Overview Cardioembolic Stroke

The heart was established as an important source for the development of

emboli when Gowers, in 1875, described a case of left middle cerebral artery
and retinal artery emboli. Cardiogenic embolism accounts for approximately
20% of ischemic strokes each year. New diagnostic techniques
(transesophageal echocardiography, cardiac magnetic resonance imaging) have
allowed clinicians to better characterize well-established sources of embolism
and to discover other potential etiologies of cardioembolic stroke (see the
following image).

Sources of cardioembolic stroke.

Cardioembolic stroke is largely preventable, warranting efforts at primary

prevention for major-risk cardioembolic sources. Once stroke due to cardiac
embolism has occurred, the likelihood of recurrence is relatively high for most
cardioembolic sources; consequently, secondary prevention is also important.[1]

Overview of the Disease Process

Mechanism of cardioembolic stroke

The underlying mechanism of cardioembolic stroke is occlusion of cerebral

vessels with debris from a cardiac source. An embolus may consist of platelet
aggregates, thrombus, platelet-thrombi, cholesterol, calcium, bacteria, etc.
Most embolic debris contains platelet aggregates.

However, no single mechanism is responsible for the development of cardiac

emboli. The specific underlying cardiac disease determines the pathophysiology
and natural history, and hence each cardioembolic source must be considered
individually. Emboli secondary to chamber abnormalities (eg, atrial fibrillation,
acute myocardial infarction) are induced mainly by stasis, whereas those
secondary to valve involvement are the result of endothelial abnormalities with
attachment of material (eg, platelets, bacteria) to their free borders.
The nature of the embolus differs depending on the source (eg, calcified
particles from calcific valves, neoplastic cells from myxomas). This must be
considered when choosing specific therapies; no single treatment covers the
wide variety of heart disease that can cause embolism to the brain.

Distribution of cardiac emboli

Emboli from the heart are distributed evenly throughout the body according to
cardiac output, but more than 80% of symptomatic or clinically recognized
emboli involve the brain. Of emboli to the brain, approximately 80% involve the
anterior circulation (ie, carotid artery territory), whereas 20% involve the
vertebrobasilar distribution, proportional to the distribution of cerebral blood
flow.

Once emboli have reached the cerebral circulation, they obstruct brain-
supplying arteries, causing ischemia to the neurons and to the blood vessels
within the area of ischemia. In contrast to thrombi, emboli are attached loosely
to the vascular walls and thus commonly migrate distally. When this occurs,
reperfusion of the damaged capillaries and arterioles allows blood to leak into
the surrounding infarcted tissue. This explains the more frequent association
of hemorrhagic infarction with cardiogenic embolism than with other causes of
ischemic stroke. In the great majority of patients with hemorrhagic infarcts, the
hemorrhagic transformation does not cause clinical worsening because the
bleeding involves necrotic tissue.

In short, cardioembolic stroke is not one disease with a single natural history.
Many different types of cardiac disorders lead to cardioembolic stroke, each
with unique clinical features, risks of initial and recurrent stroke, and optimal
therapy

Prevalence of Cardioembolic Strokes

Approximately 20% of ischemic strokes are considered cardioembolic. The

annual incidence is estimated at approximately 146,000 cases. In the United
States, atrial fibrillation represents the most common cause of cardioembolic
stroke and is a major cause of stroke in the elderly.

Worldwide, the estimated frequency of cardioembolic strokes varies from 12-

31% of ischemic strokes, depending on the criteria applied for definition, extent
of the evaluation, and study design (see Table 1, below). Consistent geographic
variation is not evident, and the frequency is likely similar throughout the
world if adjusted for mean population age.

The risk of a cardioembolic event rises with age. The older the cohort, the
higher the estimated frequency of cardioembolic stroke because of the rapidly
increasing prevalence of atrial fibrillation in elderly persons. Elderly women are
particularly affected, whereas black and Hispanic individuals reportedly have a
lower frequency of cardioembolic strokes than white persons, reflecting the
respective prevalence of atrial fibrillation among these groups. Table.
Frequency of Cardioembolic Stroke/All Ischemic Stroke

Evaluation in Suspected Cardioembolic Stroke

Clinical features

Although not sufficiently sensitive or specific to establish the diagnosis, the

following clinical features help to distinguish cardiogenic embolism from other
mechanisms of cerebral ischemia and are useful to consider in patient
management:

 Decreased level of consciousness at onset of stroke

 Neurologic symptoms of abrupt onset with maximal severity at onset
 Rapid recovery from major hemispheric deficits ("spectacular shrinking
deficit") due to reperfusion of the brain with early lysis of the embolus
 Onset of symptoms after a Valsalva-provoking activity (enhancing right-
to-left shunting in patients with a patent foramen ovale [PFO])
 Symptoms reflecting involvement of different vascular territories of the
brain

Neither seizure nor headache at the onset is a useful predictor of cardiogenic

embolism.

Cardiogenic emboli (especially from chamber sources) do not often affect the
deep penetrating arteries or manifest as a lacunar syndrome. Small cardiogenic
emboli from valvular sources (eg, calcific aortic stenosis, infective endocarditis)
can obstruct the small penetrating arteries, causing subcortical lacunar
infarcts.

A combination of gene expression profiles in blood and a measure of infarct

location on neuroimaging can be used to predict a cardioembolic, arterial, or
lacunar cause in cryptogenic stroke.[2]
Physical findings

Findings that may suggest cardiogenic embolism include the following:

 Evidence of cardiac atrial dysrhythmias (eg, atrial fibrillation, sinus node

dysfunction)
 Presence of cardiac murmurs (eg, mitral stenosis, calcific aortic stenosis)
 Signs of congestive heart failure (eg, after acute myocardial infarction,
nonischemic cardiomyopathies)
 Recent myocardial infarction (highest cerebral embolism in the first 4
weeks of acute myocardial infarction)
 Concomitant diseases (eg, systemic lupus erythematosus and Libman-
Sacks endocarditis, neoplasia, marantic endocarditis)

Concomitant signs of systemic embolism – The probability of finding such signs

in patients with suspected cardioembolic stroke is low (approximately 1%) for
most cardioembolic sources.

Major Risk Sources

Major risk sources carry a relatively high risk of initial and recurrent stroke
convincingly linked to a cardioembolic mechanism.

Atrial fibrillation

The leading cause of cardioembolic stroke is atrial fibrillation (paroxysmal and

chronic atrial fibrillation), especially in elderly individuals. This arrhythmia is
present in approximately 1% of the US population, of which approximately 5%
is in those older than 70 years, and it is found in up to 50% of all
cardioembolic strokes. The lifetime risk of developing atrial fibrillation is 1-4 for
adults older than 40 years. Atrial fibrillation conveys a 5-fold increased risk of
stroke, and one sixth of all strokes may be attributable to atrial fibrillation.[3]

Formerly associated with rheumatic valvular disease, atrial fibrillation is now

related most frequently to hypertension and ischemic heart disease (ie,
nonvalvular atrial fibrillation).

Stasis secondary to decreased contractility of the left atrium leading to

thrombus formation in its appendage is the postulated mechanism (see the
image below).
 Cardioembolic stroke. Photo of left atrial thrombus.

Transesophageal echocardiography (TEE) is more sensitive than transthoracic

echocardiography for the visualization of the left atrium and its appendage (see
the following video).

Cardioembolic stroke. Streaming video: Mobile left atrial thrombus on

echocardiography. Notice periodic bulging of the thrombus in the left atrium.
ECG on this patient indicated atrial fibrillation.

Not all atrial fibrillation–associated strokes are cardioembolic; in individual

cases, excluding other potential causes of stroke such as intrinsic
cerebrovascular disease or aortic atheroma is important.

The annual rate of stroke in atrial fibrillation varies widely from 0.5-12% per
year depending on prevalence and combination of risk factors; thus, risk
stratification is the first necessary step in choosing the best preventive therapy.
Several clinical risk stratification schemes have been proposed to identify atrial
fibrillation at high, moderate, or low risk; this is crucial for selecting which
patients would benefit most and least from anticoagulation. The CHADS2
(congestive heart failure [CHF], hypertension, age >75 y, diabetes, stroke or
transient ischemic attack [TIA]) classification scheme (see Table 2 below) is the
most validated system and accurately stratifies stroke risk.[4, 5, 6] Table.
CHADS2 Stratification Schemes for Prevention of Stroke in Nonvalvular Atrial
Fibrillation

(Open Table in a new window)

Stroke Rates by CHADS2 Score

CHADS2 Score Risk Stroke Rate Per Year, %

0 Low 1.9

1 Low 2.8

2 Moderate 4

3 High 5.9

>3 Very high >8.5

Source: Gage BF, Waterman AD, Shannon W, et al.[6]

Two randomized, controlled trials demonstrated that a strategy aimed at

restoring (and maintaining) sinus rhythm neither improves the survival rate
nor reduces the risk of stroke. In the Atrial Fibrillation Follow-up Investigation
of Rhythm Management (AFFIRM) study, no evidence indicated that the rhythm
control strategy protected patients from stroke.[7] In this trial, 4060 patients
aged 65 years or older whose atrial fibrillation was likely to be recurrent and
who were at risk for stroke were randomized to a strategy of rhythm control
(cardioversion to sinus rhythm, plus a drug[s] to maintain sinus rhythm)
versus a strategy of rate control (in which no attempt was made to restore or
maintain normal sinus rhythm).

The AFFIRM study (and similar findings from the smaller Rate Control Versus
Electrical Cardioversion [RACE] trial[8] ) led to the development of consensus
guidelines advocating a rate-control strategy for most patients with atrial
fibrillation.

Adjusted-dose warfarin (international normalized ratio [INR] 2-3) is associated

with a 60% reduction in stroke incidence, whereas the efficacy of aspirin is
modest (20% reduction). Low-dose warfarin (INR < 1.5), either alone or
combined with aspirin, is not effective, highlighting the marginal benefit of
warfarin when anticoagulation is not carefully regulated. The incidence of
intracerebral hemorrhage, the most dreaded complication of warfarin therapy,
is estimated to be 0.5% per year among elderly patients with atrial fibrillation
and is sensitive to blood pressure control. When warfarin is given to elderly
patients with atrial fibrillation, hypertension must be managed aggressively.[9]

Recommendations for primary and secondary prevention based on risk factor

stratification are presented in Table 3 below.[10]
Table. Risk-Based Approach to Antithrombotic Therapy in Patients With Atrial
Fibrillation (Open Table in a new window)

Patient Features Antithrombotic Therapy Class of

Recommendation

Age < 60 y, no heart disease Aspirin (81-325 mg/d) or I

(lone AF) no therapy

Age < 60 y, heart disease but I

no risk factors*

Age 60-74 y, no risk factors* I

Age 65-74 y with diabetes Oral anticoagulation (INR I

mellitus or CAD 2.0-3.0)

Age 75 y or older, women I

Age 75 y or older, men, no Oral anticoagulation (INR I

other risk factors 2.0-3.0) or aspirin (81-
325 mg/d)

Age 65 y or older, heart failure Oral anticoagulation (INR I

2.0-3.0)
LV EF less than 35% or I
fractional shortening less than
25%, and hypertension

Rheumatic heart disease I

(mitral stenosis)

Prosthetic heart valves Oral anticoagulation (INR I

2.0-3.0 or higher)
Previous thromboembolism I

Persistent atrial thrombus on IIA

Tee

Source: ACC/AHA/ESC 2006 Guidelines for the management of patients with

atrial fibrillation.[11]
AF = atrial fibrillation; CAD = coronary artery disease; EF = ejection fraction;
INR = international normalized ratio; LV = left ventricle; TEE = transesophageal
echocardiography.

* Risk factors for thromboembolism include heart failure (HF), (LV) ejection
fraction less than 35%, and history of hypertension.

In the setting of acute stroke secondary to atrial fibrillation, anticoagulation

with heparin has not demonstrated more benefit than early treatment with
aspirin. Initiate aspirin early, followed by warfarin as soon as the patient is
medically stable; discontinue aspirin after therapeutic anticoagulation is
achieved.[11]

In short, warfarin has demonstrated high efficacy in stroke prevention in

patients with this common arrhythmia. Disadvantages include the increased
risk of hemorrhagic complications and the need for close INR monitoring in
these patients; thus, consider patient preferences along with risk stratification
and absolute risk reduction offered by this therapy. Alternative approaches (eg,
surgical ablation of atrial appendage) are the subjects of ongoing clinical
investigation.

Rheumatic mitral stenosis

The incidence of this valvulopathy has decreased dramatically in recent

decades in the United States, but rheumatic mitral stenosis remains an
important problem in developing countries. Few estimates of absolute stroke
rates or randomized comparison of different therapies are available, but
because rheumatic mitral stenosis is generally associated closely with atrial
fibrillation, anticoagulation with warfarin (INR 2-3) is usually recommended.

Sinus node dysfunction

Also known as sick sinus syndrome or, when associated with supraventricular
tachyarrhythmias, brady-tachy syndrome, this arrhythmia usually occurs in
elderly (>70 y) individuals. The annual risk of stroke is 5-10%. Atrial and dual-
chamber pacing may reduce the stroke rate from sinus node dysfunction
somewhat, but anticoagulation (INR 2-3) is still recommended for selected
patients, such as those with associated atrial fibrillation; a lower target INR (eg,
1.6-2.5) may be tolerated better in these elderly patients.
Atrial flutter (sustained)

Sustained atrial flutter is an uncommon arrhythmia. Because of the close

association of atrial fibrillation with appendage stasis, anticoagulation (INR 2-
3) is advocated.

Prosthetic valves

Mechanical prosthetic valves carry an annual 2-4% risk of stroke, even in

patients receiving anticoagulation. Permanent anticoagulation (INR 2.5-3.5) is
mandatory. Bioprosthetic valves carry a lower annual risk rate (0.2-2.9%), and
aspirin is usually recommended unless the patient has atrial fibrillation or
evidence of atrial stasis.

Infective endocarditis

Of patients with infective endocarditis, 20% experience an embolic stroke, but

infective endocarditis accounted for less than 1% of all causes of cerebral
embolism in the Cerebral Embolism Stroke Registry.[12] Staphylococcus aureus
is the infectious agent associated with the highest stroke rate, and mitral valve
endocarditis is the most common source of emboli.

Antibiotic therapy reduces the embolic potential when administered in the

acute phase. Anticoagulation is contraindicated because of unacceptable rates
of hemorrhagic stroke due to either mycotic aneurysm rupture or septic
arteritis. In patients with prosthetic valve endocarditis, the risk of
thromboembolism is greater than the risk of intracranial hemorrhage; thus,
anticoagulation is usually recommended if no evidence of hemorrhage is found
on computed tomography (CT) scanning 24-48 hours after the stroke. The
consensus is to start anticoagulation 7 days after the stroke. The role of
antiplatelet therapy has not been established.

Nonbacterial thrombotic endocarditis

Associated with a variety of malignancies, nonbacterial thrombotic endocarditis

has also been reported in patients with severe diseases such as septicemia and
extensive burns. Mitral and aortic valves are affected most commonly, and
embolic stroke is frequent. A prothrombotic state has been postulated as the
precursor of emboli development. Treatment is directed toward control of the
underlying disease, and heparin (intravenous in the acute stage, subcutaneous
in the outpatient setting) is advocated for stroke prevention. Warfarin has failed
to show any benefit.

Atrial myxomas

These are the most common cardiac tumors, usually located on the fossa
ovalis. Atrial myxomas are believed to cause 1% of strokes in young
individuals. Most of these lesions can be detected by transthoracic
echocardiography; rarely, atrial myxomas are detected only by transesophageal
echocardiography. Surgical excision is the treatment of choice.

Acute myocardial infarction

The incidence of stroke after acute myocardial infarction is approximately 2%

in the first 3 months. Anterior myocardial infarctions with mural thrombus on
transthoracic echocardiography have been recognized as predictive of stroke.
Anticoagulation (INR 2-3) is recommended in these patients in the first 3
months, whereas antiplatelet therapy is advocated long term. The presence of
congestive heart failure after myocardial infarction usually dictates treatment
with warfarin indefinitely, although randomized comparisons with other
therapies are ongoing. Low-output cardiac failure (ejection fraction < 30%) is
also considered a high-risk situation, as is the presence of a large ventricular
aneurysm on echocardiography.

Minor Risk Sources

Unlike major risk sources, minor-risk sources are frequent in the general
population, with a low or uncertain associated risk of initial and recurrent
stroke with any of these conditions.

Patent foramen ovale

Persistent connection between the right and left atrium has a prevalence of
about 20% in the general population (see the following video). Screening for
patent foramen ovales (PFOs) can be done reliably with contrast precordial
echocardiography, which detects interatrial shunting, but transesophageal
echocardiography (TEE) is required to document the PFO and more accurately
determine its size, any associated atrial septal aneurysm, and the amount of
shunting.
Although case-control studies have documented a higher frequency of PFO in
young adults with cryptogenic ischemic stroke, it is present by chance
association in at least 50% of cases in patients with stroke. The rate of stroke
recurrence is 1-2% per year. Larger size, spontaneous right-to-left shunting,
and associated atrial septal aneurysm are postulated to identify subgroups at
high risk for recurrence.

PFO is not associated with increased risk of subsequent stroke or death among
medically treated patients with cryptogenic stroke. However, in a study, both
PFO and septal aneurysm (ASA) possibly increase the risk of subsequent stroke
(but not death) in medically treated patients younger than 55 years.[13]

Mono et al identified several concurrent etiologies for recurrent cerebrovascular

events in PFO patients, including large artery disease, small artery disease,
cardioembolism, cerebral vasculitis, thrombophilic disorder, and
antiphospholipid-antibody syndrome.[14]

In patients with a cryptogenic stroke and an atrial septal abnormality, evidence

is insufficient to determine whether warfarin or aspirin is superior in
preventing recurrent stroke or death, but minor bleeding is more frequent with
warfarin. Evidence evaluating the efficacy of surgical or endovascular closure is
insufficient.[13] Clinical trials are ongoing to compare endovascular closure
versus medical therapy. If a patient is not a participant in a clinical PFO
closure trial, the American Academy of Neurology recommendations are to
initiate medical therapy and consider closure only if there are repeated
recurrent clinical events on maximal medical therapy.[13]

Elucidation of the role of other therapeutic approaches such as surgical closure

(eg, transthoracic, percutaneous) awaits the results of clinical trials and better
characterization of the natural history. At present, PFO should not be
considered the cause of stroke until other etiologies have been thoroughly
excluded.

Atrial septal aneurysms

These aneurysms are areas of redundant atrial septal tissue that bulge
alternatively into the right or left atrium. Atrial septal aneurysms have a high
degree of association with other sources of embolism (mainly atrial fibrillation
and PFO). However, there are insufficient data available to consider atrial
septal aneurysm as an independent risk factor for stroke. When an atrial septal
aneurysm coexists with a PFO or other source of embolism, anticoagulation is
usually recommended,[13] but there are no randomized trials supporting this
policy.

Mitral valve prolapse

Mitral valve prolapse is the most common valve disease in adults; its role as an
independent risk factor for stroke is a controversial and evolving issue. In some
population-based studies, the estimated prevalence has not been greater in
patients who have had a stroke than in the general population. Long-term
aspirin therapy is recommended, although its value has not been confirmed by
randomized trials. Anticoagulation is reserved for failure of antiplatelet therapy.

Calcific aortic stenosis, bicuspid aortic valves, and mitral annular

calcification

Systemic embolism is uncommon in isolated aortic valve disease. Calcific

microemboli can be detected in retinal arteries in asymptomatic patients,
possibly reflecting the fact that most cerebral emboli are asymptomatic.
Clinical embolism often follows invasive cardiac procedures (ie, catheterization).
Because of the calcific nature of the emboli, anticoagulation is not
recommended, and antiplatelet therapy remains an empiric approach.

Mitral annular calcification is associated with advancing age, hypertension,

and atherosclerosis, and it is rarely an embolic source.

Fibroelastomas and Lambl excrescences

Diagnosis

Fibroelastomas are rare benign tumors located on the valves. Lambl

excrescences are filiform outgrowths from the free borders of the cardiac valves
and have been implicated as sources of embolism when they attain large size.
Antiplatelet therapy is initiated, followed by surgery if aspirin fails. Surgical
repair is reserved for patients who have stroke recurrence.

No quantitatively valid clinical criterion standards exist for the diagnosis of

cardioembolic stroke. The diagnosis is based on the triad of (1) identification of
a potential cardiac source of embolism, (2) absence/exclusion of other potential
sources of cerebral ischemia, and (3) consideration of clinical neurologic
features, as described in Evaluation in Suspected Cardioembolic Stroke, above.
Seizures and epilepsy should also be considered in the differential diagnosis.

Recommended Tests

Blood cultures

If fever or leukocytosis is present, blood cultures for infective endocarditis are

warranted.

CBC, coagulation profile, urinalysis, and chemistry and lipid panels

Before initiating antithrombotic therapy, a complete blood cell (CBC) count,

platelet count, prothrombin time (PT) or international normalized ratio (INR)
and activated partial thromboplastin time (aPTT), erythrocyte sedimentation
rate (ESR), serum glucose, electrolytes, lipids, urinalysis are recommended, as
well as plain radiography.

Blood dyscrasias studies

In patients with patent foramen ovale (PFO), determination of protein C, protein

S antigen, and antithrombin III antigens and activities; factor V Leiden and
activated protein C resistance; and prothrombin gene mutation are often
recommended, particularly in patients with a history of venous thrombosis or a
family history of unusual thrombosis. Several of these are acute phase
reactants and can be artificially abnormal if obtained in the weeks following
acute stroke. Protein C and S levels are suppressed by warfarin; antithrombin
III levels and activity are suppressed by heparin.