PERSPECTIVE

FRAME OF REFERENCE
Embolic Stroke

T
he term “embolic” was first suggested in 1854 by Virchow1 when he de- George Ntaios, MD
scribed a patient with occlusion of the brain arteries by clots that appeared Robert G. Hart, MD
to arise from the heart. All currently available evidence suggests that the
majority of ischemic strokes are of an embolic nature.2
The identification of the cause of ischemic stroke is a 2-step process. Initially, an
ischemic stroke is classified on a pathophysiologic basis, with the 2 main patho-
physiologic mechanisms being embolism and small-vessel disease (Figure). The
next step is to classify it further on an etiologic basis.

PATHOPHYSIOLOGY AND ETIOLOGY

OF EMBOLIC STROKE
In the majority of patients, emboli are thrombotic in nature and can be formed in
Downloaded from http://ahajournals.org by on March 8, 2020

an artery, cardiac chamber, heart valve, or vein. Less frequently, emboli may consist
of nonthrombotic material, whereas in certain cases they may contain both throm-
botic and nonthrombotic material, as it may occur in infected vegetations, valvular
calcifications, and other pathologies (Figure).2
Arteriogenic thrombi are most frequently formed at a ruptured atherosclerotic
plaque and embolize to cerebral arteries. These platelet-rich emboli tend to be
smaller than fibrin-rich emboli originating in cardiac chambers, and transient isch-
emic attacks and small cortical infarcts are relatively more common than large,
territorial infarcts associated with atrial fibrillation (AF). In a smaller proportion of
patients, emboli may originate from thrombi formed because of nonatheroscle-
rotic arterial pathologies (Figure).2
The majority of cardiac thrombi are formed within a chamber (ie, the left ven-
tricle, the left atrial appendage, or the left atrium). In other patients, thrombi are
formed on pathological cardiac valves.2 As mentioned, these thrombi may be ei- The opinions in this article are not
ther purely thrombotic in nature or mixed with nonthrombotic material such as necessarily those of the editors or
vegetations and calcified material. In some infrequent cases, nonthrombotic mate- of the American Heart Association.
rial may originate from the heart and embolize distally (Figure).2 Correspondence to: George
“Paradoxical embolism” is the term used to describe emboli that are formed in Ntaios, MD, Department of
the venous vasculature and embolize distally into the cerebral arterial vasculature, Medicine, Larissa University
bypassing the pulmonary circulation through a patent foramen ovale (PFO), atrial Hospital, School of Medicine,
University of Thessaly, Biopolis
septal defects, or pulmonary arteriovenous fistulas (Figure).2
41110, Larissa, Greece. E-mail
gntaios@med.uth.gr

THE CONCEPT OF MAJOR- VERSUS MINOR-RISK Key Words: classification

◼ embolic stroke ◼ etiology
EMBOLIC SOURCES ◼ pathophysiology
Frequently, potential sources of embolic stroke are classified as major or mi- © 2017 American Heart
nor risk. Certain pathologies such as stenotic carotid atherosclerotic plaques, Association, Inc.

Circulation. 2017;136:2403–2405. DOI: 10.1161/CIRCULATIONAHA.117.030509 December 19/26, 2017 2403

 Ntaios and Hart

Stroke due to ISCHEMIC Non-SVD,

Small Vessel Disease non-embolic
(SVD) STROKE Stroke

Non-thrombosis-mediated embolism

Non-thromboc
cardiogenic embolism
Embolic
Stroke

Valvular Chamber Non-

Atheroscleroc
Disease embolism Atheroscleroc

Cardiogenic embolism Paradoxical

Arteriogenic embolism
embolism

Thrombosis-mediated embolism

Figure. Pathophysiologic classification of ischemic stroke.

Nonthrombosis-mediated embolism may originate from septic vegetations, valvular calcified fragments, cardiac tumors (eg,
myxoma, papillary fibroelastoma, and sarcoma), fibrocartilaginous material, air, fat, and others.2 Atherosclerotic arteriogenic
embolism may originate from any part of the brain-supplying arterial tree, such as the aortic arch and the intracranial and
extracranial carotid and vertebrobasilar arteries, but mainly involves those arterial segments that are more prone to develop
Downloaded from http://ahajournals.org by on March 8, 2020

atherosclerotic plaques, such as the bifurcation of arteries, the origin of an artery from its parent vessel, as well as tortuous ar-
terial segments. Nonatherosclerotic arteriogenic embolism may originate from dissected cervical arteries, Moya Moya disease,
Takayasu arteritis, and others.2 Cardiac chamber embolism may originate from thrombus formed because of left ventricular
(LV) dysfunction with preserved or reduced ejection fraction, LV regional wall abnormalities after myocardial infarction, LV non-
compaction, atrial septal aneurysm, Chiari network, atrial asystole, sick-sinus syndrome, blood stasis into the atrial appendage,
atrial fibrillation (AF), flutter or tachycardias, and others.2 Cardiac embolism because of valvular disease may originate from
myxomatous valvulopathy with prolapse, mitral annular calcification, aortic valve disease, calcified aortic valves, and others.2
Nonthrombotic cardiac embolism may originate from myxoma, papillary fibroelastoma, sarcoma and other cardiac tumors,
fibrocartilaginous material, and others.2

mechanical cardiac valves, AF, and others are con-

sidered as major risk, whereas others such as mitral
valve prolapse, aortic valve stenosis or calcification,
and PFO are considered as minor risk.2 Although this
approach is valid, we need to realize that it actually
leads to a self-fulfilling prophecy that inevitably re-
sults in overestimation of the major-risk pathologies
as the cause of embolic stroke and simultaneously in
underestimation of the minor-risk pathologies. This
systematic error skews the distribution of causes of
embolic stroke toward the high-risk pathologies (eg,
in a patient with AF and PFO, most clinicians would
consider AF as the etiology of stroke because AF is
considered major risk). Although this may indeed be
true for the majority of cases, there are still some pa-
tients for whom the PFO, rather than AF, is the actual
cause. However, these cases would be erroneously
classified as AF-associated embolic stroke.
THE QUEST FOR IDENTIFICATION OF
THE UNDERLYING CAUSE OF EMBOLIC
STROKE
The prerequisite for the reliable identification of the
underlying cause of an embolic stroke is a thorough
diagnostic evaluation to identify a potential source of
embolism and exclude all other potential causes regard-
less of their associated risk. At times this may be rather
straightforward, leaving little room for doubt. Such
cases may include young patients who usually have no
other comorbidities or patients where the overall clini-
cal and diagnostic assessment points overwhelmingly
toward a specific cause (eg, a patient with sudden onset
of unilateral head and neck pain and ipsilateral carotid
dissection, or a patient with recent deep venous throm-
bosis and a large PFO. In these patients, it would indeed
be valid to classify the embolic stroke on an etiologic

2404 December 19/26, 2017 Circulation. 2017;136:2403–2405. DOI: 10.1161/CIRCULATIONAHA.117.030509


basis (ie, “embolic stroke due to carotid dissection” or
“embolic stroke due to deep venous thrombosis and
PFO” respectively).
However, for the majority of patients with embolic
stroke, identification of the underlying cause is less
straightforward. Most elderly patients with stroke have
multiple pathologies that could be associated with em-
bolic stroke (eg, aortic arch and carotid atherosclerosis,
left ventricular dysfunction, aortic valve disease, and
short episodes of supraventricular tachycardia). How
confident can we really be of the actual cause of an
embolic stroke in these patients? In most cases, it is not
possible to make a diagnosis of the underlying etiology
with certainty. In these patients, it is preferable to of-
fer the pathophysiological diagnosis of embolic stroke
and further enrich it with the description of all poten-
tial embolic sources rather than with the presumption
of the specific etiology. A paradigm shift is warranted
from the presumptive and endogenously uncertain di-
agnostic term of “embolic stroke due to [presumed po-
tential cause]” toward the inclusive diagnostic term of
“embolic stroke in a patient with [all potential causes].”
In this context, the words “of undetermined source” in-
cluded in the recently introduced term “embolic stroke
of undetermined source (ESUS)” may seem redundant.
Actually, this is the conceptual basis for the ongoing
trials of antithrombotic management in ESUS patients,
which actually include patients with embolic stroke of any
etiology for which there is still no clear answer about the
Downloaded from http://ahajournals.org by on March 8, 2020
optimal antithrombotic treatment.3,4 This could prove to
be the main strength of these trials: most trials are limited
by narrow eligibility criteria and consequently yield con-
clusions that apply to highly selected patient populations,
an approach that later raises concerns when physicians
are tempted to extrapolate and apply these conclusions to
broader patient populations. In contrast, the broad selec-
tion criteria in the ongoing ESUS trials allow the inclusion
of a widely representative stroke population selected on
the basis of pathophysiology (ie, embolism) rather than
best-guess etiology. In this context, ESUS can be seen as
a positive, inclusive, pathophysiology-based definition
rather than as a diagnosis of exclusion. The results of the
large ESUS trials, anticipated in 2018, are likely to inform
management of most patients with embolic stroke.3,4
Circulation. 2017;136:2403–2405. DOI: 10.1161/CIRCULATIONAHA.117.030509
Embolic Stroke
DISCLOSURES
FRAME OF REFERENCE
Dr Ntaios received through his institution research support
or fees as speaker or advisory board member from Amgen,
Bayer, BMS/Pfizer, Boehringer-Ingelheim, Elpen, Galenica,
Sanofi, and Winmedica. Dr Hart received research support
and a stipend from Bayer AG for serving as the co-principal
investigator of the NAVIGATE ESUS trial (Rivaroxaban Versus
Aspirin in Secondary Prevention of Stroke and Prevention of
Systemic Embolism in Patients With Recent Embolic Stroke of
Undetermined Source) and on the Steering & Event Adjudica-
tion Committees of the COMPASS/COMPASS MIND (MRI) trial
(Cardiovascular Outcomes for People Using Anticoagulation
Strategy).
AFFILIATIONS
Department of Medicine, Larissa University Hospital,
University of Thessaly, Greece (G.N.). Department of Medicine
(Neurology), Population Health Research Institute, McMaster
University, Hamilton, Ontario, Canada (R.G.H.).
FOOTNOTES
Circulation is available at http://circ.ahajournals.org.
REFERENCES
1. Virchow, R. Handbuch der speciellen Pathologie und Therapie. Erlangen:
Enke;1854–1876.
2. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O’Donnell MJ,
Sacco RL, Connolly SJ; Cryptogenic Stroke/ESUS International Work-
ing Group. Embolic strokes of undetermined source: the case for a new
clinical construct. Lancet Neurol. 2014;13:429–438. doi: 10.1016/S1474-
4422(13)70310-7.
3. Hart RG, Sharma M, Mundl H, Shoamanesh A, Kasner SE, Berkowitz SD,
Pare G, Kirsch B, Pogue J, Pater C, Peters G, Davalos A, Lang W, Wang Y,
Wang Y, Cunha L, Eckstein J, Tatlisumak T, Shamalov N, Mikulik R, Lavados
P, Hankey GJ, Czlonkowska A, Toni D, Ameriso SF, Gagliardi RJ, Amarenco
P, Bereczki D, Uchiyama S, Lindgren A, Endres M, Brouns R, Yoon B-W,
Ntaios G, Veltkamp R, Muir KW, Ozturk S, Arauz A, Bornstein N, Bryer A,
O’Donnell MJ, Weitz J, Peacock F, Themeles E, Connolly SJ. Rivaroxaban
for secondary stroke prevention in patients with embolic strokes of unde-
termined source: Design of the navigate esus randomized trial. Eur Stroke
J. 2016;1:146–154.
4. Diener HC, Easton JD, Granger CB, Cronin L, Duffy C, Cotton D, Brueck-
mann M, Sacco RL; RE-SPECT ESUS Investigators. Design of Randomized,
double-blind, Evaluation in secondary Stroke Prevention comparing the Ef-
ficaCy and safety of the oral Thrombin inhibitor dabigatran etexilate vs.
acetylsalicylic acid in patients with Embolic Stroke of Undetermined Source
(RE-SPECT ESUS). Int J Stroke. 2015;10:1309–1312. doi: 10.1111/ijs.12630.
December 19/26, 2017 2405