Scandinavian Cardiovascular Journal

ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/icdv20

Assessment of patients with a suspected

cardioembolic ischemic stroke. A national
consensus statement

Mark Aplin, Asger Andersen, Axel Brandes, Helena Dominguez, Jordi S. Dahl,
Dorte Damgaard, Helle K. Iversen, Kasper K. Iversen, Edith Nielsen, Niels
Risum, Michael R. Schmidt & Niels H. Andersen

To cite this article: Mark Aplin, Asger Andersen, Axel Brandes, Helena Dominguez, Jordi S.
Dahl, Dorte Damgaard, Helle K. Iversen, Kasper K. Iversen, Edith Nielsen, Niels Risum, Michael
R. Schmidt & Niels H. Andersen (2021) Assessment of patients with a suspected cardioembolic
ischemic stroke. A national consensus statement, Scandinavian Cardiovascular Journal, 55:5,
315-325, DOI: 10.1080/14017431.2021.1973085

To link to this article: https://doi.org/10.1080/14017431.2021.1973085

Published online: 02 Sep 2021.

Submit your article to this journal

Article views: 1059

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=icdv20
SCANDINAVIAN CARDIOVASCULAR JOURNAL
2021, VOL. 55, NO. 5, 315–325
https://doi.org/10.1080/14017431.2021.1973085

REVIEW ARTICLE

Assessment of patients with a suspected cardioembolic ischemic stroke.

A national consensus statement
Mark Aplina, Asger Andersenb, Axel Brandesc,d , Helena Domingueza, Jordi S. Dahlc, Dorte Damgaarde,
Helle K. Iversenf, Kasper K. Iverseng, Edith Nielsenh, Niels Risumi, Michael R. Schmidti and
Niels H. Andersenc,j
a
Department of Cardiology, Bispebjerg University Hospital, Copenhagen, Denmark; bDepartment of Cardiology, Aarhus University Hospital,
Aarhus N, Denmark; cDepartment of Cardiology, Odense University Hospital, Odense, Denmark; dDepartment of Internal Medicine –
Cardiology, University Hospital of Southern Denmark – Esbjerg, Esbjerg, Denmark; eDepartment of Neurology, Aarhus University Hospital,
Aarhus N, Denmark; fDepartment of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; gDepartment of
Cardiology, Herlev-Gentofte Hospital, Herlev, Denmark; hDepartment of Neuroradiology, Aarhus University Hospital, Aarhus N, Denmark;
i
Department of Cardiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; jDepartment of Cardiology, Aalborg University
Hospital, Aalborg, Denmark

ABSTRACT ARTICLE HISTORY

Objectives: Several cardiovascular, structural, and functional abnormalities have been considered as Received 3 November 2020
potential causes of cardioembolic ischemic strokes. Beyond atrial fibrillation, other sources of embolism Revised 17 May 2021
clearly exist and may warrant urgent action, but they are only a minor part of the many stroke mecha- Accepted 17 August 2021
nisms and strokes that seem to be of embolic origin remain without a determined source. The associa-
KEYWORDS
tions between stroke and findings like atrial fibrillation, valve calcification, or heart failure are Neurovascular disease;
confounded by co-existing risk factors for atherosclerosis and vascular disease. In addition, a patent cardiac disease;
foramen ovale which is a common abnormality in the general population is mostly an innocent echocardiography; magnetic
bystander in patients with ischemic stroke. For these reasons, experts from the national Danish soci- resonance imaging;
eties of cardiology, neurology, stroke, and neuroradiology sought to develop a consensus document guidelines; car-
to provide national recommendations on how to manage patients with a suspected cardioembolic diac embolism
stroke. Design: Comprehensive literature search and analyses were done by a panel of experts and pre-
sented at a consensus meeting. Evidence supporting each subject was vetted by open discussion and
statements were adjusted thereafter.
Results: The most common sources of embolic stroke were identified, and the statement provides
advise on how neurologist can identify cases that need referral, and what is expected by the cardiolo-
gist.
Conclusions: A primary neurological and neuroradiological assessment is mandatory and neurovascu-
lar specialists should manage the initiation of secondary prophylactic treatment. If a cardioembolic
stroke is suspected, a dedicated cardiologist experienced in the management of cardioembolism
should provide a tailored clinical and echocardiographic assessment.

Preface neurologists, neuroradiologists and cardiologists. For this

Despite an increased focus on cardioembolism being a
potential cause of cryptogenic ischemic stroke, a thorough
work-up rarely identifies a definite cardiac source of embol-
ism. For optimal tailoring of secondary preventive measures
for the individual patient, it is mandatory to recognize a
broad spectrum of cardiovascular substrates and risk factors
that may be associated with an embolic stroke.
Many stroke patients have risk factors or already estab-
lished significant vascular disease. In these patients, it may
be difficult to determine whether a cardiac source of embol-
ism is an additional risk factor.
No guideline has presented an unequivocal classification
of stroke patients. Therefore, a workup to identify the most
likely etiologies requires a multi-disciplinary effort involving
reason, representatives from the Danish society of
Cardiology, the Danish society of Neurology, the Danish
Stroke Society, and the Danish society of Neuroradiology
have developed a consensus statement providing national
recommendations for the management of patients with a
suspected cardioembolic stroke.
Methods
The statement was written following a consensus meeting
and presents a comprehensive literature search and analysis
of the subject done by a panel of experts from the four dif-
ferent societies. During the first meeting, the panel members
gave presentations on the many subjects, and the evidence

CONTACT Niels H. Andersen dr.holmark@gmail.com Department of Cardiology, Odense University Hospital, J.B. Winsløws Vej 4, Odense 5000, Denmark
Endorsed by the Danish Society of Cardiology, Danish Society of Neurology, Danish Stroke Society and Danish Society of Neuroradiology
ß 2021 Informa UK Limited, trading as Taylor & Francis Group
316 M. APLIN ET AL.
supporting each subject was then vetted by open discussion.
Statements were thereafter adjusted based on the discussion.
Additional meetings were held in smaller groups when there
were disagreements. Consensus achieved from these add-
itional meetings were then presented for the whole group.
The statement represents the panel’s collective analysis and
final evaluation.
What is a cardioembolic stroke?
A stroke is characterized by focal neurological symptoms
with an acute onset and duration of more than 24 h, which
is caused by ischemia or hemorrhage in the central nervous
system [1]. A transient ischemic attack (TIA) is a brief epi-
sode of similar neurological symptoms that last less than
24 h [1]. However, patients with symptoms that have a simi-
lar time course to a TIA and a positive diffusion-weighted
magnetic resonance imaging (DW-MRI) signal are consid-
ered as stroke patients [1].
The TOAST-classification from 1993 (Trial of Org 10172
in Acute Stroke Treatment (TOAST)) is often used to clas-
sify subtypes of acute ischemic stroke [2]. According to this
classification, a cardioembolic stroke is a cortical, cerebellar,
brain stem or subcortical infarct with a physical extent
>1.5 cm (non-lacunar) and a cardiac source of embolism
[2]. In 2005, an additional subsection of the term stroke of
unknown origin was introduced with the entity called
cryptogenic embolism [3]. This term refers to a stroke in
which there is an abrupt cut-off of a blood vessel within
otherwise normal intracranial arteries or evidence of com-
plete recanalization of an intracranial blood vessel. Multiple
acute infarctions occurring closely related in time, without
obvious abnormalities of the affected blood vessels can be
present [4]. The term “Embolic stroke of undetermined
source” (ESUS) was introduced in 2014 with the aim to
identify a subgroup of stroke patients with a non-lacunar
ischemic stroke and no convincing etiology in which –
assuming a high prevalence of atrial fibrillation – secondary
preventive efficacy of anticoagulative therapy could be pur-
sued [5]. ESUS-patients account for one in six stroke
patients [5]. They are often younger, have milder strokes
and a better survival [6]. Despite this, ESUS patients have
an up to 5% annual risk of recurrent stroke [7,8]. In ESUS
patients, two large trials that tested NOAC treatment com-
pared to aspirin came out neutral with an increased risk of
bleeding associated to NOAC treatment in one of the trials
[7,8]. This could indicate that the ESUS definition is too
wide and covers patients that have the same or better sec-
ondary preventive effect of antiplatelet therapy compared to
oral anticoagulants [9].
Sources of cardioembolism
Cardioembolic stroke may have its origin in the heart itself
or from the arteries. In the following, cardiovascular disor-
ders and risk factors are discussed for causality of their roles
as potential sources of material for embolism to vascular
beds of the central nervous system (Table 1). Figure 1 dis-
plays the most common intracardiac sources of embolism.
Atrial fibrillation
Patients with atrial fibrillation have a 3–5 times increased
risk of stroke [10]. However, 10% of patients with lacunar
infarcts also have atrial fibrillation [11], and atherosclerosis
of the large arteries is twice as common in patients with
atrial fibrillation [12]. Therefore, the average stroke patient
who is diagnosed with atrial fibrillation may have several
risk factors that could have caused the stroke [11,12].
Moreover, if indeed atrial fibrillation was a solitary source
of stroke, maintenance of sinus rhythm should reduce the
risk of stroke. Although the recently published EAST-
AFNET 4 Trial demonstrated a reduction in the risk of
stroke when early rhythm control therapy was pursued in
patients with atrial fibrillation [13], a meta-analysis of previ-
ous studies comparing rate and rhythm control therapy
found no significant effect on the incidence of stroke [14].
This means that other stroke mechanisms should be taken
into account in this subset of patients [15]. Interestingly,
atrial myopathy may actually be an important cause of
increased thrombogenicity and explain the lack of a chrono-
logical association between paroxysms of atrial fibrillation
and stroke [15]. It is likely, that fibrotic atrial myopathy and
reduced left atrial ejection fraction could also be a mediators
of thromboembolism [15]. Excessive atrial ectopic heart
beats are also associated with an increased risk of stroke,
equal to patients with overt atrial fibrillation [16]. This sup-
ports the notion that atrial fibrillation may be regarded as a
marker of increased risk, rather than the cause of thrombo-
embolism itself [17]. Current guidelines have endorsed the
use of the CHA2DS2-VASc score to guide anticoagulant
therapy in patients with documented atrial fibrillation and
increased risk of stroke, which markedly reduces stroke risk
and is indicated in all patients in the absence of contraindi-
cations [17].
Acute STEMI
The use of modern antithrombotic treatment and acute
revascularization by percutaneous coronary intervention for
ST-elevation myocardial infarction (STEMI) has significantly
reduced the risk of a cardioembolic stroke due to a dis-
lodged mural thrombus [18]. Mural thrombi are found in
less than 2% of patients [18], and the risk is highest in
patients with anterior STEMI [19]. Large end-diastolic vol-
umes, low ejection fraction, and resuscitation during the
course of the acute STEMI are all associated with mural
thrombi [19]. If a mural thrombus is found, heparin fol-
lowed by warfarin for at least three months is still recom-
mended as the first-line treatment [19]. Small observational
studies have indicated NOAC treatment to be useful [20],
but a recent non-randomized cohort study with more than
500 patients found NOACs associated with a higher rate of
systemic embolism than with warfarine [21]. Since the com-
bination of two antiplatelet drugs after coronary stenting on
 SCANDINAVIAN CARDIOVASCULAR JOURNAL 317

Table 1. Cardiac and vascular sources of emboli.

High-risk findings Factors of undetermined or low risk
Atrial fibrillation Structural and electrical atrial myopathy
Stenosis of carotid, vertebral and cerebral arteries Atherosclerotic plaques of the aorta or arteries proximal to cerebral ischemia
Intracardiac thrombi Takotsubo cardiomyopathy
-After myocardial infarction
-In cardiomyopathy or heart failure
Vegetations and thrombi on cardiac valves Large Lambl’s vegetations
-Endocarditis Pedunculated fibroelastomas
-Non-bacterial (Marantic) vegetations
-Sessile fibroelastomas
Intracardiac tumors – Myxomas
Mitral valve stenosis Mitral valve calcification
Mechanical heart valves or repairs Mitral valve prolapse
Complex congenital heart disease Paradoxical embolism through PFO/ASD
Aneurismatic interatrial septum

Figure 1. Echocardiographic images of intracardiac sources of embolism in stroke patients. Atrial fibrillation patients. Panel (A) shows a large thrombus () on the
atrial septum due to slow flow in the atrium. Panel (B) is a close-up of a thrombus () in the left atrial appendage. (C) Patient with an anterior myocardial infarction
and a mobile mural thrombus in the apex of the left ventricle (arrows). (D) Left atrial myxoma with an irregular surface (). (E) Large vegetation in the mitral valve
in a patient with endocarditis (arrows). (F) Stenotic mitral repair with a thrombus on the valve (arrows) and the left atrial appendage filled with spontaneous echo
contrast (). (G) Large thrombus on a mechanical mitral valve (arrows). (H) Deep venous thrombus in transit through a persistent foramen ovale (arrows).

top of warfarin increases the risk of bleeding [22], it is
important to stop treatment with one of the antithrombotic
drugs at an early stage [22]. There is no evidence supporting
prophylactic treatment with warfarin in any high-risk cases
to prevent mural thrombi [23].
Heart failure
The 5-year risk of stroke in heart failure patients is 3.9% in
a registry based setting, which was more than five times
higher than the general population [24]. However, heart fail-
ure patients also have more atrial fibrillation, more coronary
artery disease and more atherosclerosis [24]. Overall, studies
comparing warfarin with an antithrombotic strategy in heart
failure patients have been neutral [25]. Nevertheless, war-
farin did reduce “overall stroke” in the WATCH-trial [25]
and the incidence of ischemic stroke in the WARCEF-trial
[26]. While there is no general recommendation to treat
heart failure patients with warfarin per se, data from the
WARCEF-trail support warfarin treatment as secondary
prophylaxis in stroke patients with an ejection fraction
below 15% [26]. Very few patients with previous stroke
were included and further studies are needed, preferably
with NOACS.
Hypertrophic cardiomyopathy
Patients with hypertrophic cardiomyopathy have a high risk
of developing atrial fibrillation [27], which is related to
6–24% life-time risk of stroke, of which 11% are fatal [27].
For these reasons, anticoagulation therapy is generally rec-
ommended when atrial fibrillation is identified in these
318 M. APLIN ET AL.
patients regardless of their estimated CHA2DS2-VASc risk
score [28]. Patients with mid-ventricular obstruction and
apical aneurisms may develop stroke from a mural throm-
bus in the apex [29] and if present, it should be treated
accordingly. There are no studies that support primary
prophylactic anticoagulation strategy in this patient-group.
Takotsubo cardiomyopathy
Takotsubo cardiomyopathy is a temporary weakening of the
contraction of the left ventricle in which mural thrombi
may develop and embolize to the cerebral vasculature [30].
Mural thrombi can be found in 5% of Takotsubo cases [30],
but the risk of stroke is low (1%) and only significantly
increased during the first year after the incident [31].
Clinicians need to be aware of this potential stroke risk
when managing Takotsubo cardiomyopathy but there are no
general recommendations for anticoagulant therapy in
patients without mural thrombi. However, in patients with
Takotsubo and coincidental stroke without a visible mural
thrombus, anticoagulation is still warranted [30].
Intracardiac tumors
Cardiac tumors are very rare, but carry a high risk of
embolization [32,33]. Myxomas occur more commonly in
women at the age of 30–60 years [33], and generally local-
ized in the left atrium. Multiple myxomas can be found in
approximately 5% of cases and can be caused by the rare
disease Carney Complex (Mutation in the PRKAR1A gene)
[34]. Myxomas can cause stroke due to tumor embolism or
thrombus generated on the surface of the tumor [35]. The
risk is considerable and it is strongly recommended that
left-sided myxomas be surgically removed to reduce the risk
of stroke [35].
Fibroelastomas are common benign neoplasms of the
cardiac valvular structures [36]. The incidence increases
with age and are mainly seen in octogenarians [36]. Most
fibroelastomas are located on the heart valves (80%), espe-
cially on the aortic valve [36]. Pedunculated and very mobile
fibroelastomas are related to embolism whereas sessile and
immobile tumors rarely embolize [36]. Fibroelastomas on
the aortic valve have a higher risk of causing stroke than
fibroelastomas on the mitral valve or in the left ventricle
[36]. In patients with an embolus, surgical removal of the
fibroelastoma is recommended. Valve-sparing surgery is
often possible and the risk of recurrence is low [36]. In add-
ition, very mobile fibroelastomas found by coincidence
should be removed as primary prophylaxis, whereas immo-
bile fibroelastomas should only be followed with echocardi-
ography [32, 36]. Malignant cardiac tumors (sarcomas and
lymphomas) are extremely rare and only related to stroke in
case reports [37]. Treatment of malignant cardiac tumors
requires collaboration between cardiologists, oncologists,
and thoracic surgeons.
Infective endocarditis
The incidence of cerebrovascular complications in patients
with left-sided infective endocarditis is as high as 65–80%
[38] of which 25–40% are symptomatic [39]. The risk of
stroke increases with the size and mobility of the vegetations
[39]. Endocarditis caused by staphylococcus aureus is more
prone to embolize, and vegetations on the mitral valve carry
a higher risk than those affecting the aortic valve [39]. In
approximately 25% of endocarditis patients, stroke is the
first sign of the disease [40] and 50% of all strokes related
to infective endocarditis occur at the time of diagnosis and
before antibiotic treatment is initiated [41]. Relevant anti-
biotic treatment reduces the risk of stroke considerably [41].
Prophylactic surgery should only be considered in cases
with very large vegetations (> 30 mm) [40]. However, sur-
gery can be considered, if a patient suffers from a stroke
despite relevant antibiotic treatment and has a remaining
vegetation larger than 10 mm [42].
Antiplatelet therapy or anticoagulants are not recom-
mended as adjunctive treatment in patients with infective
endocarditis [42]. In patients with infective endocarditis and
a stroke, and already on oral anticoagulants (e.g. mechanical
valves) the risk intracranial hemorrhage may be increased,
and bridging should be done with great caution [42]. Some
even advocate for discontinuation of all forms of anticoagu-
lation in at least 2 weeks in patients with stroke and mech-
anical valve endocarditis to allow for thrombus
organization [43].
Nonbacterial thrombotic endocarditis
Marantic endocarditis, is characterized by sterile vegetations
on the heart valves and has a high embolic potential [44].
This condition is a thrombotic coagulopathy often associ-
ated with gastrointestinal or pulmonary cancers [45].
Anticoagulation with low molecular weight heparin can be
used to prevent a cardioembolic stroke; although concur-
rently increased risk of bleeding may be a problem for some
patients with cancer-associated coagulopathy [45]. Cardiac
surgery should only be considered in patients with poten-
tially curable malignancies and avoided in those with
advanced, non-curable cancer.
Patients with systemic lupus erythematosus (SLE) who
suffer a stroke should always be suspected of embolism orig-
inating from Libman-Sacks endocarditis [46].
Echocardiographic findings of Libman-Sacks vegetations in
SLE patients with stroke should lead to immediate anti-
coagulant therapy [46]. NOACs should not be considered in
these patients, since many of these patients also have anti-
phospholipid syndrome that requires blocking of the upper
coagulation pathway rather than distal blockade with a
NOAC [47].
Lambl’s excrescences are tiny hypermobile strands that
arise on the line of valve closure, and are rarely a cause of
cardioembolic stroke [48]. Lambl’s excrescences should be a
last consideration in patients with a cryptogenic stroke, and
overall risk profile should be the first priority before
embarking on surgical removal [49].

Native valve disease
Patients with mitral valve stenosis have a significantly
increased risk of stroke [50], mostly due to the strong asso-
ciation to atrial fibrillation [50], and a stroke or a systemic
embolus in a patient with mitral stenosis indicates warfarin
treatment even though the patient is in sinus rhythm [50].
In patients with moderate to severe mitral stenosis, surgery
should be considered [50]. Stenotic mitral valve repairs may
also be a source of emboli [51]. Mitral annular calcification
is also associated to stroke [52]. However, patients with
mitral valve calcification also have considerably more
comorbidity like diabetes, hypertension, or renal disease
[52]. Therefore, mitral annular calcification should not be
considered a source of embolism, but rather seen as a
marker of a high-risk stroke profile [52]. Even though
embolization from a calcified aortic valve is conceivable,
there is no evidence that clearly indicates an independent
risk ascribable to aortic valve calcification [52]. Aortic valve
stenosis is also associated with smoking, diabetes, hyperten-
sion, hypercholesterolemia, and a higher prevalence of atrial
fibrillation [53].
Mechanical heart valves
Mechanical valves are associated with a high risk of throm-
bosis and embolization, especially when placed in the mitral
position. Suboptimal anticoagulation is a key issue and com-
bination of warfarin and aspirin should be considered if
these patients develop a stroke [54]. Likewise, endocarditis
should always be suspected in patients with mechanical
valves and stroke [55].
Atherosclerosis in the carotid or cerebral arteries
By classification, it has previously been the general percep-
tion that atherosclerosis in the carotid or cerebral arteries
with less than 50% degree of stenosis, could not constitute
sufficient explanation for the patients stroke [5]. However,
observational studies have since shown that non-stenotic
plaques 3 mm or carotid intraplaque hemorrhage are sig-
nificantly more prevalent on the ipsilateral side of the stroke
in patients classified as having ESUS [56]. With the current
knowledge, significant atherosclerosis of arteries supplying
the brain should not be dismissed as causally associated
with the thromboembolic event and must be taken into con-
sideration in the full assessment of the patient with a sus-
pected cardio-embolic stroke.
Aortic dissection
Approximately 6% of patients with acute aortic dissection
present with stroke-like symptoms and 1.7% of stroke
patients who are assessed with regard to eligibility for
thrombolysis have aortic dissection [57]. Hypotension and/
or dissection in the head and neck vessels are the most
common causes of these findings and the clinician must be
extra careful in the management of stroke patients with
SCANDINAVIAN CARDIOVASCULAR JOURNAL 319
chest pain or other signs of aortic dissection. Therefore, it is
recommended to include visualization of the aortic arch
before thrombolytic treatment of patients with stroke and
acute chest pain [58].
Paradoxical embolism through a patent foramen ovale
or a shunt
In the normal population 20–34% have a patent foramen
ovale (PFO) identified by autopsies and approximately 12%
identified by echocardiography [59]. Stroke may result from
the formation of an embolus within the peripheral venous
system, which traverses through the foramen ovale to the
systemic arterial circulation [60]. This has been demon-
strated in patients with pulmonary embolisms where the
prevalence of ischemic lesions in the brain was higher in
patients with a symptomatic pulmonary embolisms and a
PFO than in those without PFO [59]. Several studies found
a secondary protective benefit from closing the PFO in
highly selected cases with stroke and suspicion of a paradox-
ically embolic mechanism [61–63]. According to the collect-
ive evidence, PFO closure in patients stroke patients aged
18–60 years with no other identifiable cause, provides an
absolute reduction in recurrent stroke of 3.4% at 5 years fol-
low-up, a periprocedural complication rate of about 4%, and
an absolute increase in the rate of non-periprocedural atrial
fibrillation (0.33% annually) [61–63]. Patients with large
shunts, aneurysmatic interatrial septa, and age < 45 years
are most likely to benefit from PFO closure [61–63]. While
efficacy of PFO closure was demonstrated as an add-on to
life-long antithrombotic or anticoagulant therapy as other-
wise indicated after stroke [61–63], subsequent retrospective
observational reports have indicated that medication may be
individualized and shortened in patients with a very low
cardiovascular risk [64].
Pulmonary arteriovenous fistulas are an exceptionally
rare mechanism of stroke [65]. They are mostly found in
patients with Morbus Osler and can potentially be the
source of paradoxical emboli. In stroke patients, large shunts
should be closed by coiling, but there is no clear evidence of
a stroke prevention benefit [66].
Congenital heart disease
Patients with right to left shunting have a high risk of para-
doxical embolization as well as air embolisms after minimal
intravenous manipulations, such as the insertion of a per-
ipheral intravenous catheter [67]. These patients should be
treated with anticoagulation in case of stroke or if the dis-
ease itself indicates treatment. However, Eisenmenger
patients have an increased risk of hemoptysis and the risk
of bleeding may well exceed the stroke-preventive benefit of
anticoagulation. High hematocrit levels (> 70%) can also be
associated with stroke in cyanosed patients [67] and phle-
botomy should be considered as a primary prevent-
ive treatment.
Subclinical supraventricular arrhythmias are common in
patients with congenital heart disease and should be pursued
320 M. APLIN ET AL.
Figure 2. Depiction of common patterns of cerebral ischemia or infarction. (A)
Cortical and cortico-subcortical infarction in territories of large cerebral arteries
indicate possible embolism for a cardiac or proximal vascular source. Several
small infarcts in different vascular territories are also suspicious of a cardioem-
bolic stroke. (B) Large (>2 cm) subcortical or striatocapsular infarctions are also
potentially embolic. (C) Lacunar infarctions are subcortical by definition and
result from small vessel occlusion. They are not considered as an embolic
stroke. A definite lacunar syndrome is a small infarct (<1.5 cm) or multiple
lacunes (including older lesions) localized in basal ganglia, internal capsula, or
the centrum semiovale. (D) Interterritorial infarctions (watershed areas) occur at
the border between cerebral vascular territories where the tissue is furthest
from arterial supply. They may be cortical or subcortical strokes, but do not cor-
relate with occlusion of a single vascular bed. They generally result from sten-
oses of one or more supplying arteries most often due to artery-to-artery
microembolisms and less common due to hypoperfusion. Hypoperfusion could
be secondary to an aortic dissection or a large STEMI. This figure is adapted
from Ringelstein et al. [74] and is based on both CT and MRI derived data.
in case a patient suffers from an embolic stroke [68]. Lastly,
any device inserted in the systemic circulation (e.g. an atrial
septal occluder) should be assessed in the case of a stroke.
Diagnostic work-up
Clinical assessment
Cardioembolic stroke cannot be identified solely based on
symptoms or the finding of characteristic patterns of neuro-
logical deficits. On the other hand, several clinical observa-
tions at admission should be noted to support suspicion of
an embolic event. The probability of underlying atrial fibril-
lation increases with age and comorbidity, and some
patients report having palpitations prior to the stroke [10].
Stroke patients with a heart murmur, or either known car-
diac disease (see above) or signs of chest pain or congestion
are highly suspicious of a cardiac origin. For a paradoxical
embolism to occur (e.g. through a PFO), a sudden increase
in right atrial blood pressure is needed and should be sus-
pected if the patient presents signs of a deep venous throm-
bosis or pulmonary embolism in close relation to the stroke.
Likewise, onset of neurological symptoms in relation to a
Valsalva maneuver, heavy lifting, coughing, or elevated
abdominal pressure during defecation, might suggest a PFO-
related mechanism of stroke [60]. PFO-related strokes have
been reported to be larger (>1.5 cm) and more likely soli-
tary cortical strokes without signs of previous strokes or
white matter lesions [69]. Fever or abnormal white blood
cell count, C-reactive protein, and Procalcitonin levels in
patients with an acute stroke should always raise suspicion
of endocarditis. However, fever at a later stage of a stroke is
not unusual. Finally, coincidental findings of a systemic
embolus outside the brain are strongly suspicious of emboli
from a central source [70]. As an example, it is not uncom-
mon to see a visceral infarct in stroke patients with atrial
fibrillation [71].
Biomarkers indicative of a cardioembolic stroke
A few studies have examined whether biomarkers such as
troponins and brain natriuretic peptides could be useful in
the identification of patients with a cardioembolic stroke
[72,73]. Both biomarkers are increased in patients with a
cardioembolic stroke, but the data do not support routine
assessment of troponins or brain natriuretic peptides in the
identification of patients with a cardiac source of embol-
ism [72,73].
Infarct patterns and imaging
We advise that infarct patterns in the hemispheres are clas-
sified according to the anatomy of the cerebral vessels and
findings on MRI/CT (Figure 2) [74]. In a study on patients
with a certain cardioembolic stroke and hemispheric stroke,
92% had cortical or subcortical infarcts >2 cm [74]. No
patients had border zone infarction, 5% had small infarcts
that could be classified as lacunar and 3% had strokes that
could not be classified [74]. In 18% of the cases, the patient
had two or more infarcts [74]. In the brain stem and cere-
bellum, the same observations cannot be found due to a dif-
ferent vascular anatomy [74].
The arbitrary distinction between lacunar and non-lacu-
nar infarcts based on size alone should be done with cau-
tion. A central lacunar infarct due to small vessel disease
may occur without other radiological manifestations of cere-
bral small vessel disease but should still be held suspicious
of a cardioembolic stroke, especially if the stroke is located
in the thalamic region or in the cerebellum [75].
Moreover, a fractionated embolus could result in several
small infarcts in different vascular territories and a distribu-
tion of previous (cortical) infarcts either bilaterally or in
both the anterior and posterior circulation is also suspicious
of a cardioembolic stroke [74].
MRI is superior in the imaging of stroke patients [76,77].
The major advantage is that 95% of ischemic strokes are
detected on MRI even though the scan is performed within

the first few hours after the onset of symptoms. On a CT
scan, a stroke is often not detected until 12–24 h after the
first onset of symptoms and small infarcts are not visible on
a CT scan. Moreover, a third of patients with a suspected
TIA will actually have an infarct on an MRI scan [76].
Finally, it is possible to detect hemorrhagic transformation
of the acute infarct by use of T2- or susceptibility weighted
imaging. Chronic ischemic lesions or microbleeds are also
better visualized with MRI. For these reasons, MRI is rec-
ommended as the primary imaging modality of choice for
all stroke patients.
Reporting of MRI findings
The neuroradiological report in a stroke patient should
include:
 Diffusion restrictions (DWI lesions) of acute ischemia
and its location. Assessment of the stroke onset by com-
paring DWI lesions with lesions in fluid attenuated
inversion recovery (FLAIR) sequence [77].
 Presence of intra cerebral bleeds, microbleeds, cortical
superficial siderosis, or hemorrhagic transformation.
 Intravasal thrombi or slow flow and their location.
 Old infarcts, chronic ischemic lesions (WMH) and
enlarged perivascular spaces.
 Coincidental pathology, i.e. tumors.
Clinical considerations before referral to a cardiologist
Optimally, the following aspects should be considered before
referral of patients with a stroke unless there is an acute
indication of echocardiography (Table 2): (1) investigation
with MRI and findings compatible with embolism. (2) The
general risk profile, patient history, and the clinical findings
(e.g. murmurs) are evaluated. (3) Examination of the carotid
and cerebral arteries with imaging to exclude a vascular
source of thrombus. (4) ECG and 72-h monitoring without
atrial fibrillation (see below). We recommend that collective
information should be reviewed and discussed with a
trained specialist in neurovascular diseases before referral. It
is important to acknowledge that stroke mechanisms are
manifold and a cardioembolic stroke can also appear in
patients with small or large vessel atherosclerosis (Figure 3).
This ambiguity necessitates a nuanced approach and only
selected patients with a stroke should be seen by a cardiolo-
gist (Table 2).
Patients with a TIA should always be referred to a neuro-
vascular specialist to verify the diagnosis and initiate workup
to determine causal or predisposing factors.
Diagnostic tools when investigating patients suspected
of a cardioembolic stroke
ECG
A normal 12 lead ECG should be obtained on admission for
stroke and if the patients experiences signs of arrhythmia.
ECG alterations that indicate previous anterior myocardial
SCANDINAVIAN CARDIOVASCULAR JOURNAL 321
infarcts, cardiomyopathies, atrial fibrillation, etc. should lead
to referral to a cardiologist.
Long-term heart rhythm monitoring
The ESC guidelines from 2020 [17] recommend at least 72 h
of continuous heat rate monitoring to detect atrial fibrilla-
tion, which is also the national recommendation at present
time. Long-term heart rhythm monitoring with implantable
devices increases the prevalence of atrial fibrillation among
patients with stroke [78]. However, the clinical consequen-
ces of long-term heart rhythm monitoring compared to the
present recommendations are unsettled. Moreover, implant-
able devices, portable devices, and pacemaker-readouts are
used increasingly implantable devices increase the detection
rate of AF, but no current evidence has shown that this
strategy decreases the risk of a recurrent stroke. Moreover,
there is also a risk of over-diagnosing atrial fibrillation [79].
However, they may be patient categories with a high a priori
risk of atrial fibrillation (e.g. octagorians, heart failure
patients, etc.) where additional long-term monitoring may
make sense but more data on how to address this issue is
warranted [80].
Nevertheless, presence of atrial fibrillation in a clinical
context later on, will obviously warrant anticoagulation in
patients with a previous stroke [17].
Echocardiography
A transthoracic echocardiogram (TTE) is the cornerstone in
the cardiac evaluation of patients with stroke of an embolic
nature. A TTE will visualize the cardiac function, heart
valves, large vegetations, tumors, mural thrombi, and the
majority of fibroelastomas [32]. It is often necessary to
apply customized projections since thrombi can be located
in between standard echocardiographic projections. In
patients with pulmonary disease or obesity, TTE can be
challenging, and the imaging quality can hamper sensitivity.
Endocarditis can be diagnosed with a TTE, but the sensi-
tivity is low. For this reason, a transesophageal echocardio-
gram (TOE) is almost always warranted in patients
suspected of endocarditis [32].
Saline contrast echocardiography can be used to detect
intracardiac shunts or arteriovenous malformation in the
pulmonary circulation. Microbubbles in the left-sided car-
diac chambers or in the aorta are indicative of a shunt and
warrant subsequent visualization of the shunt defect by a
TOE. Saline contrast echocardiography can be challenging
with a high risk of false negative results and should be per-
formed by an experienced observer. According to the evi-
dence on PFO-closure, we recommend that saline contrast
echocardiography should only be done in the following
patient categories:
Stroke patients aged 60 years or younger with absence of:
 Significant head and neck vessel atherosclerosis.
 Atrial fibrillation on at least 72 h of continu-
ous monitoring.
322 M. APLIN ET AL.

Table 2. Stratification of stroke patients for acute or deferred echocardiographic evaluation by a cardiologist.
Examined during admission
Transthoracic echocardiography
 Patients with moderate to severe symptoms of heart failure
 Acute stroke in several vascular areas in the absence of atrial fibrillation
 ECG abnormalities indicative of a previous anterior STEMIa
 Patients with congenital heart disease
Transesophageal echocardiography
 Suspicion of endocarditis: Fever and elevated infectious parameters at the time of the stroke, or infectious disease treated with antibiotics prior to the
acute stroke
 Patients with mechanical valves or left-sided devices (PFO/ASD-occluders, left atrial appendage occlude, etc.)
 Mitral valve stenosis, previous mitral valve repair
 Patients with concurring pulmonary embolism and stroke
Examined within the first month after the stroke
Transthoracic echocardiography
 Solid suspicion of a cardiac embolism (evaluated by a stroke specialist). Must include saline contrast if the patient is eligible for PFO-closure (see text)
 Patients with newly diagnosed atrial fibrillation to enable heart rate control or to detect structural heart disease
 Patients with a murmur and/or mild cardiac symptoms (angina, dyspnea)
Transesophageal echocardiography
 Positive saline contrast echocardiography
 Findings on a transthoracic echocardiogram suspicious of being a source of embolism (e.g. cardiac tumor)
a
Use of transpulmonary contrast may be necessary.

to do cardiac MRI in patients with stroke should be decided

Figure 3. Three main mechanisms behind a stroke. Having one condition does
not exclude the other from developing and in many cases the stroke etiology
can be difficult to determine.
 Already established indication for lifelong
anticoagulation.
 Another identified cause of stroke.
 A high-risk profile (hypertension, diabetes, hypercholes-
terolemia, smoking, etc.), where secondary preventive
efficacy of PFO-closure is not established.
Transpulmonary echocardiographic contrast agents can
be used to enhance the opacification of the left-sided cardiac
chambers [32]. The primary indication is to visualize mural
thrombi or tumors. Compared to normal TTE, the sensitiv-
ity can be enhanced significantly, when using a contrast
agent and should be used with a low threshold [32]. If con-
trast echocardiography cannot clearly visualize the left ven-
tricular cavity, MRI can be used [32]. The strength of MRI
is the spatial resolution enabling even small thrombi to be
visualized. However, small mural thrombi usually have a
low stroke potential, so MRI is often not necessary. When
by a specialized cardiologist and should be kept for patients
with a high a priori risk of a stroke source in the left-sided
cavities where a TTE or a TOE has not been able to provide
sufficient imaging.
A TOE is indicated when a detailed description of the
cardiac structures or visualization of an intracardiac shunt-
ing defect is needed. The procedure is not standard in the
work-up of cardiac embolism after stroke but should be per-
formed in cases with (1) possible infective endocarditis, (2)
mechanical valves, (3) cardiac tumors, and (4) suspected
intracardiac shunts. Moreover, a TOE is cornerstone in
patients that opt for immediate DC cardioversion without
adequate anticoagulation [32]. As thus explained, echocar-
diographic modalities provide a versatile platform for evalu-
ation of a stroke patient. However, it must be performed,
adjusted, and tailored by a cardiologist with knowledge of
the patient’s history, previous work-up and clear view of
findings, that could have therapeutic importance. It is not
the task of a technician. Table 2 provides an overview of
indications for and timing of echocardiography.
Conclusion
Cardioembolic stroke may arise from a multitude of condi-
tions, many of which are heavily confounded by general risk
factors for atherosclerosis and cardiovascular dysfunction.
Conditions like aortic dissection, myocardial infarction, and
infectious endocarditis may present with signs of stroke and
require acute neuro-cardiological collaboration. However,
for most cases, systematic neurological and radiographic
assessments are required to exclude the more common
micro- and macro-vascular explanation for stroke. It is also
the agreement in Denmark, that initiation of secondary
prophylactic treatment driven by the stroke-diagnosis is
handled by neurovascular specialist departments and does
not require cardiological involvement. On suspicion of car-
dioembolic stroke, individualized clinical and echocardio-
graphic assessment should be provided by a dedicated
cardiologist, who knows what to look for – and when it is

reasonable to consider specialized treatment (e.g. PFO-clos-
ure). By achieving national Neuro-Cardiological consensus,
we hope to inspire incremental collaboration and research
in the field of cardioembolic stroke.
Disclosure statement
In accordance with Taylor & Francis policy and our ethical obligation
as researchers, we are reporting that I Mark Aplin is an advisory board
member at Boehringer Ingelheim. Axel Brandes has received lecture
fees from Bayer, Bristol-Myers Squibb, MSD. Dorte Damgaard has
received lecture fees from Bayer, Boehringer Ingelheim, Bristol Myers
Squibb, and MSD. Helle K Iversen is an advisory board member at
Bayer, Bristol-Myers Squibb, Boehringer Ingelheim. These companies
may be affected by the research reported in the enclosed paper. The
authors have disclosed those interests fully to Taylor & Francis, and
they have in place an approved plan for managing any potential con-
flicts arising from this.
Funding
The consensus meeting was funded by the national societies.
Otherwise, the project did not receive any funding.
ORCID
Axel Brandes http://orcid.org/0000-0001-9145-6887
Niels H. Andersen http://orcid.org/0000-0002-5394-3016
References
[1] Sacco RL, Kasner SE, Broderick JP, et al.; Council on Nutrition,
Physical Activity and Metabolism. An updated definition of
stroke for the 21st century: a statement for healthcare profes-
sionals from the American Heart Association/American Stroke
Association. Stroke. 2013;44(7):2064–2089.
[2] Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of
subtype of acute ischemic stroke. Definitions for use in a multi-
center clinical trial. TOAST. Trial of org 10172 in acute stroke
treatment. Stroke. 1993;24(1):35–41.
[3] Ay H, Furie KL, Singhal A, et al. An evidence-based causative
classification system for acute ischemic stroke. Ann Neurol.
2005;58(5):688–697.
[4] Ay H, Benner T, Arsava EM, et al. A computerized algorithm
for etiologic classification of ischemic stroke: the Causative
Classification of Stroke System . Stroke. 2007;38(11):2979–2984.
[5] Hart RG, Diener H-C, Coutts SB, et al.; Cryptogenic Stroke/
ESUS International Working Group. Embolic strokes of
undetermined source: the case for a new clinical construct.
Lancet Neurol. 2014;13(4):429–438.
[6] Hart RG, Catanese L, Perera KS, et al. Embolic stroke of
undetermined source: a systematic review and clinical update
stroke. Stroke. 2017;48(4):867–872.
[7] Diener H-C, Sacco RL, Easton JD, et al.; RE-SPECT ESUS
Steering Committee and Investigators. Dabigatran for preven-
tion of stroke after embolic stroke of undetermined source. N
Engl J Med. 2019;380(20):1906–1917.
[8] Hart RG, Sharma M, Mundl H, et al. Rivaroxaban for stroke
prevention after embolic stroke of undetermined source. N
Engl J Med. 2018;378(23):2191–2201.
[9] Ntaios G. Embolic stroke of undetermined source: JACC review
topic of the week. J Am Coll Cardiol. 2020;75(3):333–340.
[10] Bertaglia E, Blank B, Blomstr€ om-Lundqvist C, et al. Atrial
high-rate episodes: prevalence, stroke risk, implications for
management, and clinical gaps in evidence. Europace: Eur
SCANDINAVIAN CARDIOVASCULAR JOURNAL 323
Pacing Arrhythmias Cardiac Electrophysiol: Journal of the
Working Groups on Cardiac Pacing, Arrhythmias, and Cardiac
Cellular Electrophysiology of the European Society of
Cardiology. 2019;21(10):1459–1467.
[11] Lodder J, Bamford JM, Sandercock PA, et al. Are hypertension
or cardiac embolism likely causes of lacunar infarction? Stroke.
1990;21(3):375–381.
[12] Chesebro JH, Fuster V, Halperin JL. Atrial fibrillation-risk
marker for stroke. N Engl J Med. 1990;323(22):1556–1558.
[13] Kirchhof P, Camm AJ, Goette A, EAST-AFNET 4 Trial
Investigators, et al. Early rhythm-control therapy in patients
with atrial fibrillation. N Engl J Med. 2020;383(14):1305–1316.
[14] Al-Khatib SM, Allen LaPointe NM, Chatterjee R, et al. Rate-
and rhythm-control therapies in patients with atrial fibrillation:
a systematic review. Ann Intern Med. 2014;160(11):760–773.
[15] Bisbal F, Baranchuk A, Braunwald E, et al. Atrial failure as a
clinical entity: JACC review topic of the week. J Am Coll
Cardiol. 2020;75(2):222–232.
[16] Larsen BS, Kumarathurai P, Falkenberg J, et al. Excessive atrial
ectopy and short atrial runs increase the risk of stroke beyond
incident atrial fibrillation. J Am Coll Cardiol. 2015;66(3):
232–241.
[17] Hindricks G, Potpara T, Dagres N, et al. 2020 ESC guidelines
for the diagnosis and management of atrial fibrillation devel-
oped in collaboration with the European Association of Cardio-
Thoracic surgery (EACTS). Eur Heart J. 2020; 42:373–498.
[18] Mao TF, Bajwa A, Muskula P, et al. Incidence of left ventricular
thrombus in patients with acute ST segment elevation myocardial
infarction treated with percutaneous coronary intervention. Am J
Cardiol. 2018;121(1):27–31.
[19] Driesman A, Hyder O, Lang C, et al. Incidence and predictors
of left ventricular thrombus after primary percutaneous coron-
ary intervention for anterior ST-segment elevation myocardial
infarction. Clin Cardiol. 2015;38(10):590–597.
[20] Leow AS-T, Sia C-H, Tan BY-Q, et al. A meta-summary of
case reports of non-vitamin K antagonist oral anticoagulant use
in patients with left ventricular thrombus. J Thromb
Thrombolysis. 2018;46(1):68–73.
[21] Robinson AA, Trankle CR, Eubanks G, et al. Off-label use of
direct oral anticoagulants compared with warfarin for left ven-
tricular thrombi. JAMA Cardiol. 2020;5(6):685–692.
[22] Duerschmied D, Brachmann J, Darius H, et al. Antithrombotic
therapy in patients with non-valvular atrial fibrillation under-
going percutaneous coronary intervention: should we change
our practice after the PIONEER AF-PCI and RE-DUAL PCI
trials? Clin Res Cardiol. 2018;107(7):533–538.
[23] Bastiany A, Grenier M-E, Matteau A, et al. Prevention of left
ventricular thrombus formation and systemic embolism after
anterior myocardial infarction: systematic literature review.
Can J Cardiol. 2017;33(10):1229–1236.
[24] Adelborg K, Szepligeti S, Sundbøll J, et al. Risk of stroke in
patients with heart failure: a population-based 30-year cohort
study. Stroke. 2017;48(5):1161–1168.
[25] Massie BM, Collins JF, Ammon SE, et al. Randomized trial of
warfarin, aspirin, and clopidogrel in patients with chronic heart
failure: the warfarin and antiplatelet therapy in chronic heart
failure (WATCH) trial. Circulation. 2009;119(12):1616–1624.
[26] Pullicino PM, Qian M, Sacco RL, et al.; for the WARCEF
Investigators. Recurrent stroke in the warfarin versus aspirin in
reduced cardiac ejection fraction (WARCEF) trial. Cerebrovasc
Dis. 2014;38(3):176–181.
[27] Rowin EJ, Hausvater A, Link MS, et al. Clinical profile and
consequences of atrial fibrillation in hypertrophic cardiomyop-
athy. Circulation. 2017;136(25):2420–2436.
[28] , Elliott PM, Anastasakis A, Authors/Task Force members,
et al. 2014 ESC guidelines on diagnosis and management of
hypertrophic cardiomyopathy: the task force for the diagnosis
and management of hypertrophic cardiomyopathy of the
European Society of Cardiology (ESC). Eur Heart J. 2014;
35(39):2733–2779.
324 M. APLIN ET AL.
[29] Elsheshtawy MO, Mahmoud AN, Abdelghany M, et al. Left
ventricular aneurysms in hypertrophic cardiomyopathy with
midventricular obstruction: a systematic review of literature.
Pacing Clin Electrophysiol. 2018;41(7):854–865.
[30] El-Battrawy I, Gietzen T, Ansari U, et al. Short-term and long-
term incidence of stroke in Takotsubo syndrome. ESC Heart
Fail. 2018;5(6):1191–1194.
[31] Morris NA, Chen ML, Adejumo OL, et al. Stroke risk following
Takotsubo cardiomyopathy. Neurohospitalist. 2020;10(4):
277–280.
[32] Saric M, Armour AC, Arnaout MS, et al. Guidelines for the use
of echocardiography in the evaluation of a cardiac source of
embolism. J Am Soc Echocardiogr. 2016;29(1):1–42.
[33] Bernatchez J, Gaudreault V, Vincent G, et al. Left atrial myx-
oma presenting as an embolic shower: a case report and review
of literature. Ann Vasc Surg. 2018;53:266.e13–266.e20.
[34] Correa R, Salpea P, Stratakis CA. Carney complex: an update.
Eur J Endocrinol. 2015;173(4):M85–M97.
[35] Elbardissi AW, Dearani JA, Daly RC, et al. Embolic potential of
cardiac tumors and outcome after resection: a case–control
study. Stroke. 2009;40(1):156–162.
[36] Gowda RM, Khan IA, Nair CK, et al. Cardiac papillary fibroe-
lastoma: a comprehensive analysis of 725 cases. Am Heart J.
2003;146(3):404–410.
[37] Park CK, Cho YA, Kim M, et al. Malignant lymphoma arising
in cardiac myxoma, presenting with peripheral arterial emboli.
Cardiovasc Pathol. 2018;32:26–29.
[38] Cooper HA, Thompson EC, Laureno R, et al. Subclinical brain
embolization in left-sided infective endocarditis: results from
the evaluation by MRI of the brains of patients with left-sided
intracardiac solid masses (EMBOLISM) pilot study. Circulation.
2009;120(7):585–591.
[39] Garcıa-Cabrera E, Fernandez-Hidalgo N, Almirante B, et al.
Neurological complications of infective endocarditis: risk fac-
tors, outcome, and impact of cardiac surgery: a multicenter
observational study. Circulation. 2013;127(23):2272–2284.
[40] Heiro M, Nikoskelainen J, Engblom E, et al. Neurologic mani-
festations of infective endocarditis: a 17-year experience in a
teaching hospital in Finland. Arch Intern Med. 2000;160(18):
2781–2787.
[41] Dickerman SA, Abrutyn E, Barsic B, et al.; ICE Investigators.
The relationship between the initiation of antimicrobial therapy
and the incidence of stroke in infective endocarditis: an analysis
from the ICE prospective cohort study (ICE-PCS). Am Heart J.
2007;154(6):1086–1094.
[42] Habib G, Lancellotti P, Antunes MJ, et al. 2015 ESC guidelines
for the management of infective endocarditis: the task force for
the management of infective endocarditis of the European
Society of Cardiology (ESC). Endorsed by: European association
for Cardio-Thoracic surgery (EACTS), the European
Association of Nuclear Medicine (EANM). Eur Heart J. 2015;
36(44):3075–3128.
[43] Baddour LM, Wilson WR, Bayer AS, et al.; American Heart
Association Committee on Rheumatic Fever, Endocarditis, and
Kawasaki Disease of the Council on Cardiovascular Disease in
the Young, Council on Clinical Cardiology, Council on
Cardiovascular Surgery and Anesthesia, and Stroke Council.
Infective endocarditis in adults: diagnosis, antimicrobial ther-
apy, and management of complications: a scientific statement
for healthcare professionals from the American Heart
Association. Circulation. 2015;132(15):1435–1486.
[44] Bussani R, DE-Giorgio F, Pesel G, et al. Overview and compari-
son of infectious endocarditis and non-infectious endocarditis:
a review of 814 autoptic cases. In Vivo. 2019;33(5):1565–1572.
[45] Llenas-Garcıa J, Guerra-Vales JM, Montes-Moreno S, et al.
Nonbacterial thrombotic endocarditis: clinicopathologic study
of a necropsy series. Rev Esp Cardiol. 2007;60(5):493–500.
[46] Zmaili MA, Alzubi JM, Kocyigit D, et al. A contemporary 20-
year Cleveland clinic experience of nonbacterial thrombotic
endocarditis: etiology, echocardiographic imaging, management,
and outcomes. Am J Med. 2020;134:361–369.
[47] Kajy M, Mathew A, Ramappa P. Treatment failures of direct
oral anticoagulants. Am J Ther. 2021;28(1):e87–e95.
[48] Roberts JK, Omarali I, Di Tullio MR, et al. Valvular strands
and cerebral ischemia. Effect of demographics and strand char-
acteristics. Stroke. 1997;28(11):2185–2188.
[49] Roldan CA, Shively BK, Crawford MH. Valve excrescences:
prevalence, evolution and risk for cardioembolism. J Am Coll
Cardiol. 1997;30(5):1308–1314.
[50] Baumgartner H, Falk V, Bax JJ, ESC Scientific Document
Group, et al. 2017 ESC/EACTS guidelines for the management
of valvular heart disease. Eur Heart J. 2017;38(36):2739–2791.
[51] Chan V, Mesana T, Verma S. Functional mitral stenosis follow-
ing mitral valve repair. Curr Opin Cardiol. 2017;32(2):161–165.
[52] Kizer JR, Wiebers DO, Whisnant JP, et al. Mitral annular calci-
fication, aortic valve sclerosis, and incident stroke in adults free
of clinical cardiovascular disease: the strong heart study. Stroke.
2005;36(12):2533–2537.
[53] Zhang D, Dai X, Wang C, et al. Aortic valve calcification and
risk of stroke: a systematic review and metaanalysis. J Clin
Neurosci. 2018;55:32–37.
[54] Cannegieter SC, Rosendaal FR, Wintzen AR, et al. Optimal oral
anticoagulant therapy in patients with mechanical heart valves.
N Engl J Med. 1995;333(1):11–17.
[55] Siciliano RF, Randi BA, Gualandro DM, et al. Early-onset pros-
thetic valve endocarditis definition revisited: prospective study
and literature review. Int J Infect Dis. 2018;67:3–6.
[56] Singh N, Moody AR, Panzov V, et al. Carotid intraplaque hem-
orrhage in patients with embolic stroke of undetermined
source. J Stroke Cerebrovasc Dis. 2018;27(7):1956–1959.
[57] Sakamoto Y, Koga M, Ohara T, et al. Frequency and detection
of Stanford type A aortic dissection in hyperacute stroke man-
agement. Cerebrovasc Dis. 2016;42(1–2):110–116.
[58] Gaul C, Dietrich W, Friedrich I, et al. Neurological symptoms
in type A aortic dissections. Stroke. 2007;38(2):292–297.
[59] Pristipino C, Sievert H, D’Ascenzo F, et al.; European
Haematological Society (EHA). European position paper on the
management of patients with patent foramen ovale. General
approach and left circulation thromboembolism. EuroIntervention.
2019;14(13):1389–1402.
[60] Le Moigne E, Timsit S, Ben Salem D, et al. Patent foramen
ovale and ischemic stroke in patients with pulmonary embol-
ism: a prospective cohort study. Ann Intern Med. 2019;170(11):
756–763.
[61] Saver JL, Carroll JD, Thaler DE, et al.; RESPECT Investigators.
Long-term outcomes of patent foramen ovale closure or med-
ical therapy after stroke. N Engl J Med. 2017;377(11):
1022–1032.
[62] Mas J-L, Derumeaux G, Guillon B, et al. Patent foramen ovale
closure or anticoagulation vs. antiplatelets after stroke. N Engl J
Med. 2017;377(11):1011–1021.
[63] Søndergaard L, Kasner SE, Rhodes JF, et al.; Gore REDUCE
Clinical Study Investigators. Patent foramen ovale closure or
antiplatelet therapy for cryptogenic stroke. N Engl J Med. 2017;
377(11):1033–1042.
[64] Wintzer-Wehekind J, Alperi A, Houde C, et al. Impact of dis-
continuation of antithrombotic therapy following closure of
patent foramen ovale in patients with cryptogenic embolism.
Am J Cardiol. 2019;123(9):1538–1545.
[65] Moussouttas M, Fayad P, Rosenblatt M, et al. Pulmonary
arteriovenous malformations: cerebral ischemia and neurologic
manifestations. Neurology. 2000;55(7):959–964.
[66] Contegiacomo A, Del Ciello A, Rella R, et al. Pulmonary
arteriovenous malformations: what the interventional radiolo-
gist needs to know. Radiol Med. 2019;124(10):973–988.
[67] Attar H, Sachdeva A, Sundararajan S. Cardioembolic stroke in
adults with a history of congenital heart disease. Stroke. 2016;
47(5):e79–e81.

[68] Kline J, Costantini O. Arrhythmias in congenital heart disease.
Med Clin North Am. 2019;103(5):945–956.
[69] Thaler DE, Ruthazer R, Di Angelantonio E, et al.
Neuroimaging findings in cryptogenic stroke patients with and
without patent foramen ovale. Stroke. 2013;44(3):675–680.
[70] Amarenco P, Bogousslavsky J, Caplan LR, et al. Classification
of stroke subtypes. Cerebrovasc Dis. 2009;27(5):493–501.
[71] Weisenburger-Lile D, Lopez D, Russel S, et al. IRMA study:
prevalence of subdiaphragmatic visceral infarction in ischemic
stroke and atrial fibrillation. Int J Stroke. 2017;12(4):421–424.
[72] Merkler AE, Gialdini G, Murthy SB, et al. Association between
troponin levels and embolic stroke of undetermined source. J
Am Heart Assoc. 2017;6(9):e005905.
[73] Llombart V, Antolin-Fontes A, Bustamante A, et al. B-type
natriuretic peptides help in cardioembolic stroke diagnosis:
pooled data meta-analysis. Stroke. 2015;46(5):1187–1195.
[74] Ringelstein EB, Koschorke S, Holling A, et al. Computed tomo-
graphic patterns of proven embolic brain infarctions. Ann
Neurol. 1989;26(6):759–765.
SCANDINAVIAN CARDIOVASCULAR JOURNAL 325
[75] Campbell BCV, De Silva DA, Macleod MR, et al. Ischaemic
stroke. Nat Rev Dis Primers. 2019;5(1):70.
[76] Brazzelli M, Chappell FM, Miranda H, et al. Diffusion-weighted
imaging and diagnosis of transient ischemic attack. Ann
Neurol. 2014;75(1):67–76.
[77] Thomalla G, Cheng B, Ebinger M, et al. DWI-FLAIR mismatch
for the identification of patients with acute ischaemic stroke
within 4
5 h of symptom onset (PRE-FLAIR): a multicentre
observational study. Lancet Neurol. 2011;10(11):978–986.
[78] Guo Y, Wang H, Zhang H, et al. Mobile photoplethysmo-
graphic technology to detect atrial fibrillation. J Am Coll
Cardiol. 2019;74(19):2365–2375.
[79] Sejr MH, May O, Damgaard D, et al. External continuous ECG
versus loop recording for atrial fibrillation detection in patients
who had a stroke. Heart. 2019;105(11):848–854.
[80] Schnabel RB, Haeusler KG, Healey JS, et al. Searching for atrial
fibrillation poststroke: a white paper of the AF-SCREEN inter-
national collaboration. Circulation. 2019;140(22):1834–1850.