, or angina for short, is the term used when chest
discomfort is thought to be attributable to myocardial ischemia. In patients with myocardial
ischemia, chest discomfort is often but not always present, although other associated
symptoms with ischemia may be present (such as exertional shortness of breath, nausea,
diaphoresis, fatigue). This has been termed "anginal equivalent." Myocardial ischemia in the
absence of chest discomfort or another anginal equivalent symptoms is termed "silent
ischemia." (See "Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and
prognosis".)

For patients with suspected myocardial ischemia, timely diagnosis and treatment is necessary
to treat symptoms and possibly also reduce morbidity and mortality. Rapid diagnosis is
particularly important in patients with a possible acute coronary syndrome (unstable angina,
non-ST elevation myocardial infarction, or ST-elevation myocardial infarction). (See "Initial
evaluation and management of suspected acute coronary syndrome (myocardial infarction,
unstable angina) in the emergency department".)

Myocardial ischemia can occur due to fixed epicardial coronary artery ("macrovascular")
obstruction, coronary microvascular obstruction (ischemia with no obstructive coronary artery
disease [INOCA]), or coronary artery spasm. (See "Microvascular angina: Angina pectoris with
normal coronary arteries" and "Vasospastic angina" and "Chronic coronary syndrome: Overview
of care", section on 'Introduction'.)

This topic will review the pathophysiology, clinical features, and diagnosis of ischemic chest
discomfort due to fixed epicardial coronary artery obstruction. Discussions of other cardiac and
noncardiac causes of chest pain, and their clinical presentations, are found elsewhere. Links to
those topics are found throughout this topic.

PATHOPHYSIOLOGY OF MYOCARDIAL ISCHEMIA

Myocardial ischemia, and consequently angina, occurs when myocardial oxygen demand
exceeds oxygen supply ( table 1). Detailed reviews of the pathophysiology of myocardial
ischemia are available in the scientific literature [1].

Myocardial oxygen demand — There are four major factors that determine myocardial work
and therefore myocardial oxygen demand:

● Heart rate
● Systolic blood pressure (the clinical marker of afterload)
● Myocardial wall tension or stress (the product of ventricular end-diastolic volume or
preload and myocardial muscle mass)
● Myocardial contractility

Myocardial contractility and wall stress cannot be measured clinically. As a result, myocardial
oxygen demands are estimated clinically by the multiplication product (also called the double
product) of the heart rate and the systolic blood pressure. Individuals reproducibly experience
angina during exercise testing when functional capacity exceeds a well-defined
angina threshold or absolute double product value.

Myocardial oxygen supply — The major determinants of oxygen supply are the oxygen
carrying capacity of the blood, which is affected by a variety of factors including oxygen tension
and the hemoglobin concentration; the degree of oxygen unloading from hemoglobin to the
tissues, which is related to 2,3 diphosphoglycerate levels; and the coronary artery blood flow
delivered to the myocardium. The latter is influenced by:

● Coronary artery diameter and tone (resistance) [2,3].

● Collateral blood flow.

 ● Perfusion pressure. This is determined by the pressure gradients from the aorta to the
coronary arteries. Coronary blood flow from the epicardium to endocardial capillaries is
determined by the left ventricular end-diastolic pressure.

● Heart rate, which affects the duration of diastole; importantly, coronary artery flow
primarily occurs during diastole. The percent of diastolic time decreases as the heart rate
increases. Thus, heart rate is a determining factor for both oxygen demand and supply.

MECHANISMS OF ANGINA

The mechanisms responsible for the sensation of angina are complex and not entirely
understood. An important feature is that myocardial ischemia results in the development of
acidosis and also reduces the formation of adenosine triphosphate (ATP), the loss of the normal
ATP sodium-potassium pump, the loss of myocardial membrane integrity, and the release of
chemical substances that stimulate chemosensitive and mechanoreceptive receptors
innervated by unmyelinated nerve cells found within cardiac muscle fibers and around the
coronary vessels [4]. The substances that are released include lactate, serotonin, bradykinin,
histamine, reactive oxygen species, and adenosine [5-7]. In addition, there are substances
released from platelets, which often spontaneously aggregate in the area of a coronary artery
stenosis, which may also be responsible for myocardial ischemia and angina. These include
serotonin, thromboxane A2, and 5-hydroxytyrptamine [8,9].

There is substantial evidence that the primary mediator of angina is adenosine, via stimulation
of the A1 adenosine receptor [10-13]. It is also possible that venodilation as a response to
ischemia can activate these receptors. The nerve fibers travel along the sympathetic afferent
pathways from the heart and enter the sympathetic ganglia in lower cervical and upper thoracic
spinal cord (C5-6 and T1-T6). Impulses are then transmitted via the ascending spinothalamic
pathways to the medial and lateral thalamus and ultimately activate several areas of the
cerebral cortex [4].

Angina is a discomfort that is referred to the corresponding dermatomes that supply

sympathetic afferent nerves to the same segments of the spinal cord as the heart [4].
Furthermore, stimulation of sensory receptors in different myocardial regions results in the
transmission via the same neural pathway [13]. These characteristics account for two typical
features of angina: It is often a diffuse discomfort felt in the chest, neck, lower jaw, and down
the arm (typically the left arm, although some patients experience right arm discomfort). Most
patients experience angina in the same distribution, regardless of which area of the
myocardium is ischemic [13]. An exception is often post-cardiac surgery, as this may interrupt
and alter the neural supply to the heart, which may affect the distribution of angina.

CLINICAL ENTITIES ASSOCIATED WITH MYOCARDIAL ISCHEMIA

As mentioned above, any significant imbalance between myocardial oxygen supply and
demand can lead to myocardial ischemia and angina. Patients may have a supply or a demand
problem, but many have both. (See 'Pathophysiology of myocardial ischemia' above.)

Decreased supply — In most of the world, atherosclerotic obstruction of one or more coronary
arteries (coronary artery disease) is the most common cause of myocardial ischemia. Other
clinical conditions associated with a decrease in supply due to disease in one or more coronary
arteries include coronary artery vasospasm, coronary microvascular disease, myocardial
bridging, fibrosis, embolism, dissection, and arteritis. Left ventricular hypertrophy may result in
a reduction in subendocardial blood flow and oxygen supply; this may result in angina. This
may be particularly important with the development of arterial hypertension, which may
increase left ventricular end-diastolic pressure, resulting in impairment of capillary flow in the
subendocardium.

Other examples of inadequate supply include shock (any cause), hypoxemia, anemia, and
postprandial angina resulting from a redistribution of blood flow away from territories supplied
by severely stenosed coronary arteries to those supplied by less diseased or normal arteries (ie,
a steal phenomenon) [14,15].

Increased demand — Clinical conditions associated with an increase in myocardial oxygen

demand include any situation in which there are increased catecholamines or sympathetic tone,
as with vigorous exertion or mental stress, tachycardia for any reason, hypertension, left
ventricular hypertrophy (with hypertensive heart disease or aortic stenosis), and right
ventricular hypertrophy (with pulmonary hypertension) [16].

CLINICAL FEATURES

Most patients with myocardial ischemia will present with classic angina pectoris as the primary
clinical manifestation. Classic angina pectoris is described as a pressure, heaviness, tightness,
or constriction in the center or left of the chest that is precipitated by exertion and relieved by
rest. It is generally not described as pain (sharp or dull), or needles and pins.
However, some patients with myocardial ischemia may present with angina-equivalent
symptoms such as exertional shortness of breath, nausea, diaphoresis, or fatigue rather than
chest discomfort. Patients may also experience ischemic episodes without chest discomfort or
anginal equivalent symptoms. (See "Silent myocardial ischemia: Epidemiology, diagnosis,
treatment, and prognosis".)

The initial presentation of myocardial ischemia with angina may be one of a stable pattern or
an acute coronary syndrome. Patients with recent onset of chest discomfort, episodes of rest
chest discomfort, or one or more prolonged episodes (more than 20 minutes), should be
evaluated in an acute care facility for the possibility of an acute coronary syndrome. However,
every patient has their first episode of chest discomfort so that recent onset is not necessarily
an acute coronary syndrome, particularly if the pattern of occurrence is stable and predictable
(ie, with exertion). (See "Initial evaluation and management of suspected acute coronary
syndrome (myocardial infarction, unstable angina) in the emergency department".)

History — Elements of the history that are critically important include characteristics of the
discomfort, associated symptoms, precipitating factors, and information about social and
family history.

Typical qualities of anginal pain — Clinicians should attempt to elicit information about the
following characteristics of the discomfort:

● Quality − Angina is usually characterized more as a discomfort rather than pain. Terms
frequently used by patients include squeezing, tightness, pressure, constriction, strangling,
burning, heart burn, fullness in the chest, band-like sensation, knot in the center of the
chest, lump in throat, ache, heavy weight on chest (elephant sitting on chest), like a bra too
tight, and toothache (when there is radiation to the lower jaw) [17]. In some cases, the
patient cannot qualify the nature of the discomfort, but places his or her fist in the center
of the chest, known as the "Levine sign."

It is generally not described as sharp, dull-aching, knife-like, stabbing, or pins and needles-
like. In a report of patients presenting to the emergency department, "sharp" or "stabbing"
pain was a low risk description, particularly when the pain was pleuritic or positional, was
fully reproducible by palpation, and the patient had no history of angina or myocardial
infarction [18].

The following additional characteristics are typically seen:

• Angina is typically gradual in onset and offset, with the intensity of the discomfort
increasing and decreasing over several minutes. In contrast, noncardiac pain is often of
 greatest intensity at its onset and often has an abrupt onset and offset.

• Since angina is a referred discomfort, patients tend to have the same quality of chest
discomfort with recurrent ischemic episodes [13]. Generally, it is felt in the same
location. The discomfort is generally the same prior to or with a myocardial infarction
and is the same quality as prior to revascularization by either surgery (although the
location may be different due to disruption of neural innervation of the heart) or
percutaneous coronary intervention.

• Angina is a constant discomfort that does not change with respiration or most changes
in position (one exception is lying down, which increases venous return). It is also not
provoked or worsened with palpation of the chest wall. However, the presence of a
change in pain with respiration (or position) or pain elicited by palpation does not
exclude angina as the cause.

● Location and radiation − As noted above, angina is a referred pain due to involvement of
a neural reflex pathway via the thoracic and cervical nerves. As a result, it is not felt in a
specific spot, but is usually a diffuse discomfort that may be difficult to localize.

The patient often indicates the entire chest when asked where the discomfort is felt. Pain that
localizes to one small area of the chest is more likely of chest wall or pleural origin rather than
visceral.

Angina is referred to the corresponding dermatomes (C5-6 and T1-T6) that supply afferent
nerves to the same segments of the spinal cord as the heart. Thus, angina often radiates to
other parts of the body, including the upper abdomen (epigastric), shoulders, arms (upper and
forearm), wrist, fingers, neck and throat, lower jaw and teeth (but not upper jaw), and rarely to
the back (specifically the interscapular region) [19,20]. Radiation to both arms is a stronger
predictor of acute myocardial infarction. The location and radiation of angina is usually the
same each time. Occasionally, the location and radiation, but not quality, may be different after
bypass surgery due to the disruption of the neural innervation of the heart.

Isolated back pain is unusual in patients with angina. However, it may be seen with an aortic
dissection that also involves the coronary arteries. (See "Clinical features and diagnosis of acute
aortic dissection".)

● Provoking factors − Angina is often elicited by activities and situations that increase
myocardial oxygen demand, including physical activity, cold, emotional stress, sexual
intercourse, meals, or lying down (which results in an increase in venous return and
increase in wall stress) [21-23]. Patients should be questioned about the use of cocaine or
 other recreational drugs, as they may trigger myocardial ischemia. (See "Clinical
manifestations, diagnosis, and management of the cardiovascular complications of cocaine
abuse", section on 'Myocardial ischemia/infarction'.)

Postprandial pain is generally considered to be gastrointestinal in origin. However, it may also

be anginal, especially in patients with severe ischemia (eg, left main or three vessel coronary
disease) [15].

● Timing − Angina occurs more commonly in the morning due to a diurnal increase in
sympathetic tone. Enhanced sympathetic activity raises heart rate, blood pressure, vessel
tone and resistance (resulting in a reduced vessel diameter that causes any fixed lesion to
be more occlusive), and promotes platelet aggregation (resulting in the release of
vasoactive substances, such as serotonin and thromboxane A2) [8,9].

● Duration and relief − Classic angina is often relieved with termination of the provoking
factor. Angina generally lasts for two to five minutes. It is not a fleeting discomfort, which
lasts only for a few seconds or less than a minute, and it generally does not last for 20 to 30
minutes, unless the patient is experiencing an acute coronary syndrome, especially
myocardial infarction.

Factors that reduce oxygen demand or increase oxygen supply will result in relief of angina.
These include cessation of activity or termination of the provoking factor, use of nitroglycerin
(which is a venodilator, reducing venous return, and a coronary artery vasodilator that increases
coronary blood flow), and sitting up (which reduces venous return and preload).

Relief of chest discomfort with nitroglycerin is not specific for angina, since a similar response
may be seen with esophageal spasm or other gastrointestinal problems as nitroglycerin also
relaxes smooth muscle. In a review of 459 patients presenting to an emergency department
with chest pain, the percentage of patients with relief of chest discomfort with nitroglycerin was
similar among those with and without active coronary disease (35 versus 41 percent) [24].

Atypical features — Specific chest pain characteristics can be used to help differentiate

cardiac from noncardiac causes ( table 2A-B). (See "Outpatient evaluation of the adult with
chest pain".)

In two systematic reviews, the following characteristics were found to be more typical of
nonischemic chest discomfort [25,26]:

● Pleuritic pain, sharp or knife-like pain related to respiratory movements or cough.

● Primary or sole location in the mid or lower abdominal region.
 ● Any discomfort localized with one finger.
● Any discomfort reproduced by movement or palpation.
● Constant pain lasting for days.
● Fleeting pains lasting for a few seconds or less.
● Pain radiating into the lower extremities or above the mandible.

However, some patients with an acute coronary syndrome present with atypical types of chest
pain. In one study, acute ischemia was diagnosed in 22 percent of patients who presented with
sharp or stabbing pain and 13 percent who presented with pleuritic-type pain [18].

In addition, some patients who appear to have a noncardiac cause of chest pain have other
serious conditions including acute aortic dissection, pulmonary embolism, tension
pneumothorax, myocarditis, perforating peptic ulcer, and esophageal rupture ( table 2A-B)
[27]. It is essential to consider these alternate diagnoses to avoid potentially dangerous errors
in management, such as the administration of thrombolytic therapy to a patient with an aortic
dissection.

Associated symptoms — Angina is often associated with other symptoms. Dyspnea is a

common anginal equivalent, and its presence is associated with a higher cardiovascular death
rate compared with patients with typical angina. Dyspnea in the setting of angina may reflect
pulmonary congestion due to an elevation in left ventricular end diastolic pressure related to
failure of the myocardium to relax normally in diastole (as relaxation or lusitropy is energy
dependent). The resulting diastolic "stiffness" or diastolic dysfunction results in an increase in
left ventricular end diastolic pressure, left atrial pressure, and pulmonary venous pressure,
which is transmitted to the pulmonary vessels. (See "Heart failure with preserved ejection
fraction: Clinical manifestations and diagnosis".)

Other symptoms may include belching, nausea, indigestion, diaphoresis, dizziness,

lightheadedness, clamminess, and fatigue. These have been referred to as "angina equivalent"
symptoms and appear to be more common in women compared with men. However, these
symptoms may be seen with other etiologies for chest pain, especially gastrointestinal causes.

It is common for patients with diabetes mellitus, who often have autonomic (sympathetic)
dysfunction, to experience "silent ischemia" or best termed "discomfortless ischemia." (see
"Silent myocardial ischemia: Epidemiology, diagnosis, treatment, and prognosis"). They may
also present with anginal equivalent symptoms.

Social and family history — Many patients who are ultimately diagnosed with myocardial
ischemia have key pieces of information in the social and family histories. For example, risk
factors for coronary artery disease are often present in individuals with angina due to coronary
artery disease. (See "Overview of established risk factors for cardiovascular disease", section on
'Established risk factors for atherosclerotic CVD'.)

The family history may reveal members with premature cardiovascular disease or hypertrophic
cardiomyopathy. (See "Hypertrophic cardiomyopathy: Clinical manifestations, diagnosis, and
evaluation".)

Physical examination — Ischemia can produce impairment in myocardial function, which may

result in the following findings on physical examination. All disappear with resolution of the
ischemia. Some patients have none of these features.

Increase in heart rate — Ischemia can raise the heart rate even if the patient is receiving a
beta blocker or calcium channel blocker. The increase in heart rate is induced by reflex
sympathetic nervous system activation as a response to ischemia.

Elevation in blood pressure — Ischemia often causes a hypertensive blood pressure

response. The elevation in blood pressure is induced by both sympathetic activation in response
to ischemia and stimulation of the left anterior descending coronary artery chemoreceptor. This
chemoreceptor is stimulated by serotonin secreted as a result of platelet aggregation, which
often occurs in association with angina.

New heart sounds — Ischemia-induced myocardial dysfunction can lead to changes in the

normal heart sounds. The second heart sound may become paradoxically split due to delayed
relaxation of the left ventricular myocardium and delayed closure of the aortic valve. There may
also be a third or fourth heart sound. (See "Auscultation of heart sounds".)

New/changed murmurs — Impaired myocardial function may result in a new mitral

regurgitation murmur, which appears to be due to papillary muscle dysfunction causing apical
tethering or tenting of the leaflets, or changes in the intensity or timing of pre-existing
murmurs. (See "Auscultation of cardiac murmurs in adults" and "Management and prognosis of
chronic secondary mitral regurgitation".)

Precordial pulsation — Palpation of the chest wall may reveal abnormal pulsations that
correlate with transient left ventricular dysfunction. An area of dyskinesis may develop,
especially at the apex of the left ventricle or at the anterior axillary line (location of the left
ventricular wall), reflecting disease of the left anterior descending coronary artery. (See
"Examination of the precordial pulsation".)

Palpation of the left anterior chest wall at the anterior axillary line may reveal an abnormal
tapping in systole, which reflects the presence of an area of dyskinetic contraction or aneurysm.
Transient right ventricular dysfunction may lead to a transient right ventricular heave or sternal
pulsation.

Laboratory tests — For patients in whom the history and physical examination raise the
possibility of myocardial ischemia as the cause of chest discomfort, an electrocardiogram
should be obtained. An electrocardiogram obtained when the chest discomfort is present will
often show J point and ST-segment depression, which indicates subendocardial ischemia. When
the patient is asymptomatic, the electrocardiogram may be entirely normal. (See
"Electrocardiogram in the diagnosis of myocardial ischemia and infarction", section on
'Unexpected absence of diagnostic findings'.)

A chest radiograph is often ordered but is not likely to confirm or refute the diagnosis of
myocardial ischemia. Generally, the radiography is performed to screen for other causes of
chest pain (eg, enlarged aorta, broken rib). (See "Outpatient evaluation of the adult with chest
pain", section on 'Indications for chest radiograph'.)

Cardiac biomarkers (eg, troponin) are often obtained in patients with angina. They are unlikely
to be elevated in patients with intermittent and relatively brief angina episodes. However, they
may be useful when the anginal episode is more prolonged and for prognostication. If high-
sensitivity troponin assays are used, low levels of troponin are often detected in patients
experiencing stable angina. Increased high-sensitivity troponin levels are associated with
adverse outcomes [28,29]. (See "Troponin testing: Clinical use", section on 'Diagnosis of acute
MI'.)

DIAGNOSIS

The diagnosis of myocardial ischemia can often be made with a high likelihood based on the
history, physical examination, and electrocardiogram. Such patients have classic angina (see
'Clinical features' above), either a normal physical examination or features consistent with
myocardial ischemia (see 'Physical examination' above), and an electrocardiogram that is
normal in the absence of ongoing ischemia.

For example, in the patient with classic angina and multiple risk factors for coronary artery
disease, the diagnosis is highly likely.

For some patients, additional testing is necessary to secure the diagnosis with certainty.
Testing, particularly stress testing, is of value when the history is not completely consistent with
angina or in a high-risk patient with symptoms that are atypical for ischemia.
We perform some type of stress testing in most patients for the purpose of prognosis. (See
"Stress testing to determine prognosis of coronary heart disease".)

Differential diagnosis — Discussions of other cardiac and noncardiac causes of chest pain, and
their clinical presentations, are found elsewhere. (See "Outpatient evaluation of the adult with
chest pain" and "Evaluation of the adult with chest pain in the emergency department".)

RECOMMENDATIONS OF OTHERS

We broadly agree with the approach to diagnosis made in the 2014 American College of
Cardiology Foundation/American Heart Association/American College of Physicians/American
Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for
Cardiovascular Angiography and Interventions/Society for Thoracic Surgeons focused update of
an earlier guideline for the diagnosis and management of patients with stable ischemic heart
disease [30,31].

INFORMATION FOR PATIENTS

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the
Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade
reading level, and they answer the four or five key questions a patient might have about a given
condition. These articles are best for patients who want a general overview and who prefer
short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more
sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading
level and are best for patients who want in-depth information and are comfortable with some
medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print
or e-mail these topics to your patients. (You can also locate patient education articles on a
variety of subjects by searching on "patient info" and the keyword(s) of interest.)

● Basics topic (see "Patient education: Chest pain (The Basics)")

● Beyond the Basics topic (see "Patient education: Chest pain (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

● Myocardial ischemia is one of the more common causes of chest discomfort in adults.
Angina pectoris, or angina for short, is the term used when chest discomfort is thought to
be attributable to myocardial ischemia.

● The patient with angina often has a fairly typical history ( table 3) (see 'History' above):

• Angina is usually characterized more as a discomfort (pressure, squeezing,

constriction, choking, burning, tightness, knot in throat or chest) rather than pain
(sharp, stabbing, pins and needles-like).

• Angina is typically gradual in onset and offset. Once present, it is constant and does
not change with position or respiration.

• Angina is not felt in a specific spot, but is usually a diffuse discomfort that may be
difficult to localize.

• Angina is usually elicited by activities and situations that increase myocardial oxygen
demand.

• Angina generally lasts for two to five minutes.

• Angina is often associated with other symptoms; the most common are shortness of
breath, nausea, and diaphoresis.

● Myocardial ischemia may be accompanied by a normal cardiovascular examination or the

following (see 'Physical examination' above):

• Tachycardia

• Hypertension

• New and potentially abnormal heart sounds and murmurs or changes in a pre-existing
murmur.

● The diagnosis of myocardial ischemia can often be made with a high degree of certainty
based on the history, physical examination, and electrocardiogram. Such patients have
classic angina, either a normal physical examination or features consistent with myocardial
ischemia, and an electrocardiogram that is normal in the absence of ongoing ischemia.
Some patients may require stress testing for the purpose of diagnosis, but in most cases it
is performed for prognostic reasons. (See 'Diagnosis' above.)
ACKNOWLEDGMENT

The UpToDate editorial staff thank Dr. Philip Podrid for his past contributions as an author to
this topic review.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

1. Ibáñez B, Heusch G, Ovize M, Van de Werf F. Evolving therapies for myocardial

ischemia/reperfusion injury. J Am Coll Cardiol 2015; 65:1454.
2. Hillis LD, Braunwald E. Coronary-artery spasm. N Engl J Med 1978; 299:695.
3. Ganz P, Abben RP, Barry WH. Dynamic variations in resistance of coronary arterial
narrowings in angina pectoris at rest. Am J Cardiol 1987; 59:66.

4. Foreman RD. Mechanisms of cardiac pain. Annu Rev Physiol 1999; 61:143.
5. Benson CJ, Eckert SP, McCleskey EW. Acid-evoked currents in cardiac sensory neurons: A
possible mediator of myocardial ischemic sensation. Circ Res 1999; 84:921.
6. Longhurst JC, Tjen-A-Looi SC, Fu LW. Cardiac sympathetic afferent activation provoked by
myocardial ischemia and reperfusion. Mechanisms and reflexes. Ann N Y Acad Sci 2001;
940:74.
7. Fu LW, Longhurst JC. Interactions between histamine and bradykinin in stimulation of
ischaemically sensitive cardiac afferents in felines. J Physiol 2005; 565:1007.
8. Fu LW, Longhurst JC. Activated platelets contribute to stimulation of cardiac afferents
during ischaemia in cats: role of 5-HT(3) receptors. J Physiol 2002; 544:897.

9. Fu LW, Guo ZL, Longhurst JC. Undiscovered role of endogenous thromboxane A2 in

activation of cardiac sympathetic afferents during ischaemia. J Physiol 2008; 586:3287.
10. Sylvén C, Beermann B, Jonzon B, Brandt R. Angina pectoris-like pain provoked by
intravenous adenosine in healthy volunteers. Br Med J (Clin Res Ed) 1986; 293:227.
11. Lagerqvist B, Sylvén C, Beermann B, et al. Intracoronary adenosine causes angina pectoris
like pain--an inquiry into the nature of visceral pain. Cardiovasc Res 1990; 24:609.
12. Gaspardone A, Crea F, Tomai F, et al. Muscular and cardiac adenosine-induced pain is
mediated by A1 receptors. J Am Coll Cardiol 1995; 25:251.
13. Crea F, Gaspardone A, Kaski JC, et al. Relation between stimulation site of cardiac afferent
nerves by adenosine and distribution of cardiac pain: results of a study in patients with
 stable angina. J Am Coll Cardiol 1992; 20:1498.

14. Baliga RR, Rosen SD, Camici PG, Kooner JS. Regional myocardial blood flow redistribution
as a cause of postprandial angina pectoris. Circulation 1998; 97:1144.
15. Chung WY, Sohn DW, Kim YJ, et al. Absence of postprandial surge in coronary blood flow
distal to significant stenosis: a possible mechanism of postprandial angina. J Am Coll
Cardiol 2002; 40:1976.
16. Goldberg AD, Becker LC, Bonsall R, et al. Ischemic, hemodynamic, and neurohormonal
responses to mental and exercise stress. Experience from the Psychophysiological
Investigations of Myocardial Ischemia Study (PIMI). Circulation 1996; 94:2402.
17. Kreiner M, Okeson JP, Michelis V, et al. Craniofacial pain as the sole symptom of cardiac
ischemia: a prospective multicenter study. J Am Dent Assoc 2007; 138:74.
18. Lee TH, Cook EF, Weisberg M, et al. Acute chest pain in the emergency room. Identification
and examination of low-risk patients. Arch Intern Med 1985; 145:65.
19. Constant J. The clinical diagnosis of nonanginal chest pain: the differentiation of angina
from nonanginal chest pain by history. Clin Cardiol 1983; 6:11.
20. Christie LG Jr, Conti CR. Systematic approach to evaluation of angina-like chest pain:
pathophysiology and clinical testing with emphasis on objective documentation of
myocardial ischemia. Am Heart J 1981; 102:897.
21. Juneau M, Johnstone M, Dempsey E, Waters DD. Exercise-induced myocardial ischemia in a
cold environment. Effect of antianginal medications. Circulation 1989; 79:1015.

22. Kearney MT, Charlesworth A, Cowley AJ, MacDonald IA. William Heberden revisited:
postprandial angina-interval between food and exercise and meal composition are
important determinants of time to onset of ischemia and maximal exercise tolerance. J Am
Coll Cardiol 1997; 29:302.
23. Schiffer F, Hartley LH, Schulman CL, Abelmann WH. Evidence for emotionally-induced
coronary arterial spasm in patients with angina pectoris. Br Heart J 1980; 44:62.

24. Henrikson CA, Howell EE, Bush DE, et al. Chest pain relief by nitroglycerin does not predict
active coronary artery disease. Ann Intern Med 2003; 139:979.
25. Panju AA, Hemmelgarn BR, Guyatt GH, Simel DL. The rational clinical examination. Is this
patient having a myocardial infarction? JAMA 1998; 280:1256.
26. Braunwald, E, Mark, DB, Jones, RH, et al. Unstable Angina: Diagnosis and Management. Clin
ical Practice Guideline Number 10 (amended) AHCPR Publication No. 94-0602, Agency for H
ealth Care Policy and Research and the National Heart, Lung, and Blood Institute, Public He
alth Service, US Department of Health and Human Services, Rockville, May 1994.
 27. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of
patients with ST-elevation myocardial infarction--executive summary: a report of the
American College of Cardiology/American Heart Association Task Force on Practice
Guidelines (Writing Committee to Revise the 1999 Guidelines for the Management of
Patients With Acute Myocardial Infarction). Circulation 2004; 110:588.
28. Omland T, Pfeffer MA, Solomon SD, et al. Prognostic value of cardiac troponin I measured
with a highly sensitive assay in patients with stable coronary artery disease. J Am Coll
Cardiol 2013; 61:1240.
29. de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly
sensitive assay and cardiac structure and mortality risk in the general population. JAMA
2010; 304:2503.
30. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for
the diagnosis and management of patients with stable ischemic heart disease: a report of
the American College of Cardiology Foundation/American Heart Association task force on
practice guidelines, and the American College of Physicians, American Association for
Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular
Angiography and Interventions, and Society of Thoracic Surgeons. Circulation 2012;
126:e354.

31. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused
update of the guideline for the diagnosis and management of patients with stable ischemic
heart disease: a report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines, and the American Association for Thoracic Surgery,
Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and
Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014; 64:1929.
Topic 1472 Version 37.0
GRAPHICS

Conditions provoking or exacerbating ischemia

Increased oxygen demand Decreased oxygen supply

Noncardiac Noncardiac
Hyperthermia Anemia

Hyperthyroidism Hypoxemia

Sympathomimetic toxicity (eg, cocaine use) Pneumonia

Hypertension Asthma

Anxiety Chronic obstructive pulmonary disease

Arteriovenous fistulae Pulmonary hypertension

Cardiac Interstitial pulmonary fibrosis

Hypertrophic cardiomyopathy Obstructive sleep apnea

Aortic stenosis Sickle cell disease

Dilated cardiomyopathy Sympathomimetic toxicity (eg, cocaine use)

Tachycardia Hyperviscosity

Ventricular Polycythemia

Supraventricular Leukemia

Thrombocytosis

Hypergammaglobulinemia

Cardiac

Aortic stenosis

Hypertrophic cardiomyopathy

Reproduced with permission from: ACC/AHA/ACP Guidelines for the Management of Patients with Chronic Stable Angina. J Am Coll
Cardiol 1999; 33:2092. Copyright ©1999 American College of Cardiology.

Graphic 53315 Version 2.0

Diagnoses other than cardiac ischemia for patients with chest pain

Cardiovascular not caused by Pulmonary Gastrointestinal

epicardial CAD Pleuritis Biliary

Aortic dissection* Pneumonia Cholangitis

Aortic aneurysm* Pulmonary embolus* Cholecystitis

Myocarditis* Tension pneumothorax* Choledocholithiasis

Pericarditis Colic
Psychiatric
Stress (takotsubo) cardiomyopathy* Esophageal
Affective disorders (eg,
depression) Esophagitis
Chest wall
Anxiety disorders Spasm
Cervical disc disease
Hyperventilation Reflux
Costochondritis
Panic disorder Rupture*
Fibrositis
Primary anxiety Pancreatitis
Herpes zoster (before the rash)
Somatoform disorders Peptic ulcer disease
Neuropathic pain
Thought disorders (eg, fixed Nonperforating
Rib fracture
delusions)
Perforating*
Sternoclavicular arthritis

* Potentially life-threatening conditions.

Adapted with permission from: ACC/AHA/ACP Guidelines for the Management of Patients with Chronic Stable Angina. J Am Coll
Cardiol 1999; 33:2092. Copyright ©1999 American College of Cardiology.

Graphic 53227 Version 4.0

Characteristics of major noncardiac causes of chest pain

Duration of
Condition Character of pain
pain
Gastroesophageal 5 to 60 Visceral, substernal, worse with recumbency, no radiation, relief
reflux minutes with food, antacids

Esophageal spasm 5 to 60 Visceral, spontaneous, substernal, associated with cold liquids,

minutes relief with nitroglycerin

Peptic ulcer Hours Visceral, burning, epigastric, relief with food, antacids, normal ECG

Biliary disease Hours Visceral, epigastric, interscapular colic, occurs after meals

Cervical disc Variable Superficial, positional, arm, neck

Musculoskeletal Variable Superficial, positional, worse with movement, local tenderness

Hyperventilation 2 to 3 minutes Visceral, substernal, tachypneic, anxious

Thyroiditis Persistent Aggravated by swallowing, neck, throat tenderness

Excludes pain above the neck or below the umbilicus.

ECG: electrocardiogram.

Graphic 77753 Version 3.0

Coronary artery surgery study definitions of angina

Definite angina
Substernal discomfort precipitated by exertion, with a
typical radiation to the shoulder, jaw or inner aspect
of the
arm relieved by rest or nitroglycerin in less than 10 minutes

Probable angina
Has most of the features of definite angina but may not
be entirely typical in some aspects

"Probably not" angina

Defined as an atypical overall pattern of chest pain
that does not fit the description of definite angina

"Definitely not"
angina
Chest pain is unrelated to activity, appears to be
clearly of non-cardiac origin and is not relieved by
nitroglycerin

Adapted from CASS Investigators. National Heart Lung and Blood Institute Coronary Artery Study, Circulation 1981; 63(Suppl I):I-
81.

Graphic 59572 Version 1.0

Contributor Disclosures
Simon A Mahler, MD, MS Equity Ownership/Stock Options: Impathiq Inc [Chest pain]. Patent Holder:
Impathiq [Chest pain]. Grant/Research/Clinical Trial Support: National Heart, Lung, and Blood Institute
[Chest pain]; Donaghue Foundation [Chest pain]; Siemens [acute coronary syndrome]; Abbott Laboratories
[acute coronary syndrome]; Roche Diagnostics [acute coronary syndrome]; Pathfast [acute coronary
syndrome]; Ortho Clinical Diagnostics [Congestive heart failure, acute coronary syndrome]; Quidel [acute
coronary syndrome]. Consultant/Advisory Boards: Roche Diagnostics [acute coronary syndrome]; Amgen
[Coronary artery disease]; Genetesis [Chest pain]; Abbott Laboratories [acute coronary syndrome]; Quidel
[acute coronary syndrome]. Other Financial Interest: Impathiq Inc [Chest pain]. Juan Carlos Kaski, DSc,
MD, DM (Hons), FRCP, FESC, FACC, FAHA Consultant/Advisory Boards: Servier [Angina]. Speaker’s Bureau:
Menarini [Angina pectoris]; Servier [Angina pectoris]. Nisha Parikh, MD, MPH Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy