Coronary artery disease

Summary

Coronary artery disease (CAD) is a condition that is most commonly caused

by atherosclerosis and the subsequent reduction in blood supply to the myocardium, resulting in
a mismatch between myocardial oxygen supply and demand. Acute retrosternal chest
pain (angina) is the cardinal symptom of CAD. Other symptoms
include dyspnea, dizziness, anxiety, and nausea. Patients with stable CAD may have stable
angina or be asymptomatic, while severe ischemia may lead to acute coronary syndrome,
including myocardial infarction (MI). Stable CAD can be diagnosed using cardiac stress
testing, nonstress cardiac imaging, and/or coronary catheterization. The management of stable
CAD involves secondary prevention of atherosclerosis (e.g., smoking cessation, and treatment of
diabetes mellitus, hypertension, and dyslipidemia), antiplatelet agents, antianginal
medication (e.g., beta blockers), and, in severe cases, revascularization (e.g., percutaneous
transluminal coronary angioplasty).

For the diagnostics and management of acute chest pain, see “Acute coronary syndrome” and
“Chest pain.” See also “Atherosclerosis” and “Myocardial infarction.”

Definition

Coronary artery disease

 Coronary artery disease (CAD): ischemic heart disease due to narrowing or

blockage of coronary arteries, most commonly due to atherosclerosis, resulting in a
mismatch between myocardial oxygen supply and demand

Chest pain and angina

Historical terminology for types of chest pain [1][2][3]

 Typical angina fulfills all of the following criteria:

o Retrosternal chest pain of characteristic nature and duration (e.g.,
transient retrosternal pressure)
o Provoked by exertion or emotional stress
o Relieved by rest and/or nitroglycerin
  Atypical angina: fulfills only two of the aforementioned criteria
 Nonanginal chest pain: fulfills one or none of the aforementioned criteria

Epidemiology

 CAD is the leading cause of death in the US and worldwide.

Etiology

 Atherosclerosis is the most common cause (see “Risk factors for atherosclerosis”).

Pathophysiology

Plaque formation and coronary artery stenosis [6][7]

 For plaque formation, see “Pathogenesis of atherosclerosis.”

 Coronary flow reserve (CFR): the difference between maximum coronary blood flow
and coronary flow at rest (a measure of the ability of the coronary capillaries to dilate
and increase blood flow to the myocardium).

Myocardial oxygen supply-demand mismatch [8]

 Definition: mismatch between the amount of oxygen the myocardium receives and

the amount it requires
 Factors reducing oxygen supply
o Coronary atherosclerosis ; and sequelae, including:
 Rupture of an unstable atherosclerotic plaque (most common
cause)
 Thrombosis
 Stenosis
o Vasospasms
o ↑ Heart rate
o Anemia
 Factors increasing oxygen demand
 o ↑ Heart rate
o ↑ Afterload
o Anemia

An increased heart rate reduces oxygen supply and increases oxygen demand.

Effect of vascular stenosis on resistance to blood flow [9]

Vascular stenosis increases vascular resistance significantly.

Myocardial ischemia [8]

 Reversible ischemia: Tissue is ischemic but not irreversibly dead and, therefore, still

potentially salvageable.
 Irreversible ischemia

Coronary steal syndrome

 Definition: a phenomenon of vasodilator-induced alteration of coronary blood flow

in patients with coronary atherosclerosis resulting in myocardial ischemia and
symptoms of angina
 Pathomechanism
o Long-standing CAD requires maximal coronary arterial dilation distal to
the stenosis to maintain normal myocardial function.
 Clinical relevance
o Coronary steal is the underlying mechanism of pharmacological stress
testing.
o Administration of vasodilators (e.g., dipyridamole)
→ coronary vasodilation → decreased hydrostatic pressure in the
normal coronary arteries → blood shunting back to well-
perfused myocardium → decreased flow to
the ischemic myocardium → myocardial ischemia downstream to the
pathologically dilated vessels → angina pectoris and/or ECG changes

Coronary steal syndrome should not be confused with coronary-subclavian steal syndrome.

Clinical features

Angina

 Angina is the cardinal symptom of CAD.

 Patients with CAD usually become symptomatic when the degree of
coronary stenosis reaches ≥ 70%.
 Typically retrosternal chest pain or pressure
o No chest wall tenderness
o May gradually increase in intensity
o May be absent, especially in geriatric and diabetic patients.

Stable angina

 Symptoms are reproducible/predictable and severity, frequency, and threshold for

reproduction of symptoms do not change.
 Symptoms often subside within minutes with rest or after administration
of nitroglycerin
 Common triggers include physical/mental stress or exposure to cold

Anginal equivalents [1][11]

 Possible manifestations
o Pain referred to the left arm, neck, jaw, epigastric region, or back.
o Gastrointestinal discomfort
o Dyspnea
o Dizziness, palpitations
o Restlessness, anxiety
o Autonomic symptoms (e.g., diaphoresis, nausea, vomiting, syncope)
Diagnostics

Symptomatic patients without known CAD [12][2][2]

Initial evaluation

 Clinical evaluation
o frequency of angina episodes
o Physical examination may be normal; look for:
 Clinical features of peripheral vascular disease

Resting ECG [12]

 Best initial test

 Usually normal in stable angina
 Findings that suggest previous MI or unstable angina: These typically necessitate
further workup (see “Acute coronary syndrome”).
o ST-segment depression
o T-wave inversion or T-wave flattening

Pretest probability

Pretest probability of obstructive CAD by age, sex, and symptoms

Further cardiac testing

Overview

 Noninvasive testing
o cardiac stress testing
 Invasive testing: coronary angiography

Cardiac stress testing [12][1][15][16][17][2]

Description
  Heart rate is monitored throughout the study [18]
o Estimated maximum heart rate = 220 – age (in years)
o Target heart rate = 85% of the maximum heart rate

Types of stress induction

 Exercise stress tests (e.g., treadmill or bicycle): first-line

Modalities and diagnostic endpoints

Evidence of stress-induced ischemia

Modality Findings

 Downsloping ST depression or horizontal ST depression of ≥ 0.1 mV (1 mm) at

peak exercise intensity
 ST elevation of ≥ 0.1 mV (1 mm) in leads with no preexisting Q waves (except
ECG
in V1 or aVR) : considered to be a high-risk ECG finding consistent with acute
coronary syndrome
 STEMI-equivalent ECG findings

 Changes in global left ventricular function during or after stress

Echocardiography
 New or worsening wall motion abnormalities

Myocardial
perfusion  Decreased myocardial perfusion after stress
scan (e.g., SPECT,
PET)

CMR  New wall motion abnormality or perfusion abnormality

General criteria for test termination

 A diagnostic endpoint is reached (preferred)

 Significant cardiac arrhythmia
Test preparation

 Hold methylxanthines (e.g., caffeine, aminophylline) for 12 hours prior to testing

 Hold dipyridamole for 48 hours prior to adenosine and regadenoson stress tests
 Beta blockers, CCBs, and nitrates can affect diagnostic value and may be held prior
to testing at the treating clinician's discretion.

Comparison of cardiac stress tests [12][1][13][15][2]

Test
characteristi Cardiac exercise stress test Cardiac pharmacological stress test
cs

Procedure  Stress is induced by  Stress is induced by substances

exercise on a that simulate the effect of

treadmill or bicycle. exercise on the myocardium:

 Duration varies by o Positive inotrop

protocol (e.g., Bruce es or chronotrop

protocol). [19] es (e.g., dobuta

 Metabolic mine)

equivalents (METs) o Vasodilators (e.

: A measure g., dipyridamole

of energy , adenosine,

expenditure used to or regadenoson)

estimate exercise

tolerance. [17]

o 1 

ME

T =

3.5

mL 

O2/

kg/

min

ute

o Ap

pro
 Comparison of cardiac stress tests [12][1][13][15][2]

Test
characteristi Cardiac exercise stress test Cardiac pharmacological stress test
cs

x. 5 

ME

Ts 

are

req

uire

d to

fulf

ill

eve

ryd

ay

acti

viti

es,

suc

h as

cli

mbi

ng

flig

ht

of

stai

rs.

Typical  Exercise ECG  One of the following imaging

modalities [1]
testing: ECG is used modalities:

to assess ischemia o Echocardiograp

hy
 Comparison of cardiac stress tests [12][1][13][15][2]

Test
characteristi Cardiac exercise stress test Cardiac pharmacological stress test
cs

o Radionuclide

myocardial

perfusion

imaging:

a nuclear
 OR exercise stress
scan that uses a
imaging: cardiac
radioactive
(e.g., echocardiograp
tracer to
hy, radionuclide
evaluate myocar
myocardial
dial viability,
perfusion imaging,
detect ischemia,
or CMR) are used to
and
assess ischemia
assess perfusion 

and LV function

o CMR

 ECG monitoring is typically

added to cardiac imaging

Contraindic
ations  Physical impairment  If using dobutamine:

to exercise obstructive cardiomyopathy, aorti

 Hemodynamically c dissection, tachyarrhythmias

significant arrhythmi  If using adenosine, regadenoson,

as or dipyridamole:

 Unstable o Active bronchos

angina or acute MI ( pasm or reactive

within the past 2 airway disease

days) o Low systolic BP 

 Symptomatic severe (< 90 mm Hg)

aortic stenosis o Second-degree

 Acute heart disease: AV block, third-

e.g., degree AV
 Comparison of cardiac stress tests [12][1][13][15][2]

Test
characteristi Cardiac exercise stress test Cardiac pharmacological stress test
cs

block, or sinus

node disease in

patients without

active endocarditis, a pacemaker

acute myocarditis or   Systolic blood pressure (BP) >

pericarditis, decomp 200 mm Hg or diastolic BP > 110

ensated heart failure mm Hg

 Unstable angina, acute coronary

syndrome, and being within 2–4

days of MI

Specif
ic  Cyanosis, pallor, ata
criteri
a for xia, dizziness,
test  Wheezing, cyanosis, pallor
termi or near-syncope
nation  Systolic BP < 80 mm Hg
 Severe dyspnea
 For dobutamine only:
 Moderate to
o Exaggerated
severe angina
hypertensive
 Decrease
response
in systolic BP > 10
Cli 
nic mm Hg below the
al Syst
patient's resting

BP with other signs


of ischemia
OR 
 Consider in patients

with an exaggerated
o Target heart
hypertensive
rate exceeded
response (relative

indication).

EC
G  Consider  Chest
 Comparison of cardiac stress tests [12][1][13][15][2]

Test
characteristi Cardiac exercise stress test Cardiac pharmacological stress test
cs

if excessive downslo
pain with excessive downsloping
ping ST
ST depression or horizontal ST
depression or horizo
depression of > 0.2 mV (2
ntal ST
mm) at any point
depression of > 0.2
 Symptomatic second-degree AV
mV (2 mm) is
block or third-degree AV block
detected.

Coronary angiography [12][22]

 Indications
o Chronic stable angina
 High clinical suspicion for CAD
 Abnormal results from noninvasive testing
 Persistent symptoms of angina despite appropriate therapy
 Uses
o Direct visualization of coronary arteries
o To determine the feasibility of direct therapeutic intervention
using percutaneous coronary intervention
o Cardiac catheterization can provide information on several
parameters; coronary blood flow; cardiac output

Patients with acute chest pain and other concerning clinical findings (e.g., hypotension)

or ECG changes that are suggestive of acute coronary syndrome (e.g., new heart

blocks or arrhythmias) should undergo cardiac catheterization.

Treatment

Approach [12]

 All patients: pharmacotherapy for CAD

o Start secondary prevention of CAD, i.e., antiplatelet agents
o Start antianginal medication.
 Select patients: revascularization
o Not routinely recommended for stable CAD
o Techniques
 Percutaneous coronary intervention (PCI)
 Coronary artery bypass grafting (CABG)

Pharmacotherapy for CAD

Antianginal drugs

 First-line agent: beta blockers
 Second-line agents: CCBs, nitrates, ranolazine
o combination therapy; beta blocker PLUS a nitrate

Effects of antianginal medications

Parameters that Beta

Nitrates Combination of a beta blocker and a nitrate
impact MVO2 blockers

Blood pressure ↓ ↓ ↓

↑
Heart rate ↓ Unchanged or slightly ↓
(reflectory)

↑
Inotropy (contractility) ↓ Unchanged
(reflectory)
Ejection time ↑ ↓ Unchanged
Unchanged o
End-diastolic volume ↓ Unchanged or slightly ↓
r↑
Overall effect
↓ ↓ ↓↓
on MVO2

Overview of pharmacotherapeutic agents for CAD

 Pharmacotherapy for CAD [12]

Therap
Drug
eutic Example agents Specific indications and effects
class
goal

 Aspirin DOSAGE 
[12]

 Clopidogrel DOSA

GE: in patients with

contraindications
Antipla  Recommended for all patients
telet to aspirin [12]
agents with CAD
 Dual antiplatelet

therapy with aspirin 

and clopidogrel may

be used in certain
Seconda
ry circumstances. [27]
preventi
on

 Preferred: ACE

inhibitors,  Indicated in patients with concomitant:

e.g., lisinopril DOS o Hypertension

AGE, ramipril DO o Diabetes mellitus

ACEIs 
or ARB SAGE o LVEF ≤ 40%
s
 Alternative: ARBs, o Chronic kidney

e.g., losartan DOS disease

AGE, valsartan D  Has cardiovascular protective effects

OSAGE

Seconda Beta
ry blocker  Carvedilol DOSA  Consider for all patients with stable
preventi s
on and GE angina.
antiangi
nal  Metoprolol DOSA  Further indications
treatme
nt GE o After MI or acute

 Bisoprolol DOSA coronary syndrome in

GE patients with

normal LVEF

o LVEF ≤
 Pharmacotherapy for CAD [12]

Therap
Drug
eutic Example agents Specific indications and effects
class
goal

40% with heart

failure or prior MI

o Consider as first-

line antihypertensive

therapy in patients

with CAD and hypert

ension. [28]

 All beta blockers are equally effective

in patients with CAD. [12]

 May improve exercise tolerance

 Partial beta agonists such

as pindolol and acebutolol should be

used with caution. [28]

 See “Beta blocker adverse effects.”

Antiang CCBs
inal  Dihydropyridines:  Add to beta blockers if symptoms
treatme
nt e.g., amlodipine DO persist despite adequate dose titration.

SAGE, nifedipine   All CCBs are equally effective for

DOSAGE symptomatic

 Nondihydropyridine relief; dihydropyridines are preferred in

s: patients with cardiac conduction

e.g., verapamil DO defects.

SAGE, diltiazem D  Avoid short-acting dihydropyridines,

OSAGE as they may worsen angina in patients

with fixed lesions.

 Adverse effects

include headache, dizziness, palpitation

s, flushing, peripheral edema,

and constipation.
 Pharmacotherapy for CAD [12]

Therap
Drug
eutic Example agents Specific indications and effects
class
goal

Nitrates
 Short-acting nitrate:   Short-acting nitrates:

nitroglycerin sublin o Can prevent

gual exertional angina

tablets DOSAGE o Suitable for relief of

 Long-acting nitrates acute angina

:  Long-acting nitrates: adjunctive or

o Iso alternative long-term treatment to beta

sor blockers in patients with stable angina.

bid  Adverse effects include headache,

e flushing, and hypotension.

din

itra

te 

OS

o Iso

sor

bid

mo

no

nitr

ate 

OS

G
 Pharmacotherapy for CAD [12]

Therap
Drug
eutic Example agents Specific indications and effects
class
goal

 Consider as an alternative to beta-

blockers, or as an adjunctive treatment

for stable angina that is refractory

to first-line treatment

 Reduces MVO2 without altering heart

rate or BP [29]

o Inhibition of late

inward sodium chann

els on

cardiac myocytes → r

educed calcium influx

via sodium-calcium c

hannel pump
Metabo  Ranolazine DOSA → reduced wall stress
lic
modula GE and MVO2 [30]
tors
o Decreased rate

of fatty acid beta-

oxidation (aerobic

process) with a

simultaneous increase

in glycolysis (anaerob

ic process) [31]

o Adverse effects

include nausea, consti

pation, headache, dizz

iness, bradyarrhythmi

as, and QT

prolongations.
Revascularization for stable CAD [12][25]
Acute coronary syndrome

 Indications
o High-risk anatomic lesions involving multiple or critical vessels
o Activity-limiting symptoms due to any significant coronary artery
stenosis that persist:
 Despite optimal medical treatment
 OR due to contraindications to pharmacotherapy
 Options
o CABG
o PCI

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Prognosis

 Prognostic factors
o Left ventricular function: increased mortality if EF < 50%
o Involvement of left main coronary artery or involvement of more than one
vessel is associated with a worse prognosis

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Prevention

Secondary prevention of CAD

 Lifestyle modifications
 Lifelong antiplatelet therapy with aspirin or clopidogrel
 Treatment of comorbidities
o Hypertension
 First-line treatment: beta blockers
 especially in patients post MI
 o Diabetes mellitus
Individualized glycemic goals (e.g., HbA1c < 7%)

 Lipid-lowering therapy
o See “Treatment of hypercholesterolemia in adults.”

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Subtypes and variants

Vasospastic angina

Description

 Angina caused by transient coronary spasms

 Not affected by exertion (may also occur at rest)
 Typically occurs early in the morning

Etiology

 Cigarette smoking; use of stimulants (e.g., cocaine, amphetamines), alcohol,

or triptans
 Stress, hyperventilation, exposure to cold
 Common atherosclerotic risk factors (except smoking) do not apply to vasospastic
angina.

Diagnosis [38][11]

 Cardiac biomarkers
o Measure serial troponin I and/or troponin T levels during periods of acute
chest pain

Diagnostic criteria for vasospastic angina [38][11]

Criteria Description

Typical clinical features  Spontaneous angina with a rapid response to short-acting nitrates and ≥ 1 of the

following:

o Occurrence at rest (especially at night or early morning)

 Diagnostic criteria for vasospastic angina [38][11]

Criteria Description

o Precipitated by hyperventilation

o Responsive to treatment with CCBs (but not beta blockers)

o Reported lower exercise tolerance in the morning

 One of the following ECG changes in ≥ 2 contiguous leads during an anginal episode:

Transient ischemic ECG o ST elevation or ST depression ≥ 0.1 mV (1 mm)

changes
o New negative U waves

 Coronary artery constriction > 90%, associated with angina and ischemic ECG

changes [11][38]
Coronary
spasm on angiography o Can occur spontaneously during coronary angiography

o Can be induced by coronary artery spasm provocation testing

 Definitive vasospastic angina: the presence of typical clinical features as well as documentation of

either transient ischemic ECG changes or coronary spasm during coronary angiography

 Suspected vasospastic angina: the presence of typical clinical features as well as equivocal or

unavailable transient ischemic ECG changes and equivocal coronary artery spasm criteria, i.e., changes are seen

but do not meet the criteria listed above

Treatment [11][41]

 General recommendations
o Smoking cessation
o Avoid beta-blockers
 Pharmacotherapy: The goal is to prevent spasms and arrhythmias, and to improve
symptoms during acute attacks. [11][39]
o calcium channel blockers
o Alternatively:
 Long-acting nitrates

Prognosis
 The persistence of symptoms is common.