# Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC

George Ntaios, Helmut Baumgartner, Wolfram Doehner, Erwan Donal, Thor Edvardsen, Jeff S Healey, Bernard Iung, Hooman Kamel, Scott E Kasner, Eleni Korompoki, et al.

► To cite this version:

George Ntaios, Helmut Baumgartner, Wolfram Doehner, Erwan Donal, Thor Edvardsen, et al. | Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC. European Heart Journal, 2024, 45 (19), pp.1701-1715. 10.1093/eurheartj/ehae150. hal-04615272

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Submitted on 18 Jun 2024

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# Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC

George Ntaios, Helmut Baumgartner, Wolfram Doehner, Erwan Donal, Thor Edvardsen, Jeff S Healey, Bernard Iung, Hooman Kamel, Scott E Kasner, Eleni Korompoki, et al.

► To cite this version:

George Ntaios, Helmut Baumgartner, Wolfram Doehner, Erwan Donal, Thor Edvardsen, et al. | Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC. European Heart Journal, 2024, 45 (19), pp.1701-1715. 10.1093/eurheartj/ehae150. hal-04615272

HAL Id: hal-04615272

https://hal.science/hal-04615272v1

Submitted on 18 Jun 2024

**HAL** is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire **HAL**, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

<figure><img src="image_1.png" /></figure>

Distributed under a Creative Commons Attribution 4.0 International License
# Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC

George Ntaios ID <fnref n="1" />*, Helmut Baumgartner ID ², Wolfram Doehner ID ³, Erwan Donal ID ⁴, Thor Edvardsen ID ⁵, Jeff S. Healey ID ⁶, Bernard Iung ID ⁷, Hooman Kamel ID ⁸, Scott E. Kasner ID ⁹, Eleni Korompoki ID ¹⁰, Babak B. Navi ID ⁸,¹¹, Christian Pristipino ID ¹², Luca Saba ID ¹³, Renate B. Schnabel ID ¹⁴,¹⁵, Emma Svennberg ID ¹⁶, and Gregory Y.H. Lip ID ¹⁷,¹⁸

Online publish-ahead-of-print 30 April 2024

## Abstract

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.

<footnote n="1">¹Department of Internal Medicine, School of Health Sciences, University of Thessaly, Larissa University Hospital, Larissa 41132, Greece; ²Department of Cardiology III: Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Muenster, Germany; ³Department of Cardiology (Campus Virchow), Center of Stroke Research Berlin, German Centre for Cardiovascular Research (DZHK) partner site Berlin, Berlin Institute of Health-Center for Regenerative Therapies, Deutsches Herzzentrum der Charité, Charité, Berlin, Germany; ⁴Service de Cardiologie et CIC-IT 1414, CHU Rennes, Rennes, France; ⁵Department of Cardiology, Faculty of Medicine, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway; ⁶Cardiology Division, McMaster University, Hamilton, Canada; ⁷Bichat Hospital, APHP and Université Paris-Cité, INSERM LVTS U1148, Paris, France; ⁸Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medicine, New York, NY, USA; ⁹Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; ¹⁰Department of Clinical Therapeutics, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; ¹¹Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; ¹²Interventional and Intensive Cardiology Unit, San Filippo Neri Hospital, ASL Roma 1, Rome, Italy; ¹³Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari—Polo di Monserrato, Cagliari, Italy; ¹⁴Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ¹⁵DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Germany; ¹⁶Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; ¹⁷Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart & Chest Hospital, Liverpool, UK; and ¹⁸Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark</footnote>
# Embolic strokes of undetermined source: a clinical consensus statement of the ESC Council on Stroke, the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC

George Ntaios ID <fnref n="1" />*, Helmut Baumgartner ID ², Wolfram Doehner ID ³, Erwan Donal ID ⁴, Thor Edvardsen ID ⁵, Jeff S. Healey ID ⁶, Bernard Iung ID ⁷, Hooman Kamel ID ⁸, Scott E. Kasner ID ⁹, Eleni Korompoki ID ¹⁰, Babak B. Navi ID ⁸,¹¹, Christian Pristipino ID ¹², Luca Saba ID ¹³, Renate B. Schnabel ID ¹⁴,¹⁵, Emma Svennberg ID ¹⁶, and Gregory Y.H. Lip ID ¹⁷,¹⁸

Online publish-ahead-of-print 30 April 2024

## Abstract

One in six ischaemic stroke patients has an embolic stroke of undetermined source (ESUS), defined as a stroke with unclear aetiology despite recommended diagnostic evaluation. The overall cardiovascular risk of ESUS is high and it is important to optimize strategies to prevent recurrent stroke and other cardiovascular events. The aim of clinicians when confronted with a patient not only with ESUS but also with any other medical condition of unclear aetiology is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize secondary prevention. However, specifically in ESUS, this may be challenging as multiple potential thromboembolic sources frequently coexist. Also, it can be delusively reassuring because despite the implementation of specific treatments for the individual pathology presumed to be the actual thromboembolic source, patients can still be vulnerable to stroke and other cardiovascular events caused by other pathologies already identified during the index diagnostic evaluation but whose thromboembolic potential was underestimated. Therefore, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is important to assess the overall thromboembolic risk of the patient through synthesis of the individual risks linked to all pathologies present, regardless if presumed causally associated or not. In this paper, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in ESUS patients through the composition of individual risks associated with all prevalent pathologies.

<footnote n="1">¹Department of Internal Medicine, School of Health Sciences, University of Thessaly, Larissa University Hospital, Larissa 41132, Greece; ²Department of Cardiology III: Adult Congenital and Valvular Heart Disease, University Hospital Muenster, Muenster, Germany; ³Department of Cardiology (Campus Virchow), Center of Stroke Research Berlin, German Centre for Cardiovascular Research (DZHK) partner site Berlin, Berlin Institute of Health-Center for Regenerative Therapies, Deutsches Herzzentrum der Charité, Charité, Berlin, Germany; ⁴Service de Cardiologie et CIC-IT 1414, CHU Rennes, Rennes, France; ⁵Department of Cardiology, Faculty of Medicine, Oslo University Hospital, Rikshospitalet, University of Oslo, Oslo, Norway; ⁶Cardiology Division, McMaster University, Hamilton, Canada; ⁷Bichat Hospital, APHP and Université Paris-Cité, INSERM LVTS U1148, Paris, France; ⁸Clinical and Translational Neuroscience Unit, Feil Family Brain and Mind Research Institute, Department of Neurology, Weill Cornell Medicine, New York, NY, USA; ⁹Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; ¹⁰Department of Clinical Therapeutics, Alexandra Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; ¹¹Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; ¹²Interventional and Intensive Cardiology Unit, San Filippo Neri Hospital, ASL Roma 1, Rome, Italy; ¹³Department of Radiology, Azienda Ospedaliero Universitaria (A.O.U.), di Cagliari—Polo di Monserrato, Cagliari, Italy; ¹⁴Department of Cardiology, University Heart & Vascular Center Hamburg, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; ¹⁵DZHK (German Center for Cardiovascular Research), partner site Hamburg/Kiel/Luebeck, Germany; ¹⁶Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; ¹⁷Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University, Liverpool Heart & Chest Hospital, Liverpool, UK; and ¹⁸Danish Center for Health Services Research, Department of Clinical Medicine, Aalborg University, Aalborg, Denmark</footnote>
## Graphical Abstract

<figure><img src="image_2.png" /></figure>

AHRE, atrial high-rate episode; DIC, disseminated intravascular coagulation; ISHT, International Society on Thrombosis and Haemostasis; LV, left ventricular; RoPE, Risk of Paradoxical Embolism; SCAF, subclinical atrial fibrillation; VTE, venous thromboembolism.

## Keywords

Embolic stroke of undetermined source • Aetiology • Atherosclerosis • Patent foramen ovale • Left atrial disease • Left ventricular disease • Valvular heart disease • Cancer

## Introduction

One in six patients with ischaemic stroke has an embolic stroke of undetermined source (ESUS), defined as a stroke that despite recommended diagnostic workup, a convincing underlying cause like atrial fibrillation (AF), atherosclerotic plaque with high-grade stenosis, and others could not be identified.¹⁻³ The term ESUS is not synonymous with the term 'cryptogenic stroke', as the latter also includes patients with multiple aetiologies, such as patients with both AF and atherosclerotic carotid stenosis ipsilateral to the infarct, and it also includes patients with incomplete diagnostic workup⁴ (Figure 1). The introduction of the ESUS concept in 2014 was based on explicit definition and diagnostic criteria, facilitated clinical research, and was widely adopted in clinical practice.¹,⁵ Recently, an update of the ESUS criteria and diagnostic algorithm was published.⁵

Several pathologies can be the source of embolism in an ESUS patient, and they can be broadly categorized into supracardiac atherosclerosis, patent foramen ovale (PFO), and other right-to-left shunts, left atrial (LA) disease (including atrial arrhythmias and atrial cardiomyopathy), left ventricular (LV) disease, valvular heart disease, and cancer.¹⁻⁴ The overall cardiovascular risk of ESUS patients is high, and their 5-year cumulative probability for stroke recurrence and other cardiovascular events is 29% and 38%, respectively, which highlights the importance of optimizing secondary preventive strategies to prevent recurrent strokes and other cardiovascular outcomes.³

The aim of any physician, when confronted with a patient not only with ESUS but also with any other medical condition of unclear

aetiology, is to identify the *actual* cause amongst a list of potential differential diagnoses, in order to optimize strategies of treatment and prevention. However, specifically in patients with ESUS, this may be challenging and delusively reassuring.⁶ It can be *challenging* because in the majority of ESUS patients, multiple overlapping potential embolic sources exist, and it is frequently unclear which one was the actual embolic source.⁷,⁸ Also, it can be *delusively reassuring* because despite the establishment of specific secondary preventive measures for the individual pathology presumed to be the actual embolic source, a patient can still be vulnerable to future stroke and other cardiovascular events caused by other pathologies that were already present during the ESUS diagnostic workup but their thromboembolic potential was underestimated. In this context, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is of utmost importance to assess the *overall* thromboembolic risk of the patient through the synthesis of the individual risks linked to all prevalent pathologies, regardless if they are deemed to be causally associated with ESUS or not. A paradigm shift is justified, away from the assumption-based and inherently uncertain diagnostic label of *embolic stroke due to [presumed potential cause]* to the more comprehensive diagnostic term of *embolic stroke in a patient with [all potential causes]*.⁶ This can facilitate an integrated comprehensive approach to secondary prevention through the initiation of a bundle of therapeutic strategies according to the findings of the diagnostic workup, thereby optimizing the odds of achieving good patient outcomes.
## Graphical Abstract

<figure><img src="image_2.png" /></figure>

AHRE, atrial high-rate episode; DIC, disseminated intravascular coagulation; ISHT, International Society on Thrombosis and Haemostasis; LV, left ventricular; RoPE, Risk of Paradoxical Embolism; SCAF, subclinical atrial fibrillation; VTE, venous thromboembolism.

## Keywords

Embolic stroke of undetermined source • Aetiology • Atherosclerosis • Patent foramen ovale • Left atrial disease • Left ventricular disease • Valvular heart disease • Cancer

## Introduction

One in six patients with ischaemic stroke has an embolic stroke of undetermined source (ESUS), defined as a stroke that despite recommended diagnostic workup, a convincing underlying cause like atrial fibrillation (AF), atherosclerotic plaque with high-grade stenosis, and others could not be identified.¹⁻³ The term ESUS is not synonymous with the term 'cryptogenic stroke', as the latter also includes patients with multiple aetiologies, such as patients with both AF and atherosclerotic carotid stenosis ipsilateral to the infarct, and it also includes patients with incomplete diagnostic workup⁴ (Figure 1). The introduction of the ESUS concept in 2014 was based on explicit definition and diagnostic criteria, facilitated clinical research, and was widely adopted in clinical practice.¹,⁵ Recently, an update of the ESUS criteria and diagnostic algorithm was published.⁵

Several pathologies can be the source of embolism in an ESUS patient, and they can be broadly categorized into supracardiac atherosclerosis, patent foramen ovale (PFO), and other right-to-left shunts, left atrial (LA) disease (including atrial arrhythmias and atrial cardiomyopathy), left ventricular (LV) disease, valvular heart disease, and cancer.¹⁻⁴ The overall cardiovascular risk of ESUS patients is high, and their 5-year cumulative probability for stroke recurrence and other cardiovascular events is 29% and 38%, respectively, which highlights the importance of optimizing secondary preventive strategies to prevent recurrent strokes and other cardiovascular outcomes.³

The aim of any physician, when confronted with a patient not only with ESUS but also with any other medical condition of unclear

aetiology, is to identify the actual cause amongst a list of potential differential diagnoses, in order to optimize strategies of treatment and prevention. However, specifically in patients with ESUS, this may be challenging and delusively reassuring.⁶ It can be challenging because in the majority of ESUS patients, multiple overlapping potential embolic sources exist, and it is frequently unclear which one was the actual embolic source.⁷,⁸ Also, it can be delusively reassuring because despite the establishment of specific secondary preventive measures for the individual pathology presumed to be the actual embolic source, a patient can still be vulnerable to future stroke and other cardiovascular events caused by other pathologies that were already present during the ESUS diagnostic workup but their thromboembolic potential was underestimated. In this context, rather than trying to presume which particular mechanism is the actual embolic source in an ESUS patient, it is of utmost importance to assess the overall thromboembolic risk of the patient through the synthesis of the individual risks linked to all prevalent pathologies, regardless if they are deemed to be causally associated with ESUS or not. A paradigm shift is justified, away from the assumption-based and inherently uncertain diagnostic label of embolic stroke due to [presumed potential cause] to the more comprehensive diagnostic term of embolic stroke in a patient with [all potential causes].⁶ This can facilitate an integrated comprehensive approach to secondary prevention through the initiation of a bundle of therapeutic strategies according to the findings of the diagnostic workup, thereby optimizing the odds of achieving good patient outcomes.
<figure><img src="image_3.png" /><figcaption>**Figure 1** Distinction between the terms *cryptogenic stroke* and *embolic stroke of undetermined source*. ESUS, embolic stroke of undetermined source</figcaption></figure>

In this position paper by the European Society of Cardiology (ESC) Council on Stroke in collaboration with the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology, and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in patients with ESUS through the composition of individual risks associated with each of the six aforementioned broad pathologies (*Graphical Abstract*). It is emphasized that these are based largely on expert opinion and are summarized in *Table 1*. In addition, we discuss the potential implications for clinical practice and research and identify key knowledge gaps that should be addressed in future research.

## Supracardiac atherosclerosis

The degree of carotid stenosis is considered the lead parameter for the assessment of a causal relation between the atherosclerotic process and an ischaemic event and for the prediction of the risk of stroke or transient ischaemic attack (TIA). This association was demonstrated >40 years ago in trials that showed the benefit of revascularization in patients with severe stenosis.⁹ At that time, the degree of arterial stenosis was the only characteristic of the plaque that could be assessed *in vivo* with angiography. Nowadays, imaging technology not only can visualize the entire supracardiac arterial tree but can also provide detailed information about the structure and composition of the plaque and its potential risk of rupture.¹⁰ Specific features of the plaque are associated with the risk of ischaemic events, regardless of the degree of stenosis.¹¹ The prevalence of complex carotid artery plaque in patients with ESUS is more than five times higher ipsilateral to the infarct than contralateral.¹²⁻¹⁴ Also, the prevalence of complex carotid artery plaque in ESUS is two times higher compared with cardioembolic or small vessel stroke.¹⁵ These findings underline the important association between the risk of ischaemic events and the vulnerability of the plaque, not only in ESUS patients but generally in any patient with carotid plaque, which can be assessed by several parameters, as follows.

*Intra-plaque haemorrhage* (IPH) is defined by the accumulation of blood components within the atheromatous plaque and is considered the most important feature of plaque vulnerability. In a meta-analysis of seven cohort studies including 560 patients with symptomatic carotid stenosis

and 136 patients with asymptomatic carotid stenosis, IPH was a stronger predictor of stroke than any known clinical risk factor. Amongst patients with a <50% stenosis, the annualized rates of ipsilateral stroke were 9.0% amongst patients with IPH and 0.7% amongst patients without.¹⁶ With magnetic resonance imaging (MRI), which is the best imaging technique for its detection, IPH can be classified according to its time of formation, either as fresh/acute (<1 week), recent (1–6 weeks), or remote/old (>6 weeks).¹⁷ The risk of cerebrovascular events is highest with acute/ recent IPH but remains elevated for more than 18 months.¹⁸

The *fibrous cap* (FC), a layer of fibrous connective tissue that separates the core of the plaque from the arterial lumen, is another feature for the assessment of plaque vulnerability, preferably in MRI. A longitudinal prospective MRI-based study in 126 patients with symptomatic carotid stenosis who were followed for an average of 1 year showed that thin and/or ruptured FC was significantly associated with cerebrovascular events.¹⁹ Also, a thin and/or ruptured FC is highly associated with a recent stroke/TIA. For example, in an MRI-based study, patients with ruptured FC were 23 times more likely to have had a recent stroke/TIA compared with patients with thick FC.²⁰ In another prospective longitudinal study, the disruption of the FC was a risk factor for cerebrovascular events.²¹

Another feature of vulnerability is the presence of carotid *intraluminal thrombus*, which presents with neurologic symptoms in up to 92% of cases.²² In a retrospective cross-sectional study of 726 carotid brain MRI examinations, the strongest predictor of a carotid-source stroke was intraluminal thrombus followed by IPH.²³ In another computed tomography angiography (CTA)-based study on 673 patients, the presence of intraluminal thrombi was highly predictive of the symptomatic side in carotid disease.²⁴

The *luminal surface* of carotid plaques can be classified as smooth, irregular, or ulcerated.²⁵ A smooth surface is identified as plain luminal morphology without any sign of ulceration or irregularity. An irregular surface is identified as the presence of small alterations of the luminal surface of the plaque, and its association with cerebrovascular events was described in the Northern Manhattan Study.²⁶ An ulcerated surface is defined as an intimal defect that is >1 mm in width and exposes the necrotic core of the atheromatous plaque,²⁷ and its association with cerebrovascular events is well established.²⁸⁻³⁰

The *lipid-rich necrotic core* (LRNC) is a heterogeneous tissue composed, amongst others, of cholesterol crystal, debris of apoptotic cells, and particles of calcium. The LRNC, preferably assessed in MRI, plays a key role in the progression and vulnerability of atherosclerotic plaques. A study of 120 asymptomatic patients with carotid plaque showed that a large LRNC size correlates with ipsilateral cerebrovascular events and that a LRNC > 40% of the wall area was prone to FC rupture in comparison with patients with a LRNC < 40%.³¹ In another study of 62 patients, a LRNC within the plaque strongly predicted cerebrovascular events.³² A systematic review and meta-analysis reported similar results showing that LRNC predicted stroke/TIA in asymptomatic subjects.³³

Another important feature of plaque vulnerability is the *maximum plaque thickness* (MPT). This is distinct from stenosis as a thick plaque can occur without necessarily causing severe narrowing of the lumen. In a CTA-based study of 85 ESUS patients, >3 mm plaque thickness of the non-calcified component was present ipsilateral to stroke in 35% of patients and contralateral in 15%.³⁴ In an MRI cross-sectional study of 1072 subjects, the MPT was more strongly associated with cerebral ischaemic symptoms than was the degree of stenosis.³⁵

The role of calcium in atherosclerosis remains controversial, but it is generally agreed that the size, shape, and position of calcification may all affect plaque development.³⁶ Amongst the different types of calcium configuration, the *positive rim sign*, defined as the presence of thin
<figure><img src="image_3.png" /><figcaption>**Figure 1** Distinction between the terms *cryptogenic stroke* and *embolic stroke of undetermined source*. ESUS, embolic stroke of undetermined source</figcaption></figure>

In this position paper by the European Society of Cardiology (ESC) Council on Stroke in collaboration with the European Association of Cardiovascular Imaging and the European Heart Rhythm Association of the ESC, a multi-disciplinary panel of clinicians/researchers from various backgrounds of expertise and specialties (cardiology, internal medicine, neurology, radiology, and vascular surgery) proposes a comprehensive multi-dimensional assessment of the overall thromboembolic risk in patients with ESUS through the composition of individual risks associated with each of the six aforementioned broad pathologies (*Graphical Abstract*). It is emphasized that these are based largely on expert opinion and are summarized in *Table 1*. In addition, we discuss the potential implications for clinical practice and research and identify key knowledge gaps that should be addressed in future research.

## Supracardiac atherosclerosis

The degree of carotid stenosis is considered the lead parameter for the assessment of a causal relation between the atherosclerotic process and an ischaemic event and for the prediction of the risk of stroke or transient ischaemic attack (TIA). This association was demonstrated >40 years ago in trials that showed the benefit of revascularization in patients with severe stenosis.⁹ At that time, the degree of arterial stenosis was the only characteristic of the plaque that could be assessed *in vivo* with angiography. Nowadays, imaging technology not only can visualize the entire supracardiac arterial tree but can also provide detailed information about the structure and composition of the plaque and its potential risk of rupture.¹⁰ Specific features of the plaque are associated with the risk of ischaemic events, regardless of the degree of stenosis.¹¹ The prevalence of complex carotid artery plaque in patients with ESUS is more than five times higher ipsilateral to the infarct than contralateral.¹²⁻¹⁴ Also, the prevalence of complex carotid artery plaque in ESUS is two times higher compared with cardioembolic or small vessel stroke.¹⁵ These findings underline the important association between the risk of ischaemic events and the vulnerability of the plaque, not only in ESUS patients but generally in any patient with carotid plaque, which can be assessed by several parameters, as follows.

*Intra-plaque haemorrhage* (IPH) is defined by the accumulation of blood components within the atheromatous plaque and is considered the most important feature of plaque vulnerability. In a meta-analysis of seven cohort studies including 560 patients with symptomatic carotid stenosis

and 136 patients with asymptomatic carotid stenosis, IPH was a stronger predictor of stroke than any known clinical risk factor. Amongst patients with a <50% stenosis, the annualized rates of ipsilateral stroke were 9.0% amongst patients with IPH and 0.7% amongst patients without.¹⁶ With magnetic resonance imaging (MRI), which is the best imaging technique for its detection, IPH can be classified according to its time of formation, either as fresh/acute (<1 week), recent (1–6 weeks), or remote/old (>6 weeks).¹⁷ The risk of cerebrovascular events is highest with acute/ recent IPH but remains elevated for more than 18 months.¹⁸

The *fibrous cap* (FC), a layer of fibrous connective tissue that separates the core of the plaque from the arterial lumen, is another feature for the assessment of plaque vulnerability, preferably in MRI. A longitudinal prospective MRI-based study in 126 patients with symptomatic carotid stenosis who were followed for an average of 1 year showed that thin and/or ruptured FC was significantly associated with cerebrovascular events.¹⁹ Also, a thin and/or ruptured FC is highly associated with a recent stroke/TIA. For example, in an MRI-based study, patients with ruptured FC were 23 times more likely to have had a recent stroke/TIA compared with patients with thick FC.²⁰ In another prospective longitudinal study, the disruption of the FC was a risk factor for cerebrovascular events.²¹

Another feature of vulnerability is the presence of carotid *intraluminal thrombus*, which presents with neurologic symptoms in up to 92% of cases.²² In a retrospective cross-sectional study of 726 carotid brain MRI examinations, the strongest predictor of a carotid-source stroke was intraluminal thrombus followed by IPH.²³ In another computed tomography angiography (CTA)-based study on 673 patients, the presence of intraluminal thrombi was highly predictive of the symptomatic side in carotid disease.²⁴

The *luminal surface* of carotid plaques can be classified as smooth, irregular, or ulcerated.²⁵ A smooth surface is identified as plain luminal morphology without any sign of ulceration or irregularity. An irregular surface is identified as the presence of small alterations of the luminal surface of the plaque, and its association with cerebrovascular events was described in the Northern Manhattan Study.²⁶ An ulcerated surface is defined as an intimal defect that is >1 mm in width and exposes the necrotic core of the atheromatous plaque,²⁷ and its association with cerebrovascular events is well established.²⁸⁻³⁰

The *lipid-rich necrotic core* (LRNC) is a heterogeneous tissue composed, amongst others, of cholesterol crystal, debris of apoptotic cells, and particles of calcium. The LRNC, preferably assessed in MRI, plays a key role in the progression and vulnerability of atherosclerotic plaques. A study of 120 asymptomatic patients with carotid plaque showed that a large LRNC size correlates with ipsilateral cerebrovascular events and that a LRNC > 40% of the wall area was prone to FC rupture in comparison with patients with a LRNC < 40%.³¹ In another study of 62 patients, a LRNC within the plaque strongly predicted cerebrovascular events.³² A systematic review and meta-analysis reported similar results showing that LRNC predicted stroke/TIA in asymptomatic subjects.³³

Another important feature of plaque vulnerability is the *maximum plaque thickness* (MPT). This is distinct from stenosis as a thick plaque can occur without necessarily causing severe narrowing of the lumen. In a CTA-based study of 85 ESUS patients, >3 mm plaque thickness of the non-calcified component was present ipsilateral to stroke in 35% of patients and contralateral in 15%.³⁴ In an MRI cross-sectional study of 1072 subjects, the MPT was more strongly associated with cerebral ischaemic symptoms than was the degree of stenosis.³⁵

The role of calcium in atherosclerosis remains controversial, but it is generally agreed that the size, shape, and position of calcification may all affect plaque development.³⁶ Amongst the different types of calcium configuration, the *positive rim sign*, defined as the presence of thin
<table><caption>**Table 1** Features to assess the overall thromboembolic risk in embolic stroke of undetermined source patients</caption><thead><tr><th></th><th>Moderately increased thromboembolic risk</th><th>Slightly increased thromboembolic risk</th></tr></thead><tbody><tr><td>Supracardiac<br>atherosclerosis</td><td><ul><li>Acute or recent intra-plaque haemorrhage</li><li>Thin/ruptured fibrous cap</li><li>Intraluminal thrombus</li><li>Ulcerated plaque morphology</li></ul></td><td><ul><li>Lipid-rich necrotic core &gt; 40% of the wall area.</li><li>Maximum plaque thickness of the non-calcified component &gt; 3 mm</li><li>Irregular plaque morphology</li><li>Positive rim sign</li><li>Healed ulcerated plaque</li></ul></td></tr><tr><td>Patent foramen ovale<br>(Figure 3)</td><td><ul><li>Recent DVT or pulmonary embolism AND presence of ASA or large shunt, regardless of patient age or RoPE score</li><li>Presence of ASA or large shunt AND RoPE ≥ 7 and age &lt; 60 years</li></ul></td><td><ul><li>Presence of ASA or large shunt AND RoPE &lt; 7, regardless of patient age</li><li>Absence of ASA or large shunt AND RoPE ≥ 7, regardless of patient age</li><li>Recent DVT or pulmonary embolism, AND absence of ASA or large shunt, regardless of patient age or RoPE score</li></ul></td></tr><tr><td>Left atrial disease</td><td><ul><li>LA spontaneous echocardiographic contrast</li><li>Cor triatriatum</li></ul></td><td></td></tr><tr><td>Atrial arrhythmias</td><td><ul><li>AHRE or SCAF lasting &gt;24 h and occurring within a month after stroke</li><li>Any episode of atrial fibrillation lasting &gt;30 s during stroke unit telemetry.</li></ul></td><td><ul><li>AHRE or SCAF lasting &lt;24 h and occurring later than a month after stroke</li></ul></td></tr><tr><td>Atrial cardiomyopathy</td><td></td><td><ul><li>Significant LA enlargement (LA diameter &gt; 4.6 cm)</li></ul></td></tr><tr><td>Left ventricular<br>disease</td><td><ul><li>large or dyskinetic scar tissue</li><li>LV aneurysm</li><li>LV non-compaction with deep trabeculations or sponious LV</li><li>Severe restrictive cardiomyopathy with decrease in cardiac output despite a preserved LV ejection fraction, e.g. cardiac amyloidosis.</li></ul></td><td><ul><li>Moderately decreased LV systolic function and/or very enlarged LV with spontaneous echo-contrast</li><li>Cardiomyopathies, e.g. hypertrophic cardiomyopathy or amyloidosis</li><li>Acute phase of an ischaemic cardiopathy</li></ul></td></tr><tr><td>Valvular heart<br>disease</td><td></td><td><ul><li>Large redundant Barlow mitral valve disease</li><li>Massive mitral valve calcifications</li><li>Aortic valve calcifications</li></ul></td></tr><tr><td>Cancer</td><td><ul><li>Cardiac vegetation(s) with negative blood cultures</li><li>ISTH overt DIC score ≥5 with D-dimer &gt; 4000 ng/mL AND fibrinogen &lt; 100 mg/dL AND platelet count &lt; 100 10<sup>3</sup>/µL (OR PT prolongation &gt; 3 s)</li></ul></td><td><ul><li>Cancer spread beyond primary site OR recent progression of disease OR centrally located primary or metastatic lung cancer</li><li>D-dimer &gt; 2500 ng/mL in the absence of an acute DVT or pulmonary embolism</li><li>Acute infarction in multiple cerebral arterial territories</li><li>Bilateral high-intensity transient signals on transcranial Doppler in the absence of a known central embolic source</li></ul></td></tr></tbody></table>

AHRE, atrial high-rate episode; ASA, atrial septal aneurysm; DIC, disseminated intravascular coagulation; DVT, deep venous thrombosis; ISTH, International Society on Thrombosis and Haemostasis; LA, left atrial; LV, left ventricle; PFO, patent foramen ovale; RoPE, Risk of Paradoxical Embolism Score; SCAF, subclinical atrial fibrillation.

(&lt;2 mm) adventitial calcifications with internal low attenuation plaque of ≥2 mm in maximum thickness in CTA, is associated with the presence of IPH.37,38 On the other hand, other calcium configurations such as intimal or superficial calcifications, or type 3, deep, or bulky calcifications, are rarely associated with the occurrence of cerebrovascular events.39

Intra-plaque neovascularization can be detected with contrast-enhanced ultrasound (CEUS), computed tomography (CT) and MRI, and requires the administration of contrast media for the detection and quantification of neovascularization.40 It can be seen in advanced atherosclerotic lesions, but, currently, routine clinical practice has not adopted non-invasive imaging assessment of plaque inflammation and neovascularization due to limitations related to the technical complexity of this analysis. A prospective CEUS study of 155 patients showed

that intraplaque neovascularization is associated with recurrent cerebrovascular events regardless of the severity of carotid stenosis.41 An MRI study showed that adventitial enhancement, a marker of neovascularization, was associated with cerebrovascular events.42 The importance of wall enhancement as an additional marker of stroke risk stratification was also highlighted using CT.43 Currently, it is also possible to explore the level of inflammation within the plaque mainly with fluorodeoxyglucose positron emission tomography,44 but this parameter is also not currently adopted as a routine non-invasive imaging assessment.

Recently, the Carotid Plaque-RADS stroke risk classification system was introduced, which offers a morphological assessment of the thromboembolic risk associated with carotid plaques in addition to the prevailing quantitative parameter of stenosis.45
<table><caption>**Table 1** Features to assess the overall thromboembolic risk in embolic stroke of undetermined source patients</caption><thead><tr><th></th><th>Moderately increased thromboembolic risk</th><th>Slightly increased thromboembolic risk</th></tr></thead><tbody><tr><td>Supracardiac<br>atherosclerosis</td><td><ul><li>Acute or recent intra-plaque haemorrhage</li><li>Thin/ruptured fibrous cap</li><li>Intraluminal thrombus</li><li>Ulcerated plaque morphology</li></ul></td><td><ul><li>Lipid-rich necrotic core &gt; 40% of the wall area.</li><li>Maximum plaque thickness of the non-calcified component &gt; 3 mm</li><li>Irregular plaque morphology</li><li>Positive rim sign</li><li>Healed ulcerated plaque</li></ul></td></tr><tr><td>Patent foramen ovale<br>(Figure 3)</td><td><ul><li>Recent DVT or pulmonary embolism AND presence of ASA or large shunt, regardless of patient age or RoPE score</li><li>Presence of ASA or large shunt AND RoPE ≥ 7 and age &lt; 60 years</li></ul></td><td><ul><li>Presence of ASA or large shunt AND RoPE &lt; 7, regardless of patient age</li><li>Absence of ASA or large shunt AND RoPE ≥ 7, regardless of patient age</li><li>Recent DVT or pulmonary embolism, AND absence of ASA or large shunt, regardless of patient age or RoPE score</li></ul></td></tr><tr><td>Left atrial disease</td><td><ul><li>LA spontaneous echocardiographic contrast</li><li>Cor triatriatum</li></ul></td><td></td></tr><tr><td>Atrial arrhythmias</td><td><ul><li>AHRE or SCAF lasting &gt;24 h and occurring within a month after stroke</li><li>Any episode of atrial fibrillation lasting &gt;30 s during stroke unit telemetry.</li></ul></td><td><ul><li>AHRE or SCAF lasting &lt;24 h and occurring later than a month after stroke</li></ul></td></tr><tr><td>Atrial cardiomyopathy</td><td></td><td><ul><li>Significant LA enlargement (LA diameter &gt; 4.6 cm)</li></ul></td></tr><tr><td>Left ventricular<br>disease</td><td><ul><li>large or dyskinetic scar tissue</li><li>LV aneurysm</li><li>LV non-compaction with deep trabeculations or sponious LV</li><li>Severe restrictive cardiomyopathy with decrease in cardiac output despite a preserved LV ejection fraction, e.g. cardiac amyloidosis.</li></ul></td><td><ul><li>Moderately decreased LV systolic function and/or very enlarged LV with spontaneous echo-contrast</li><li>Cardiomyopathies, e.g. hypertrophic cardiomyopathy or amyloidosis</li><li>Acute phase of an ischaemic cardiopathy</li></ul></td></tr><tr><td>Valvular heart<br>disease</td><td></td><td><ul><li>Large redundant Barlow mitral valve disease</li><li>Massive mitral valve calcifications</li><li>Aortic valve calcifications</li></ul></td></tr><tr><td>Cancer</td><td><ul><li>Cardiac vegetation(s) with negative blood cultures</li><li>ISTH overt DIC score ≥5 with D-dimer &gt; 4000 ng/mL AND fibrinogen &lt; 100 mg/dL AND platelet count &lt; 100 10<sup>3</sup>/µL (OR PT prolongation &gt; 3 s)</li></ul></td><td><ul><li>Cancer spread beyond primary site OR recent progression of disease OR centrally located primary or metastatic lung cancer</li><li>D-dimer &gt; 2500 ng/mL in the absence of an acute DVT or pulmonary embolism</li><li>Acute infarction in multiple cerebral arterial territories</li><li>Bilateral high-intensity transient signals on transcranial Doppler in the absence of a known central embolic source</li></ul></td></tr></tbody></table>

AHRE, atrial high-rate episode; ASA, atrial septal aneurysm; DIC, disseminated intravascular coagulation; DVT, deep venous thrombosis; ISTH, International Society on Thrombosis and Haemostasis; LA, left atrial; LV, left ventricle; PFO, patent foramen ovale; RoPE, Risk of Paradoxical Embolism Score; SCAF, subclinical atrial fibrillation.

($<$2 mm) adventitial calcifications with internal low attenuation plaque of ≥2 mm in maximum thickness in CTA, is associated with the presence of IPH.³⁷,³⁸ On the other hand, other calcium configurations such as intimal or superficial calcifications, or type 3, deep, or bulky calcifications, are rarely associated with the occurrence of cerebrovascular events.³⁹

Intra-plaque neovascularization can be detected with contrast-enhanced ultrasound (CEUS), computed tomography (CT) and MRI, and requires the administration of contrast media for the detection and quantification of neovascularization.⁴⁰ It can be seen in advanced atherosclerotic lesions, but, currently, routine clinical practice has not adopted non-invasive imaging assessment of plaque inflammation and neovascularization due to limitations related to the technical complexity of this analysis. A prospective CEUS study of 155 patients showed

that intraplaque neovascularization is associated with recurrent cerebrovascular events regardless of the severity of carotid stenosis.⁴¹ An MRI study showed that adventitial enhancement, a marker of neovascularization, was associated with cerebrovascular events.⁴² The importance of wall enhancement as an additional marker of stroke risk stratification was also highlighted using CT.⁴³ Currently, it is also possible to explore the level of inflammation within the plaque mainly with fluorodeoxyglucose positron emission tomography,⁴⁴ but this parameter is also not currently adopted as a routine non-invasive imaging assessment.

Recently, the Carotid Plaque-RADS stroke risk classification system was introduced, which offers a morphological assessment of the thromboembolic risk associated with carotid plaques in addition to the prevailing quantitative parameter of stenosis.⁴⁵
The proposed features to assess the thromboembolic risk in patients with ESUS and supracardiac atherosclerosis are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

We note that this section focuses and discusses the embolic source *per se* (i.e. the atherosclerotic plaque) and not the pathophysiologic entities that contribute to it like diabetes mellitus, arterial hypertension, smoking, dyslipidaemia, and others. The risk assessment and management of these pathologies are covered extensively in the related ESC Clinical Practice Guidelines. This is the case also for the next sessions of this Clinical Consensus Statement.

## Patent foramen ovale and other right-to-left shunts

Stroke due to paradoxical embolism may occur when a thrombus traverses a right-to-left shunt from the venous circulation into the arterial system and subsequently causes occlusion and infarction. The most common right-to-left shunt associated with stroke is PFO, but also other pathologies may exist such as other septal defects or intrapulmonary shunts. Alternatively, the thrombus may be formed de novo within the PFO tunnel. Epidemiologic studies have demonstrated a consistent relationship between ischaemic stroke and PFO in patients without another identifiable stroke aetiology. However, as PFO is a relatively common congenital anomaly found in about one-quarter of adults, its pathogenic role in stroke was contested for decades. Strokes occurring in patients with PFO were labelled as cryptogenic owing to this uncertainty, and the implementation of ESUS criteria in 2014 maintained the status of PFO as an undetermined source.¹ Since 2017, several trials demonstrated that percutaneous closure of PFO reduced the risk of subsequent stroke amongst patients who otherwise met ESUS criteria.⁴⁷ A meta-analysis using individual patient data from all trials reported a hazard ratio (HR) of 0.41 [95% confidence interval (CI) 0.28–0.60] for closure compared with medical therapy alone.⁴⁸

These persuasive efficacy data underline that PFO can have significant thromboembolic risk in ESUS patients, the magnitude of which can be further evaluated by clinical and anatomic data, as well as clinical judgement after a thorough diagnostic workup.⁴⁹ A classification has been proposed using the PFO-Associated Stroke CAusal Likelihood (PASCAL) algorithm.⁵⁰ PASCAL combines the Risk of Paradoxical Embolism (RoPE) score, based on clinical characteristics, with key cardiac anatomic features of the PFO such as large right-to-left shunt and atrial septal aneurysm, both of which are associated with increased stroke risk⁵¹ and with signs of concurrent venous thromboembolism.⁵⁰

The PASCAL algorithm was initially proposed based on inferences from epidemiology and pathophysiology, but the aforementioned individual patient data meta-analysis provided compelling retrospective validation.⁵⁰ However, PASCAL was derived solely from clinical trial populations, nearly all patients were <60 years, and it has not been prospectively validated. The relative efficacy of closure compared with medical therapy alone was greater for patients in the PASCAL category ‘probably related’ (HR 0.10; 95% CI 0.03–0.35) compared with the category ‘possibly related’ (HR 0.38; 95% CI 0.22–0.65), and no benefit was observed for those in the category ‘relation unlikely’ (HR 1.14; 95% CI 0.53–2.46).⁵⁰ The PASCAL classification is a rational and practical tool to aid in clinical decision-making. There are many other factors that have been reported to be associated with a causal role of PFO, including clinical features such as deep vein thrombosis, pulmonary or

systemic embolism occurring close to the ischaemic stroke (within 48–72 h of stroke onset), stroke occurring at awakening in patients with sleep apnoea, circumstances that promote venous thrombotic events (e.g. prolonged travel, dehydration, or hypercoagulable state), stroke onset coincident with a Valsalva manoeuvre, a permanently increased right-to-left pressure gradient (due to chronic arterial pulmonary hypertension or right heart diseases), a history of non-cerebral embolism, a history of migraine with aura, and decompression illness, and anatomic features including the presence of a Eustachian valve or Chiari network, but these were not integrated into the PASCAL tool and require further research. Also, there is no quality evidence to support that ESUS patients should have venous ultrasound to detect potential embolic sources.

In patients < 60 years with ‘possible’ or ‘probable’ PFO-related stroke according to PASCAL who have no other probable embolic source, the PFO could be considered as the actual cause of stroke and hence, not considered as an ESUS. Accordingly, this is also proposed in the updated ESUS criteria.⁵ Moreover, the role of other simultaneously additional or alternative pathways for right-to-left shunt, including other cardiac septal defects or pulmonary arteriovenous malformations, deserves further investigation.

Therefore, the proposed criteria for assessing the thromboembolic risk in patients with ESUS and PFO expand beyond the PASCAL classification, which largely applies to younger patients and does not include all related clinical features. Instead, a broader set of criteria also including age and venous thrombotic events is proposed in Table 1 and Figure 4, and patient cases are illustrated in Figures 2 and 3.

## Left atrial disease

The presence of thrombus in the LA or the LA appendage (LAA) carries a very high embolic risk.⁵² Thrombi have a prevalence of approximately 3% in anticoagulated persons with AF,⁵³ which is higher in non-paroxysmal than in paroxysmal AF (approximately 4.8% and 1%, respectively).⁵³ The risk is even higher, approximately 9%, in non-anticoagulated persons with AF.⁵⁴ Conversely, in persons without an AF diagnosis, its prevalence is low but can be associated with mitral valve disease,⁵⁵ atrial cardiomyopathy,⁵⁵,⁵⁶ or covert AF. In a patient with stroke, the presence of LA thrombus is a convincing aetiology of cardioembolic stroke, and such patients should not be classified as ESUS. *Spontaneous echocardiographic contrast* in the LA is the cardiac factor which is most strongly related to LAA thrombus.⁵⁷

*Cor triatriatum sinistrum* is a congenital cardiac anomaly in which the LA is divided into two chambers by a membrane. It is a rare finding as it represents only 0.4% of all congenital heart defects.⁵⁸ Given its rarity, finding a cor triatriatum sinistrum in a patient with ESUS should be regarded as a probable stroke aetiology.

## Atrial arrhythmias

The strong association of AF with thromboembolic events in observational studies, coupled with the profound effect of oral anticoagulation (OAC) on stroke prevention in persons with AF, provided undisputed evidence about the role of AF in stroke.⁵⁹ However, it should be emphasized that the beneficial role of OAC is proven only in AF detected with the standard 12-lead ECG (frequently termed as clinical AF) and not AF detected after stroke (frequently termed as AFDAS) such as AF detected during telemetry at the stroke unit or during non-invasive monitoring like Holter ECG or 14-day patch ECG soon after
The proposed features to assess the thromboembolic risk in patients with ESUS and supracardiac atherosclerosis are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

We note that this section focuses and discusses the embolic source *per se* (i.e. the atherosclerotic plaque) and not the pathophysiologic entities that contribute to it like diabetes mellitus, arterial hypertension, smoking, dyslipidaemia, and others. The risk assessment and management of these pathologies are covered extensively in the related ESC Clinical Practice Guidelines. This is the case also for the next sessions of this Clinical Consensus Statement.

## Patent foramen ovale and other right-to-left shunts

Stroke due to paradoxical embolism may occur when a thrombus traverses a right-to-left shunt from the venous circulation into the arterial system and subsequently causes occlusion and infarction. The most common right-to-left shunt associated with stroke is PFO, but also other pathologies may exist such as other septal defects or intrapulmonary shunts. Alternatively, the thrombus may be formed de novo within the PFO tunnel. Epidemiologic studies have demonstrated a consistent relationship between ischaemic stroke and PFO in patients without another identifiable stroke aetiology. However, as PFO is a relatively common congenital anomaly found in about one-quarter of adults, its pathogenic role in stroke was contested for decades. Strokes occurring in patients with PFO were labelled as cryptogenic owing to this uncertainty, and the implementation of ESUS criteria in 2014 maintained the status of PFO as an undetermined source.¹ Since 2017, several trials demonstrated that percutaneous closure of PFO reduced the risk of subsequent stroke amongst patients who otherwise met ESUS criteria.⁴⁷ A meta-analysis using individual patient data from all trials reported a hazard ratio (HR) of 0.41 [95% confidence interval (CI) 0.28–0.60] for closure compared with medical therapy alone.⁴⁸

These persuasive efficacy data underline that PFO can have significant thromboembolic risk in ESUS patients, the magnitude of which can be further evaluated by clinical and anatomic data, as well as clinical judgement after a thorough diagnostic workup.⁴⁹ A classification has been proposed using the PFO-Associated Stroke CAusal Likelihood (PASCAL) algorithm.⁵⁰ PASCAL combines the Risk of Paradoxical Embolism (RoPE) score, based on clinical characteristics, with key cardiac anatomic features of the PFO such as large right-to-left shunt and atrial septal aneurysm, both of which are associated with increased stroke risk⁵¹ and with signs of concurrent venous thromboembolism.⁵⁰

The PASCAL algorithm was initially proposed based on inferences from epidemiology and pathophysiology, but the aforementioned individual patient data meta-analysis provided compelling retrospective validation.⁵⁰ However, PASCAL was derived solely from clinical trial populations, nearly all patients were <60 years, and it has not been prospectively validated. The relative efficacy of closure compared with medical therapy alone was greater for patients in the PASCAL category ‘probably related’ (HR 0.10; 95% CI 0.03–0.35) compared with the category ‘possibly related’ (HR 0.38; 95% CI 0.22–0.65), and no benefit was observed for those in the category ‘relation unlikely’ (HR 1.14; 95% CI 0.53–2.46).⁵⁰ The PASCAL classification is a rational and practical tool to aid in clinical decision-making. There are many other factors that have been reported to be associated with a causal role of PFO, including clinical features such as deep vein thrombosis, pulmonary or

systemic embolism occurring close to the ischaemic stroke (within 48–72 h of stroke onset), stroke occurring at awakening in patients with sleep apnoea, circumstances that promote venous thrombotic events (e.g. prolonged travel, dehydration, or hypercoagulable state), stroke onset coincident with a Valsalva manoeuvre, a permanently increased right-to-left pressure gradient (due to chronic arterial pulmonary hypertension or right heart diseases), a history of non-cerebral embolism, a history of migraine with aura, and decompression illness, and anatomic features including the presence of a Eustachian valve or Chiari network, but these were not integrated into the PASCAL tool and require further research. Also, there is no quality evidence to support that ESUS patients should have venous ultrasound to detect potential embolic sources.

In patients < 60 years with ‘possible’ or ‘probable’ PFO-related stroke according to PASCAL who have no other probable embolic source, the PFO could be considered as the actual cause of stroke and hence, not considered as an ESUS. Accordingly, this is also proposed in the updated ESUS criteria.⁵ Moreover, the role of other simultaneously additional or alternative pathways for right-to-left shunt, including other cardiac septal defects or pulmonary arteriovenous malformations, deserves further investigation.

Therefore, the proposed criteria for assessing the thromboembolic risk in patients with ESUS and PFO expand beyond the PASCAL classification, which largely applies to younger patients and does not include all related clinical features. Instead, a broader set of criteria also including age and venous thrombotic events is proposed in Table 1 and Figure 4, and patient cases are illustrated in Figures 2 and 3.

## Left atrial disease

The presence of thrombus in the LA or the LA appendage (LAA) carries a very high embolic risk.⁵² Thrombi have a prevalence of approximately 3% in anticoagulated persons with AF,⁵³ which is higher in non-paroxysmal than in paroxysmal AF (approximately 4.8% and 1%, respectively).⁵³ The risk is even higher, approximately 9%, in non-anticoagulated persons with AF.⁵⁴ Conversely, in persons without an AF diagnosis, its prevalence is low but can be associated with mitral valve disease,⁵⁵ atrial cardiomyopathy,⁵⁵,⁵⁶ or covert AF. In a patient with stroke, the presence of LA thrombus is a convincing aetiology of cardioembolic stroke, and such patients should not be classified as ESUS. *Spontaneous echocardiographic contrast* in the LA is the cardiac factor which is most strongly related to LAA thrombus.⁵⁷

*Cor triatriatum sinistrum* is a congenital cardiac anomaly in which the LA is divided into two chambers by a membrane. It is a rare finding as it represents only 0.4% of all congenital heart defects.⁵⁸ Given its rarity, finding a cor triatriatum sinistrum in a patient with ESUS should be regarded as a probable stroke aetiology.

## Atrial arrhythmias

The strong association of AF with thromboembolic events in observational studies, coupled with the profound effect of oral anticoagulation (OAC) on stroke prevention in persons with AF, provided undisputed evidence about the role of AF in stroke.⁵⁹ However, it should be emphasized that the beneficial role of OAC is proven only in AF detected with the standard 12-lead ECG (frequently termed as clinical AF) and not AF detected after stroke (frequently termed as AFDAS) such as AF detected during telemetry at the stroke unit or during non-invasive monitoring like Holter ECG or 14-day patch ECG soon after
<figure><img src="image_4.png" /><figcaption>**Figure 2** Examples of graphical illustration of the overall thromboembolic risk in embolic stroke of undetermined source patients. (Left upper panel) Patient with embolic stroke of undetermined source and metastatic lung cancer and vegetations at the aortic valve with sterile cultures and an ipsilateral-to-the-infarct atherosclerotic plaque in the common carotid artery causing 40% stenosis with smooth plaque surface and thick fibrous cap. (Right upper panel) A 68-year-old patient with embolic stroke of undetermined source and an ipsilateral-to-the-infarct atherosclerotic plaque in the internal carotid artery causing 40% stenosis with acute intra-plaque haemorrhage on magnetic resonance imaging; aortic valve calcification; and a patent foramen ovale with small shunt and no atrial septal aneurysm. (Left middle panel) Patient with embolic stroke of undetermined source and coronary artery disease with a large dyskinetic scar tissue in the left ventricular wall due to previous myocardial infarction and aortic valve stenosis with thin leaflets and no calcification. (Right middle panel) Patient with embolic stroke of undetermined source and an ipsilateral-to-the-infarct atherosclerotic plaque in the carotid bulb causing 40% stenosis with thick fibrous cap and irregular plaque morphology, but without intra-plaque haemorrhage or superimposed thrombus; heart failure with left ventricular ejection fraction 40%; and a large redundant Barlow mitral valve disease. (Left lower panel) Patient with embolic stroke of undetermined source and spontaneous echocardiographic contrast in the left atrium; an ipsilateral-to-the-infarct non-ulcerated atherosclerotic plaque in the common carotid artery with thick plaque, lipid-rich necrotic core > 40% of the wall area without intra-plaque haemorrhage, or superimposed thrombus; and a calcified aortic valve. (Right lower panel) A 56-year-old patient with embolic stroke of undetermined source and a patent foramen ovale with atrial septal aneurysm and Risk of Paradoxical Embolism score 7 and an ipsilateral-to-the-infarct atherosclerotic plaque in the internal carotid artery causing 30% stenosis with significant calcification</figcaption></figure>

stroke. New-onset AF is identified in approximately 13% of stroke patients during the in-hospital phase,⁶⁰ and such patients should not be classified as ESUS.¹ More episodes of asymptomatic AF may be detected in the outpatient setting with the use of cardiac rhythm

monitoring devices.⁶⁰ With the use of prolonged, continuous cardiac monitoring in patients following stroke, short-lasting episodes (minutes to hours) of asymptomatic AF with a very low burden of AF (defined as <1% of AF over monitoring time) are often detected, and this entity
<figure><img src="image_4.png" /><figcaption>**Figure 2** Examples of graphical illustration of the overall thromboembolic risk in embolic stroke of undetermined source patients. (Left upper panel) Patient with embolic stroke of undetermined source and metastatic lung cancer and vegetations at the aortic valve with sterile cultures and an ipsilateral-to-the-infarct atherosclerotic plaque in the common carotid artery causing 40% stenosis with smooth plaque surface and thick fibrous cap. (Right upper panel) A 68-year-old patient with embolic stroke of undetermined source and an ipsilateral-to-the-infarct atherosclerotic plaque in the internal carotid artery causing 40% stenosis with acute intra-plaque haemorrhage on magnetic resonance imaging; aortic valve calcification; and a patent foramen ovale with small shunt and no atrial septal aneurysm. (Left middle panel) Patient with embolic stroke of undetermined source and coronary artery disease with a large dyskinetic scar tissue in the left ventricular wall due to previous myocardial infarction and aortic valve stenosis with thin leaflets and no calcification. (Right middle panel) Patient with embolic stroke of undetermined source and an ipsilateral-to-the-infarct atherosclerotic plaque in the carotid bulb causing 40% stenosis with thick fibrous cap and irregular plaque morphology, but without intra-plaque haemorrhage or superimposed thrombus; heart failure with left ventricular ejection fraction 40%; and a large redundant Barlow mitral valve disease. (Left lower panel) Patient with embolic stroke of undetermined source and spontaneous echocardiographic contrast in the left atrium; an ipsilateral-to-the-infarct non-ulcerated atherosclerotic plaque in the common carotid artery with thick plaque, lipid-rich necrotic core > 40% of the wall area without intra-plaque haemorrhage, or superimposed thrombus; and a calcified aortic valve. (Right lower panel) A 56-year-old patient with embolic stroke of undetermined source and a patent foramen ovale with atrial septal aneurysm and Risk of Paradoxical Embolism score 7 and an ipsilateral-to-the-infarct atherosclerotic plaque in the internal carotid artery causing 30% stenosis with significant calcification</figcaption></figure>

stroke. New-onset AF is identified in approximately 13% of stroke patients during the in-hospital phase,⁶⁰ and such patients should not be classified as ESUS.¹ More episodes of asymptomatic AF may be detected in the outpatient setting with the use of cardiac rhythm

monitoring devices.⁶⁰ With the use of prolonged, continuous cardiac monitoring in patients following stroke, short-lasting episodes (minutes to hours) of asymptomatic AF with a very low burden of AF (defined as <1% of AF over monitoring time) are often detected, and this entity
<figure><img src="image_5.png" /><figcaption>**Figure 3** Features associated with thromboembolic risk in embolic stroke of undetermined source patients. (Panel 1) Computed tomography angiography axial scan of the right internal carotid artery in a 73-year-old symptomatic male patient with a 45% stenosis according to the NASCET criteria. A hypodense plaque is visible (arrow) with very low attenuation (<30 Hounsfield units). (Panel 2) MR shows intra-plaque haemorrhage at the bifurcation of the right carotid artery in a 75-year-old symptomatic male patient. (Panel 3) Computed tomography angiography axial scan of the right common carotid artery with a floating thrombus in a 69-year-old female patient. (Panel 4) Patent foramen ovale. (Left) Aneurysm of inter-atrial septum with small inter-atrial shunt in colour Doppler (transthoracic echocardiography, parasternal short-axis view). (Right) Massive right-to-left interatrial shunt during contrast echo with Valsalva manoeuvre. (Panel 5) A mitral inflow Doppler in a restrictive cardiomyopathy (amyloid) showing restrictive physiology, E/A > 3, Deceleration time < 120 ms and a short isovolumetric relaxation time. (Panel 6) Brain infarcts in all three cerebral arterial territories (three-territory sign) in a patient with advanced ceacal adenocarcinoma. (Panel 7) Pacemaker recording of an episode of atrial flutter with ventricular pacing. From top to bottom, tracings show atrial electrogram, ventricular electrogram, surface electrocardiogram (ECG), and pacemaker marker channels. (Panel 8) Surface electrocardiographic recording of a short run of non-sustained atrial tachycardia. (Panel 9) Pacemaker atrial electrogram showing an irregular atrial high-rate episode. (Panel 10) Spontaneous echo contrast in the left ventricle (arrows) of a patient with known dilated cardiomyopathy and left ventricular ejection fraction of 12%. (Panel 11) Thrombus (arrow) of the left atrial appendage in a patient with rheumatic mitral stenosis in transoesophageal echocardiography. (Panel 12) Echocardiography demonstrating a severely dilated left atrium in an ESUS patient without known atrial fibrillation. Reprinted from Kamel et al.<sup>46</sup> with permission. (Panel 13) Extensive parietal thrombus of left atrium (arrow) in a patient with rheumatic mitral stenosis at 2D transoesophageal echocardiography (left) and 3D transoesophageal echocardiography (right). (Panel 14) Left ventricular noncompaction at four-channel late gadolinium enhancement, T1 mapping, and short-axis view in cardiac magnetic resonance imaging</figcaption></figure>

is termed as *subclinical atrial fibrillation* (SCAF) or *atrial high-rate episodes* (AHRE) if ECG/electrograms are not available.⁶¹ The risk of stroke is higher in persons with SCAF/AHRE than in patients without, but lower than in patients with clinical AF.⁶¹,⁶² In the non-anticoagulated groups of the ARTESIA and NOAH-AFNET 6 trials, the rate of ischaemic stroke was 1.1–1.2/100 person-years.⁶²,⁶³ It seems plausible that a causal association between SCAF/AHRE and ESUS is stronger in patients with episodes that last longer (e.g. >24 h⁶⁴,⁶⁵) or occur proximal to the stroke,⁶⁴,⁶⁶ rather than in patients with shorter episodes occurring distally. The role of OAC in individuals with SCAF/AHRE was recently tested in the ARTESIA and NOAH-AFNET 6 trials.⁶²,⁶³ In the

study-level meta-analysis of these two trials, there was significant reduction in the rate of ischaemic stroke with OAC [relative risk (RR) 0.68; 95% CI 0.50–0.92, with no sign of heterogeneity) and significant increase in the rate of major bleeding (RR 1.62; 95% CI 1.05–2.5).⁶⁷ The duration of AHRE did not interact with the efficacy or safety of anticoagulation, either using the 24-h threshold or as a continuous covariate in the NOAH-AFNET 6 trial.⁶⁸ Only 9.4% of included patients had previous stroke/TIA or systemic embolism. Further analyses of the trials are warranted to identify which parameters, clinical and non-clinical (like the burden of arrhythmia, imaging findings, and biomarkers), can provide a better estimate of the risk of stroke.
<figure><img src="image_5.png" /><figcaption>**Figure 3** Features associated with thromboembolic risk in embolic stroke of undetermined source patients. (Panel 1) Computed tomography angiography axial scan of the right internal carotid artery in a 73-year-old symptomatic male patient with a 45% stenosis according to the NASCET criteria. A hypodense plaque is visible (arrow) with very low attenuation (<30 Hounsfield units). (Panel 2) MR shows intra-plaque haemorrhage at the bifurcation of the right carotid artery in a 75-year-old symptomatic male patient. (Panel 3) Computed tomography angiography axial scan of the right common carotid artery with a floating thrombus in a 69-year-old female patient. (Panel 4) Patent foramen ovale. (Left) Aneurysm of inter-atrial septum with small inter-atrial shunt in colour Doppler (transthoracic echocardiography, parasternal short-axis view). (Right) Massive right-to-left interatrial shunt during contrast echo with Valsalva manoeuvre. (Panel 5) A mitral inflow Doppler in a restrictive cardiomyopathy (amyloid) showing restrictive physiology, E/A > 3, Deceleration time < 120 ms and a short isovolumetric relaxation time. (Panel 6) Brain infarcts in all three cerebral arterial territories (three-territory sign) in a patient with advanced ceacal adenocarcinoma. (Panel 7) Pacemaker recording of an episode of atrial flutter with ventricular pacing. From top to bottom, tracings show atrial electrogram, ventricular electrogram, surface electrocardiogram (ECG), and pacemaker marker channels. (Panel 8) Surface electrocardiographic recording of a short run of non-sustained atrial tachycardia. (Panel 9) Pacemaker atrial electrogram showing an irregular atrial high-rate episode. (Panel 10) Spontaneous echo contrast in the left ventricle (arrows) of a patient with known dilated cardiomyopathy and left ventricular ejection fraction of 12%. (Panel 11) Thrombus (arrow) of the left atrial appendage in a patient with rheumatic mitral stenosis in transoesophageal echocardiography. (Panel 12) Echocardiography demonstrating a severely dilated left atrium in an ESUS patient without known atrial fibrillation. Reprinted from Kamel et al.<sup>46</sup> with permission. (Panel 13) Extensive parietal thrombus of left atrium (arrow) in a patient with rheumatic mitral stenosis at 2D transoesophageal echocardiography (left) and 3D transoesophageal echocardiography (right). (Panel 14) Left ventricular noncompaction at four-channel late gadolinium enhancement, T1 mapping, and short-axis view in cardiac magnetic resonance imaging</figcaption></figure>

is termed as *subclinical atrial fibrillation* (SCAF) or *atrial high-rate episodes* (AHRE) if ECG/electrograms are not available.⁶¹ The risk of stroke is higher in persons with SCAF/AHRE than in patients without, but lower than in patients with clinical AF.⁶¹,⁶² In the non-anticoagulated groups of the ARTESIA and NOAH-AFNET 6 trials, the rate of ischaemic stroke was 1.1–1.2/100 person-years.⁶²,⁶³ It seems plausible that a causal association between SCAF/AHRE and ESUS is stronger in patients with episodes that last longer (e.g. >24 h⁶⁴,⁶⁵) or occur proximal to the stroke,⁶⁴,⁶⁶ rather than in patients with shorter episodes occurring distally. The role of OAC in individuals with SCAF/AHRE was recently tested in the ARTESIA and NOAH-AFNET 6 trials.⁶²,⁶³ In the

study-level meta-analysis of these two trials, there was significant reduction in the rate of ischaemic stroke with OAC [relative risk (RR) 0.68; 95% CI 0.50–0.92, with no sign of heterogeneity) and significant increase in the rate of major bleeding (RR 1.62; 95% CI 1.05–2.5).⁶⁷ The duration of AHRE did not interact with the efficacy or safety of anticoagulation, either using the 24-h threshold or as a continuous covariate in the NOAH-AFNET 6 trial.⁶⁸ Only 9.4% of included patients had previous stroke/TIA or systemic embolism. Further analyses of the trials are warranted to identify which parameters, clinical and non-clinical (like the burden of arrhythmia, imaging findings, and biomarkers), can provide a better estimate of the risk of stroke.
<figure><img src="image_6.png" /><figcaption>**Figure 4** Assessment of thromboembolic risk related to patent foramen ovale in embolic stroke of undetermined source patients based on the morphological features of the patent foramen ovale, the Risk of Paradoxical Embolism score, patient age, and history of recent venous thromboembolism. The right lower part of the figure is blank because the maximum Risk of Paradoxical Embolism score that a patient > 60 years can have is 6. ASA, atrial septal aneurysm; VTE, venous thromboembolism</figcaption></figure>

## Atrial cardiomyopathy

The size of the LA has been consistently associated with a higher risk of AF⁶⁹ and stroke.⁷⁰,⁷¹ Enlargement of the LA may be associated with age-related progressive remodelling, stretch from pressure and volume overload, and oxidative stress and inflammation and could form an arrhythmogenic and thrombogenic milieu.⁷²,⁷³ The possible role of LA dilatation in ESUS is supported by a post hoc analysis of the NAVIGATE-ESUS trial that showed that oral rivaroxaban was associated with a reduced risk of recurrent stroke amongst patients with ESUS and a LA diameter of >4.6 cm.⁷⁴ The ARCADIA trial assessed the role of OAC with apixaban in patients with ESUS and signs of atrial cardiopathy.⁷⁵ The trial was stopped after its planned interim analysis for futility as there was no difference in stroke recurrence rate between apixaban- and aspirin-assigned patients.

The proposed features to assess the thromboembolic risk in patients with ESUS and LA disease are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

other cardiomyopathies, as well as in patients with reduced LV function in valvular heart disease.⁸¹ In patients with stroke and LV thrombus, the causal association should be regarded as definite cardioembolism and such patients should not be classified as ESUS. The management of LV thrombi was recently reviewed.⁸² Oral anticoagulation is recommended in patients with LV non-compaction cardiomyopathy and prior embolic event.⁸³ Left ventricular spontaneous echo-contrast can be seen in patients with low cardiac output and is highly associated with the occurrence of thrombi and potential systemic emboli. The acute phase of ischaemic heart diseases is also associated with an increased risk of stroke.⁸⁴ Although the incidence of LV thrombus after acute anterior myocardial infarction with new-onset wall motion abnormalities is low, an increased RR persists in the present era despite current revascularization strategies and dual antiplatelet therapy.⁸⁵

The proposed features to assess the thromboembolic risk in patients with ESUS and LV disease are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

## Left ventricular disease

Left ventricular systolic dysfunction is commonly related to stroke, and it is important to diagnose LV disease (including heart failure with preserved ejection fraction) and initiate state-of-the-art heart failure therapy.⁷⁶ Ischaemic heart disease and dilated cardiomyopathies with reduced LV ejection fraction (LVEF) are the most common causes of LV dysfunction which may cause stroke.⁷⁷ Per the ESUS definition, patients with LVEF < 30% are not classified as ESUS given the well-established association between severely reduced LVEF and stroke. Several studies assessed the role of OAC in patients with reduced LVEF. The WARCEF trial reported that OAC in persons in sinus rhythm and severely reduced LVEF reduced the rate of ischaemic stroke compared with warfarin but increased the risk of major bleeding.⁷⁸ Similar conclusions were drawn by a recent meta-analysis of all related trials in which OAC in persons with heart failure and sinus rhythm was associated with a 43% RR reduction of stroke or systemic embolism, which was offset by a 92% RR increase of major bleeding.⁷⁹

Other forms of LV disease may be also the underlying source of ESUS. Cardiac amyloidosis can lead to severe restrictive cardiomyopathy with reduced cardiac output despite preserved LVEF and subsequent thrombus in the LV and also in the LA.⁸⁰ Thrombus formation may develop in case of large or dyskinetic scars or LV aneurysms in the chronic phase of myocardial infarction, in hypertrophic, LV non-compaction and

## Valvular heart disease

Prosthetic cardiac valves, mitral stenosis, and vegetations due to infective endocarditis are considered as major risk sources of cardioembolism, and in their presence, a patient with stroke should not be classified as ESUS.¹ Beyond these entities, the association between valvular pathologies and stroke is weak. The native valvular heart diseases are rare sources of cardiac emboli if we exclude the specific context of endocarditis⁸⁶,⁸⁷ and cardiac tumours.⁷⁷,⁸⁸ In persons with AF, significant aortic valve disease and mitral regurgitation are associated with an increased risk of systemic embolism as compared with patients without valvular disease.⁸⁹

Highly redundant myxomatous mitral valves (Barlow disease) and massive valvular calcifications are two valvular pathologies that are associated with increased embolic risk.⁹⁰ These calcifications are becoming more prevalent.⁹¹ They are found on the aortic valve⁹² and also on the mitral valve, especially the posterior mitral valve leaflet and the annulus. The valvular calcifications can be associated with more diffuse atherosclerotic disease, such as complex aortic atheroma.⁹³

Lambl's excrescences, or else valvular strands, are thin filiform mobile processes that can be found in the mitral and aortic valves. Although it was hypothesized that they are associated with increased stroke risk, observational studies reported inconsistent results.⁹⁴,⁹⁵ In a recent analysis, Lambl's excrescences were not associated with ESUS.⁹⁵
<figure><img src="image_6.png" /><figcaption>**Figure 4** Assessment of thromboembolic risk related to patent foramen ovale in embolic stroke of undetermined source patients based on the morphological features of the patent foramen ovale, the Risk of Paradoxical Embolism score, patient age, and history of recent venous thromboembolism. The right lower part of the figure is blank because the maximum Risk of Paradoxical Embolism score that a patient > 60 years can have is 6. ASA, atrial septal aneurysm; VTE, venous thromboembolism</figcaption></figure>

## Atrial cardiomyopathy

The size of the LA has been consistently associated with a higher risk of AF⁶⁹ and stroke.⁷⁰,⁷¹ Enlargement of the LA may be associated with age-related progressive remodelling, stretch from pressure and volume overload, and oxidative stress and inflammation and could form an arrhythmogenic and thrombogenic milieu.⁷²,⁷³ The possible role of LA dilatation in ESUS is supported by a post hoc analysis of the NAVIGATE-ESUS trial that showed that oral rivaroxaban was associated with a reduced risk of recurrent stroke amongst patients with ESUS and a LA diameter of >4.6 cm.⁷⁴ The ARCADIA trial assessed the role of OAC with apixaban in patients with ESUS and signs of atrial cardiopathy.⁷⁵ The trial was stopped after its planned interim analysis for futility as there was no difference in stroke recurrence rate between apixaban- and aspirin-assigned patients.

The proposed features to assess the thromboembolic risk in patients with ESUS and LA disease are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

other cardiomyopathies, as well as in patients with reduced LV function in valvular heart disease.⁸¹ In patients with stroke and LV thrombus, the causal association should be regarded as definite cardioembolism and such patients should not be classified as ESUS. The management of LV thrombi was recently reviewed.⁸² Oral anticoagulation is recommended in patients with LV non-compaction cardiomyopathy and prior embolic event.⁸³ Left ventricular spontaneous echo-contrast can be seen in patients with low cardiac output and is highly associated with the occurrence of thrombi and potential systemic emboli. The acute phase of ischaemic heart diseases is also associated with an increased risk of stroke.⁸⁴ Although the incidence of LV thrombus after acute anterior myocardial infarction with new-onset wall motion abnormalities is low, an increased RR persists in the present era despite current revascularization strategies and dual antiplatelet therapy.⁸⁵

The proposed features to assess the thromboembolic risk in patients with ESUS and LV disease are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

## Left ventricular disease

Left ventricular systolic dysfunction is commonly related to stroke, and it is important to diagnose LV disease (including heart failure with preserved ejection fraction) and initiate state-of-the-art heart failure therapy.⁷⁶ Ischaemic heart disease and dilated cardiomyopathies with reduced LV ejection fraction (LVEF) are the most common causes of LV dysfunction which may cause stroke.⁷⁷ Per the ESUS definition, patients with LVEF < 30% are not classified as ESUS given the well-established association between severely reduced LVEF and stroke. Several studies assessed the role of OAC in patients with reduced LVEF. The WARCEF trial reported that OAC in persons in sinus rhythm and severely reduced LVEF reduced the rate of ischaemic stroke compared with warfarin but increased the risk of major bleeding.⁷⁸ Similar conclusions were drawn by a recent meta-analysis of all related trials in which OAC in persons with heart failure and sinus rhythm was associated with a 43% RR reduction of stroke or systemic embolism, which was offset by a 92% RR increase of major bleeding.⁷⁹

Other forms of LV disease may be also the underlying source of ESUS. *Cardiac amyloidosis* can lead to severe restrictive cardiomyopathy with reduced cardiac output despite preserved LVEF and subsequent thrombus in the LV and also in the LA.⁸⁰ Thrombus formation may develop in case of large or dyskinetic scars or LV aneurysms in the chronic phase of myocardial infarction, in hypertrophic, LV non-compaction and

## Valvular heart disease

Prosthetic cardiac valves, mitral stenosis, and vegetations due to infective endocarditis are considered as major risk sources of cardioembolism, and in their presence, a patient with stroke should not be classified as ESUS.¹ Beyond these entities, the association between valvular pathologies and stroke is weak. The native valvular heart diseases are rare sources of cardiac emboli if we exclude the specific context of endocarditis⁸⁶,⁸⁷ and cardiac tumours.⁷⁷,⁸⁸ In persons with AF, significant aortic valve disease and mitral regurgitation are associated with an increased risk of systemic embolism as compared with patients without valvular disease.⁸⁹

Highly redundant myxomatous mitral valves (Barlow disease) and massive valvular calcifications are two valvular pathologies that are associated with increased embolic risk.⁹⁰ These calcifications are becoming more prevalent.⁹¹ They are found on the aortic valve⁹² and also on the mitral valve, especially the posterior mitral valve leaflet and the annulus. The valvular calcifications can be associated with more diffuse atherosclerotic disease, such as complex aortic atheroma.⁹³

Lambl's excrescences, or else valvular strands, are thin filiform mobile processes that can be found in the mitral and aortic valves. Although it was hypothesized that they are associated with increased stroke risk, observational studies reported inconsistent results.⁹⁴,⁹⁵ In a recent analysis, Lambl's excrescences were not associated with ESUS.⁹⁵
The proposed features to assess the thromboembolic risk in patients with ESUS and valvular heart disease are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

## Cancer

Cancer is a complex disease that can cause ischaemic stroke through several mechanisms, including hypercoagulable processes such as non-bacterial thrombotic endocarditis (NBTE) and intravascular coagulation, direct vascular injury such as tumour emboli and external compression, and treatment complications such as radiation vasculopathy and chemotherapy-induced cardiomyopathy.⁹⁶,⁹⁷ In the year before cancer is diagnosed, there is a 59% increased risk of ischaemic stroke.⁹⁸ Looking in reverse, 2%–10% of patients with ischaemic stroke are diagnosed with cancer in the subsequent year.⁹⁹⁻¹⁰² Once cancer is diagnosed, stroke risk remains elevated and is doubled in the 6 months thereafter.¹⁰³ The increased stroke risk in patients with cancer follows a U-shaped curve, with risks peaking near the time of cancer diagnosis and then many years later, and the later peak driven by cumulative deleterious effects of cancer treatments.⁹⁶ In the USA, 14% of patients hospitalized with ischaemic stroke in 2019 had active or prior cancer.¹⁰⁴ About 50% of cancer-related strokes are classified as ESUS after standard evaluation.¹⁰⁵ Many cancer patients with strokes classified as ESUS have a distinctive phenotype with advanced or progressive cancer, very elevated clotting markers, and evidence for a central embolic process on imaging.¹⁰⁶ These observations highlight the important link between cancer and stroke and raise the question of whether cancer-related stroke should be considered its own stroke subtype.

According to autopsy data from a cancer centre in the 1980s, NBTE is a leading cause of stroke in patients with cancer.¹⁰⁷ Non-bacterial thrombotic endocarditis is characterized by sterile platelet-fibrin vegetations on cardiac valves. Vegetations are generally small and friable, and therefore, definitive diagnosis antemortem is rare, even with transoesophageal echocardiography.¹⁰⁸,¹⁰⁹ Immunohistochemical analyses of thrombectomy specimens have demonstrated similar clot profiles between cancer patients with non-infectious cardiac vegetations and those with ESUS, suggesting that NBTE is an underappreciated cause of cancer-related stroke.¹¹⁰

Advanced solid or haematological cancer can cause disseminated intravascular coagulation (DIC) leading to stroke. The International Society on Thrombosis and Haemostasis (ISTH) has established criteria, based on levels of D-dimer, fibrinogen, platelet count, and prothrombin time, to diagnose overt DIC in patients with malignancy.¹¹¹ While D-dimer elevations are common in patients with cancer and stroke, overt DIC fulfilling ISTH criteria is rare.⁹⁷

Embolic stroke of undetermined source in cancer patients often has a distinctive clinical phenotype with fewer prevalent vascular risk factors; cancer types associated with increased risks of thromboembolism (e.g. lung, pancreas, gastric, colorectal, ovarian, bladder, and non-Hodgkin's lymphoma); cancers that are newly diagnosed, metastatic, or progressing through treatment; and multi-territory embolic-appearing infarct patterns.¹⁰⁵ Cancer patients with ESUS also often have activation of multiple pathways promoting thrombosis, including platelets, coagulation factors, endothelium, neutrophil extracellular traps, and extracellular vesicles.¹⁰⁵,¹⁰⁶,¹¹² The most consistent markers routinely available in practice are the multi-territorial infarct pattern and D-dimer.

Small, diffuse, predominantly cortical, acute infarcts involving multiple cerebral arterial territories occur in 30%–70% of patients with active cancer and ESUS.¹⁰⁶,¹¹³,¹¹⁴ This infarct pattern, while not specific, can

help identify previously occult cancer in patients with ESUS¹⁰⁰ and is associated with an increased risk of early neurological deterioration.¹¹⁵ When involving all three cerebral arterial territories, it has been termed the three-territory sign.¹¹⁶

Transcranial Doppler (TCD) high-intensity transient signals (HITS), surrogates for circulating microemboli, are present in 38%–58% of patients with cancer and ESUS, a rate much higher than in stroke patients without cancer, correlate with plasma D-dimer levels, and are associated with adenocarcinoma histology and an increased risk of recurrent stroke or death.¹¹⁷,¹¹⁸ If bilateral, HITS suggest a central embolic process.

Extreme elevations of thrombotic end-products such as plasma D-dimer are common in patients with cancer and ESUS.¹⁰⁰ In a prospective study of 50 patients with solid cancer and acute ischaemic stroke, the median D-dimer value was 2.552 ng/mL, compared with median values of 405 and 670 ng/mL in matched patients with stroke only and cancer only, respectively.¹⁰⁶ In this study, D-dimer levels were associated with an increased risk of recurrent stroke and death.¹¹⁷ The optimal threshold to identify an occult cancer or posit causation to a known cancer is uncertain, with reported cut-offs ranging from 820 to 10 000 ng/mL.¹⁰²,¹¹⁹,¹²⁰ We chose a cut-off of 2500 ng/mL for our proposed criteria, as it is close to most published cut-offs and is five times the upper limit of normal. It is worth noting that D-dimer is not specific and can be increased by thromboembolic events besides stroke, AF, prosthetic heart valves, trauma, surgery, and poor sample collection. Many other haematological, inflammatory, and tumour markers are also increased in cancer-related stroke, including P-selectin, thrombin-antithrombin, thrombomodulin, soluble intercellular adhesion molecule, vascular cellular adhesion molecule, CA19-9, CA125, and C-reactive peptide.¹⁰⁶,¹²¹,¹²² However, the relative difference for these markers between cancer and non-cancer patients is not as large as for D-dimer, and many are costly and not routinely available in practice.¹⁰⁶ It is emphasized that plasma D-dimer and TCD HITS are not specific to cancer as an ESUS aetiology but rather serve as quantitative surrogate markers for central embolic processes, which may contribute to ESUS, including atrial cardiomyopathy and atrial arrhythmias.

Tumour embolism is likely an under-recognized cause of stroke in patients with cancer. Centrally located primary or metastatic lung cancers can invade the pulmonary veins or cardiac chambers and embolize to the brain causing stroke.¹²³ Patients with tumour embolism who survive long enough may develop metastases at the site of their stroke.

Nearly all cancer treatments have been associated with increased stroke risk, particularly platinum-based chemotherapy, tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, and hormonal therapy.⁹⁶ However, these associations are often confounded by indication and disappear after adjustment for cancer status,¹²⁴ and in most cases, cancer treatments are probably innocent bystanders or triggers for stroke and not the actual cause. The exceptions to this are surgery causing perioperative stroke through direct injury to the heart or cervicocephalic vessels and radiation causing delayed vasculopathy or heart disease, although in these scenarios, patients' stroke mechanism is known.¹²⁵ For this position paper, we have restricted thromboembolism risk to the cancer itself and not its treatments, which we believe are separate entities with differing characteristics and outcomes.

The criteria that we proposed for the assessment of thromboembolic risk amongst patients with cancer and ESUS should not affect management decisions, as the prothrombotic effects seen in cancer and stroke are multi-fold and involve platelets as much as coagulation factors, and bleeding risks in these patients are exceedingly high.¹¹⁷
The proposed features to assess the thromboembolic risk in patients with ESUS and valvular heart disease are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

## Cancer

Cancer is a complex disease that can cause ischaemic stroke through several mechanisms, including hypercoagulable processes such as non-bacterial thrombotic endocarditis (NBTE) and intravascular coagulation, direct vascular injury such as tumour emboli and external compression, and treatment complications such as radiation vasculopathy and chemotherapy-induced cardiomyopathy.⁹⁶,⁹⁷ In the year before cancer is diagnosed, there is a 59% increased risk of ischaemic stroke.⁹⁸ Looking in reverse, 2%–10% of patients with ischaemic stroke are diagnosed with cancer in the subsequent year.⁹⁹⁻¹⁰² Once cancer is diagnosed, stroke risk remains elevated and is doubled in the 6 months thereafter.¹⁰³ The increased stroke risk in patients with cancer follows a U-shaped curve, with risks peaking near the time of cancer diagnosis and then many years later, and the later peak driven by cumulative deleterious effects of cancer treatments.⁹⁶ In the USA, 14% of patients hospitalized with ischaemic stroke in 2019 had active or prior cancer.¹⁰⁴ About 50% of cancer-related strokes are classified as ESUS after standard evaluation.¹⁰⁵ Many cancer patients with strokes classified as ESUS have a distinctive phenotype with advanced or progressive cancer, very elevated clotting markers, and evidence for a central embolic process on imaging.¹⁰⁶ These observations highlight the important link between cancer and stroke and raise the question of whether cancer-related stroke should be considered its own stroke subtype.

According to autopsy data from a cancer centre in the 1980s, NBTE is a leading cause of stroke in patients with cancer.¹⁰⁷ Non-bacterial thrombotic endocarditis is characterized by sterile platelet-fibrin vegetations on cardiac valves. Vegetations are generally small and friable, and therefore, definitive diagnosis antemortem is rare, even with transoesophageal echocardiography.¹⁰⁸,¹⁰⁹ Immunohistochemical analyses of thrombectomy specimens have demonstrated similar clot profiles between cancer patients with non-infectious cardiac vegetations and those with ESUS, suggesting that NBTE is an underappreciated cause of cancer-related stroke.¹¹⁰

Advanced solid or haematological cancer can cause disseminated intravascular coagulation (DIC) leading to stroke. The International Society on Thrombosis and Haemostasis (ISTH) has established criteria, based on levels of D-dimer, fibrinogen, platelet count, and prothrombin time, to diagnose overt DIC in patients with malignancy.¹¹¹ While D-dimer elevations are common in patients with cancer and stroke, overt DIC fulfilling ISTH criteria is rare.⁹⁷

Embolic stroke of undetermined source in cancer patients often has a distinctive clinical phenotype with fewer prevalent vascular risk factors; cancer types associated with increased risks of thromboembolism (e.g. lung, pancreas, gastric, colorectal, ovarian, bladder, and non-Hodgkin's lymphoma); cancers that are newly diagnosed, metastatic, or progressing through treatment; and multi-territory embolic-appearing infarct patterns.¹⁰⁵ Cancer patients with ESUS also often have activation of multiple pathways promoting thrombosis, including platelets, coagulation factors, endothelium, neutrophil extracellular traps, and extracellular vesicles.¹⁰⁵,¹⁰⁶,¹¹² The most consistent markers routinely available in practice are the multi-territorial infarct pattern and D-dimer.

Small, diffuse, predominantly cortical, acute infarcts involving multiple cerebral arterial territories occur in 30%–70% of patients with active cancer and ESUS.¹⁰⁶,¹¹³,¹¹⁴ This infarct pattern, while not specific, can

help identify previously occult cancer in patients with ESUS¹⁰⁰ and is associated with an increased risk of early neurological deterioration.¹¹⁵ When involving all three cerebral arterial territories, it has been termed the three-territory sign.¹¹⁶

Transcranial Doppler (TCD) high-intensity transient signals (HITS), surrogates for circulating microemboli, are present in 38%–58% of patients with cancer and ESUS, a rate much higher than in stroke patients without cancer, correlate with plasma D-dimer levels, and are associated with adenocarcinoma histology and an increased risk of recurrent stroke or death.¹¹⁷,¹¹⁸ If bilateral, HITS suggest a central embolic process.

Extreme elevations of thrombotic end-products such as plasma D-dimer are common in patients with cancer and ESUS.¹⁰⁰ In a prospective study of 50 patients with solid cancer and acute ischaemic stroke, the median D-dimer value was 2.552 ng/mL, compared with median values of 405 and 670 ng/mL in matched patients with stroke only and cancer only, respectively.¹⁰⁶ In this study, D-dimer levels were associated with an increased risk of recurrent stroke and death.¹¹⁷ The optimal threshold to identify an occult cancer or posit causation to a known cancer is uncertain, with reported cut-offs ranging from 820 to 10 000 ng/mL.¹⁰²,¹¹⁹,¹²⁰ We chose a cut-off of 2500 ng/mL for our proposed criteria, as it is close to most published cut-offs and is five times the upper limit of normal. It is worth noting that D-dimer is not specific and can be increased by thromboembolic events besides stroke, AF, prosthetic heart valves, trauma, surgery, and poor sample collection. Many other haematological, inflammatory, and tumour markers are also increased in cancer-related stroke, including P-selectin, thrombin-antithrombin, thrombomodulin, soluble intercellular adhesion molecule, vascular cellular adhesion molecule, CA19-9, CA125, and C-reactive peptide.¹⁰⁶,¹²¹,¹²² However, the relative difference for these markers between cancer and non-cancer patients is not as large as for D-dimer, and many are costly and not routinely available in practice.¹⁰⁶ It is emphasized that plasma D-dimer and TCD HITS are not specific to cancer as an ESUS aetiology but rather serve as quantitative surrogate markers for central embolic processes, which may contribute to ESUS, including atrial cardiomyopathy and atrial arrhythmias.

Tumour embolism is likely an under-recognized cause of stroke in patients with cancer. Centrally located primary or metastatic lung cancers can invade the pulmonary veins or cardiac chambers and embolize to the brain causing stroke.¹²³ Patients with tumour embolism who survive long enough may develop metastases at the site of their stroke.

Nearly all cancer treatments have been associated with increased stroke risk, particularly platinum-based chemotherapy, tyrosine kinase inhibitors, vascular endothelial growth factor inhibitors, and hormonal therapy.⁹⁶ However, these associations are often confounded by indication and disappear after adjustment for cancer status,¹²⁴ and in most cases, cancer treatments are probably innocent bystanders or triggers for stroke and not the actual cause. The exceptions to this are surgery causing perioperative stroke through direct injury to the heart or cervicocephalic vessels and radiation causing delayed vasculopathy or heart disease, although in these scenarios, patients' stroke mechanism is known.¹²⁵ For this position paper, we have restricted thromboembolism risk to the cancer itself and not its treatments, which we believe are separate entities with differing characteristics and outcomes.

The criteria that we proposed for the assessment of thromboembolic risk amongst patients with cancer and ESUS should not affect management decisions, as the prothrombotic effects seen in cancer and stroke are multi-fold and involve platelets as much as coagulation factors, and bleeding risks in these patients are exceedingly high.¹¹⁷
The proposed features to assess the thromboembolic risk in patients with ESUS and cancer are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

## Diagnostic evaluation

It is evident that the complexity of ESUS precludes a one-size-fits-all approach in the diagnostic evaluation of patients. Diagnostic algorithms for ESUS have been proposed,¹²⁶ but the large number of associated pathologies, the even larger number of risk factors that contribute to these pathologies, and the availability of several diagnostic methods to assess the heart and the arteries require an individualized approach. This should be guided by specific patient characteristics, scalable quantifiable proxies of these pathologies, as well as availability and expertise in imaging techniques. These could include age, comorbidities, and smoking/diet habits, lipid profile, and other organ-specific blood biomarkers as discussed throughout the previous sections, estimation of the cardiovascular risk of the patient using validated risk scores, estimation of the likelihood of covert AF using validated prognostic scores like the AF-ESUS score,¹²⁷,¹²⁸ vascular ultrasound, CT/CTA, and MRI/magnetic resonance angiography to visualize the arterial circulation and the heart, and others. This highly personalized integrated strategy warrants broad expertise in several fields and calls for clinicians who care for stroke patients to broaden their skills across these domains. We need stroke specialists to take ownership of all these facets, rather than just diffusing responsibility across a whole bunch of consulting specialists.¹²⁹

## Implications for clinical practice and research

Patients with ESUS have a considerable risk for stroke recurrence and other cardiovascular events, which highlights the importance to optimize preventive strategies to mitigate this risk. For several decades, there were no clear criteria to define the term 'cryptogenic stroke', which hindered clinical research in this field. In 2014, the introduction of the ESUS concept with explicit definition and criteria led to an improved standardization of this population and hence potentiated clinical research with several randomized trials assessing the role of preventive strategies.¹ The first intervention that was tested in the general ESUS population was OAC with direct oral anticoagulants. However, the results of three randomized trials were disappointing.¹³⁰⁻¹³² Consequently, it was suggested that future research on ESUS should be tailored to patients with specific characteristics that point towards specific embolic sources.⁴⁶ The present position paper has the potential to further enhance research in this population, as it can support a more accurate and homogeneous phenotypic clustering of patients according to their characteristics and consequently facilitate randomized trials of targeted preventive strategies.

## Key knowledge gaps

Further evidence is needed to optimize secondary prevention in ESUS. Future secondary prevention trials in ESUS could provide this, as it has been the case for trials of percutaneous PFO closure, which, through their positive results, provided practice-changing evidence for patients < 60 years. Table 2 presents a list of open questions. For example, in patients with ESUS and supracardiac atherosclerosis, trials of intensive antithrombotic treatment (e.g. addition of a factor Xa inhibitor or low-dose rivaroxaban to standard antiplatelet treatment); intensive

<table><caption>**Table 2** Key knowledge gaps</caption><tr><td>•</td><td>In patients with ESUS and supracardiac atherosclerosis, is intensive lipid-lowering treatment superior compared with standard of care for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and supracardiac atherosclerosis, is intensive antithrombotic treatment superior compared with currently recommended antiplatelet treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and supracardiac atherosclerosis and increased levels of lipoprotein(a), is lowering of lipoprotein(a) beneficial for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and supracardiac atherosclerosis and increased markers of inflammation, is anti-inflammatory treatment beneficial for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and supracardiac atherosclerosis, is intervention with endarterectomy or stenting superior compared with medical-only treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and PFO who are >60 years of age, is percutaneous PFO closure superior compared with medical-only treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and LA spontaneous echo contrast, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In which subgroups of patients with AHRE/SCAF does the benefit of OAC clearly outweigh the harm of associated bleeding?</td></tr><tr><td>•</td><td>How can we improve the prediction of stroke risk in patients with AHRE/SCAF?</td></tr><tr><td>•</td><td>What is the optimal definition of AF burden?</td></tr><tr><td>•</td><td>What is the minimal AF burden which merits OAC in ESUS patients?</td></tr><tr><td>•</td><td>In patients with ESUS and significant LA enlargement, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and LV disease, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and valvular heart disease, is valvular intervention superior compared with medical-only treatment for the prevention of stroke recurrence?</td></tr><tr><td>•</td><td>In patients with ESUS and cancer, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?</td></tr></table>

lipid-lowering treatment to more aggressive targets than currently recommended; anti-inflammatory drugs; lowering of lipoprotein(a); and intervention with endarterectomy or stenting are warranted. Also, in patients with ESUS and PFO who are >60 years of age, trials of percutaneous PFO closure are needed. In addition, for specific populations of patients with LA, LV disease, or with SCAF/AHRE, further trials of OAC are necessary. The minimal AF burden that merits OAC is unknown. Also, in patients with ESUS and cancer, trials of OAC alone or a combination of OAC and antiplatelet therapy are warranted.
The proposed features to assess the thromboembolic risk in patients with ESUS and cancer are presented in Table 1, and patient cases are illustrated in Figures 2 and 3.

## Diagnostic evaluation

It is evident that the complexity of ESUS precludes a one-size-fits-all approach in the diagnostic evaluation of patients. Diagnostic algorithms for ESUS have been proposed,¹²⁶ but the large number of associated pathologies, the even larger number of risk factors that contribute to these pathologies, and the availability of several diagnostic methods to assess the heart and the arteries require an individualized approach. This should be guided by specific patient characteristics, scalable quantifiable proxies of these pathologies, as well as availability and expertise in imaging techniques. These could include age, comorbidities, and smoking/diet habits, lipid profile, and other organ-specific blood biomarkers as discussed throughout the previous sections, estimation of the cardiovascular risk of the patient using validated risk scores, estimation of the likelihood of covert AF using validated prognostic scores like the AF-ESUS score,¹²⁷,¹²⁸ vascular ultrasound, CT/CTA, and MRI/magnetic resonance angiography to visualize the arterial circulation and the heart, and others. This highly personalized integrated strategy warrants broad expertise in several fields and calls for clinicians who care for stroke patients to broaden their skills across these domains. We need stroke specialists to take ownership of all these facets, rather than just diffusing responsibility across a whole bunch of consulting specialists.¹²⁹

## Implications for clinical practice and research

Patients with ESUS have a considerable risk for stroke recurrence and other cardiovascular events, which highlights the importance to optimize preventive strategies to mitigate this risk. For several decades, there were no clear criteria to define the term 'cryptogenic stroke', which hindered clinical research in this field. In 2014, the introduction of the ESUS concept with explicit definition and criteria led to an improved standardization of this population and hence potentiated clinical research with several randomized trials assessing the role of preventive strategies.¹ The first intervention that was tested in the general ESUS population was OAC with direct oral anticoagulants. However, the results of three randomized trials were disappointing.¹³⁰⁻¹³² Consequently, it was suggested that future research on ESUS should be tailored to patients with specific characteristics that point towards specific embolic sources.⁴⁶ The present position paper has the potential to further enhance research in this population, as it can support a more accurate and homogeneous phenotypic clustering of patients according to their characteristics and consequently facilitate randomized trials of targeted preventive strategies.

## Key knowledge gaps

Further evidence is needed to optimize secondary prevention in ESUS. Future secondary prevention trials in ESUS could provide this, as it has been the case for trials of percutaneous PFO closure, which, through their positive results, provided practice-changing evidence for patients < 60 years. Table 2 presents a list of open questions. For example, in patients with ESUS and supracardiac atherosclerosis, trials of intensive antithrombotic treatment (e.g. addition of a factor Xla inhibitor or low-dose rivaroxaban to standard antiplatelet treatment); intensive

<caption>**Table 2** Key knowledge gaps</caption>

* In patients with ESUS and supracardiac atherosclerosis, is intensive lipid-lowering treatment superior compared with standard of care for the prevention of stroke recurrence?

* In patients with ESUS and supracardiac atherosclerosis, is intensive antithrombotic treatment superior compared with currently recommended antiplatelet treatment for the prevention of stroke recurrence?

* In patients with ESUS and supracardiac atherosclerosis and increased levels of lipoprotein(a), is lowering of lipoprotein(a) beneficial for the prevention of stroke recurrence?

* In patients with ESUS and supracardiac atherosclerosis and increased markers of inflammation, is anti-inflammatory treatment beneficial for the prevention of stroke recurrence?

* In patients with ESUS and supracardiac atherosclerosis, is intervention with endarterectomy or stenting superior compared with medical-only treatment for the prevention of stroke recurrence?

* In patients with ESUS and PFO who are >60 years of age, is percutaneous PFO closure superior compared with medical-only treatment for the prevention of stroke recurrence?

* In patients with ESUS and LA spontaneous echo contrast, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?

* In which subgroups of patients with AHRE/SCAF does the benefit of OAC clearly outweigh the harm of associated bleeding?

* How can we improve the prediction of stroke risk in patients with AHRE/SCAF?

* What is the optimal definition of AF burden?

* What is the minimal AF burden which merits OAC in ESUS patients?

* In patients with ESUS and significant LA enlargement, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?

* In patients with ESUS and LV disease, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?

* In patients with ESUS and valvular heart disease, is valvular intervention superior compared with medical-only treatment for the prevention of stroke recurrence?

* In patients with ESUS and cancer, is OAC superior compared with antiplatelet treatment for the prevention of stroke recurrence?

AF, atrial fibrillation; AHRE, atrial high-rate episode; ESUS, embolic stroke of undetermined source; LA, left atrial; LV, left ventricle; OAC, oral anticoagulation; PFO, patent foramen ovale; SCAF, subclinical atrial fibrillation.

lipid-lowering treatment to more aggressive targets than currently recommended; anti-inflammatory drugs; lowering of lipoprotein(a); and intervention with endarterectomy or stenting are warranted. Also, in patients with ESUS and PFO who are >60 years of age, trials of percutaneous PFO closure are needed. In addition, for specific populations of patients with LA, LV disease, or with SCAF/AHRE, further trials of OAC are necessary. The minimal AF burden that merits OAC is unknown. Also, in patients with ESUS and cancer, trials of OAC alone or a combination of OAC and antiplatelet therapy are warranted.
## Synthesis and concluding remarks

When the negative results of the trials of OAC compared with aspirin in the general ESUS population were published,¹³⁰⁻¹³² criticism was addressed towards the ESUS concept. It was suggested that ESUS is not a useful concept and has failed. This is far from the truth: on the contrary, what has actually failed by the results of these trials is not the ESUS concept itself, but the hypothesis that OAC is beneficial in all of these patients and, consequently, the hypothesis that the majority of ESUS is due to covert AF. As clearly stated in the landmark paper that introduced ESUS,¹ in the publication that introduced the updated ESUS criteria and diagnostic algorithm,⁵ in the present position paper and elsewhere,⁴,⁴⁶ the underlying aetiologies in ESUS are numerous and frequently overlapping. The failure of the hypothesis that covert AF is a leading aetiology of ESUS as emphatically implied by the results of the NAVIGATE-ESUS¹³⁰ and RE-SPECT ESUS¹³¹ trials, urges the research community to redirect focus on assessing the role of other preventive strategies in ESUS, as discussed above, which could potentially improve the prognosis in this patient population.

The high prevalence of ESUS, the considerable risk for stroke recurrence, the modern diagnostic imaging techniques, and the availability of several medical and interventional strategies that could potentially reduce stroke risk in ESUS-associated pathologies like supracardiac atherosclerosis, PFO, LA, or LV disease, valvular heart disease, and cancer identify ESUS as an important priority in stroke research in the coming years, which may hopefully improve outcomes in this large patient population.

## Acknowledgements

We thank Dr Afshin Khalatbari and Dr Tim Fairbairn (both in Liverpool) for kindly providing panel images 9, 11 and 14 in Figure 3. Document Reviewers: Diana A. Gorog (Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, UK; Centre for Health Services Research, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK), Alison Halliday (ESC Council on Stroke; Emeritus Professor of Vascular Surgery, University of Oxford, Oxfordshire, UK; Hunterian Professor, Royal College of Surgeons of England), Jan Kovac (University Hospitals of Leicester NHS Trust Leicester, Leicester, UK), Radosław Lenarczyk (Division of Medical Sciences in Zabrze, Department of Cardiology, Congenital Heart Disease and Electrotherapy, Silesian Center for Heart Disease, The Medical University of Silesia, Zabrze, Poland), Sandor Nardai (Department of Neurointervention, National Institute of Mental Health, Neurology and Neurosurgery, Budapest, Hungary; Department of Neurosurgery, Semmelweis University, Budapest, Hungary), Marco Proietti (Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Division of Subacute Care, IRCCS Istituti Clinici Scientifici Maugeri, Milan, Italy), and José Miguel Rivera-Caravaca (Faculty of Nursing, University of Murcia, Murcia, Spain; Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain).

## Declarations

### Disclosure of Interest

G.N. reports Advisory Boards/Research support/Speaker fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Javelin Medical,

Novartis, and Sanofi, Clinical trial steering/executive committees for Janssen and Javelin Medical. H.B. reports no conflicts of interest over the last 3 years. W.D. reports consulting fees from Aimediq, Bayer, Boehringer Ingelheim, Boston Scientific, Lilly, Medtronic, Pfizer, Sanofi-Aventis, SphingoTec, and Vifor Pharma; travel support from Pharmacosmos; and research support to the Institute from EU (Horizon2020), the German Ministry of Education and Research, German Center for Cardiovascular Research, Boehringer Ingelheim, Vifor Pharma, and ZS Pharma, all outside this manuscript. E.D. reports no conflicts of interest. T.E. reports no conflicts of interest. J.S.H. reports research grants and speaking fees from Boston Scientific, Medtronic, and BMS/Pfizer; speaking fees from Servier; Consulting fees from Bayer and Boston Scientific and research grants from Novartis. B.I. reports no conflict of interest. H.K. reports PI for the ARCADIA trial (NIH/NINDS U01NS095869), which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); Deputy Editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; endpoint adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. S.E.K. reports grants from Genentech, Medtronic, DiaMedica, and Bayer; consulting fees from AbbVie and Shionogi; fees from AstraZeneca for participation in a Data Safety Monitoring Board; and royalties from UpToDate. E.K. has received funding from European Union's Horizon 2020 research and innovation programme under grant agreement no 754517; speaker honoraria/travel grants: Bayer, Pfizer, Amgen, Elpen, Innovis, and Sanofi. B.B.N. reports no conflicts of interest. C.P. reports no conflicts of interest. L.S. reports no conflicts of interest. R.B.S. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under the grant agreement no 648131, from the European Union's Horizon 2020 research and innovation programme under the grant agreement no 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114), German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239), and Wolfgang Seefried project funding German Heart Foundation and has received lecture fees and advisory board fees from BMS/Pfizer outside this work. E.S. reports institutional lecture fees from Bayer, Bristol-Myers Squibb-Pfizer, Boehringer Ingelheim, Johnson & Johnson, and Merck Sharp & Dohme. G.Y.H.L. reports being a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos. No fees are received personally. G.Y.H.L. is co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no 899871. D.A.G. reports institutional research grants from Bayer, AstraZeneca, Werfen, and Medtronic and speaker fees from AstraZeneca. M.P. is the Italian national principal investigator of the AFFIRMO project on multi-morbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no 899871. A.H., J.K., R.L., S.N., and J.M.R.-C. declared no disclosure of interest for this contribution.

### Data Availability

No data were generated or analysed for this manuscript.
## Synthesis and concluding remarks

When the negative results of the trials of OAC compared with aspirin in the general ESUS population were published,¹³⁰⁻¹³² criticism was addressed towards the ESUS concept. It was suggested that ESUS is not a useful concept and has failed. This is far from the truth: on the contrary, what has actually failed by the results of these trials is not the ESUS concept itself, but the hypothesis that OAC is beneficial in all of these patients and, consequently, the hypothesis that the majority of ESUS is due to covert AF. As clearly stated in the landmark paper that introduced ESUS,¹ in the publication that introduced the updated ESUS criteria and diagnostic algorithm,⁵ in the present position paper and elsewhere,⁴,⁴⁶ the underlying aetiologies in ESUS are numerous and frequently overlapping. The failure of the hypothesis that covert AF is a leading aetiology of ESUS as emphatically implied by the results of the NAVIGATE-ESUS¹³⁰ and RE-SPECT ESUS¹³¹ trials, urges the research community to redirect focus on assessing the role of other preventive strategies in ESUS, as discussed above, which could potentially improve the prognosis in this patient population.

The high prevalence of ESUS, the considerable risk for stroke recurrence, the modern diagnostic imaging techniques, and the availability of several medical and interventional strategies that could potentially reduce stroke risk in ESUS-associated pathologies like supracardiac atherosclerosis, PFO, LA, or LV disease, valvular heart disease, and cancer identify ESUS as an important priority in stroke research in the coming years, which may hopefully improve outcomes in this large patient population.

## Acknowledgements

We thank Dr Afshin Khalatbari and Dr Tim Fairbairn (both in Liverpool) for kindly providing panel images 9, 11 and 14 in Figure 3. Document Reviewers: Diana A. Gorog (Faculty of Medicine, National Heart and Lung Institute, Imperial College, London, UK; Centre for Health Services Research, School of Life and Medical Sciences, University of Hertfordshire, Hatfield, UK), Alison Halliday (ESC Council on Stroke; Emeritus Professor of Vascular Surgery, University of Oxford, Oxfordshire, UK; Hunterian Professor, Royal College of Surgeons of England), Jan Kovac (University Hospitals of Leicester NHS Trust Leicester, Leicester, UK), Radosław Lenarczyk (Division of Medical Sciences in Zabrze, Department of Cardiology, Congenital Heart Disease and Electrotherapy, Silesian Center for Heart Disease, The Medical University of Silesia, Zabrze, Poland), Sandor Nardai (Department of Neurointervention, National Institute of Mental Health, Neurology and Neurosurgery, Budapest, Hungary; Department of Neurosurgery, Semmelweis University, Budapest, Hungary), Marco Proietti (Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; Division of Subacute Care, IRCCS Istituti Clinici Scientifici Maugeri, Milan, Italy), and José Miguel Rivera-Caravaca (Faculty of Nursing, University of Murcia, Murcia, Spain; Department of Cardiology, Hospital Clínico Universitario Virgen de la Arrixaca, Instituto Murciano de Investigación Biosanitaria (IMIB-Arrixaca), CIBERCV, Murcia, Spain).

## Declarations

### Disclosure of Interest

G.N. reports Advisory Boards/Research support/Speaker fees from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Javelin Medical,

Novartis, and Sanofi, Clinical trial steering/executive committees for Janssen and Javelin Medical. H.B. reports no conflicts of interest over the last 3 years. W.D. reports consulting fees from Aimediq, Bayer, Boehringer Ingelheim, Boston Scientific, Lilly, Medtronic, Pfizer, Sanofi-Aventis, SphingoTec, and Vifor Pharma; travel support from Pharmacosmos; and research support to the Institute from EU (Horizon2020), the German Ministry of Education and Research, German Center for Cardiovascular Research, Boehringer Ingelheim, Vifor Pharma, and ZS Pharma, all outside this manuscript. E.D. reports no conflicts of interest. T.E. reports no conflicts of interest. J.S.H. reports research grants and speaking fees from Boston Scientific, Medtronic, and BMS/Pfizer; speaking fees from Servier; Consulting fees from Bayer and Boston Scientific and research grants from Novartis. B.I. reports no conflict of interest. H.K. reports PI for the ARCADIA trial (NIH/NINDS U01NS095869), which receives in-kind study drug from the BMS-Pfizer Alliance for Eliquis® and ancillary study support from Roche Diagnostics; other funding from NIH (R01HL144541, R01NS123576, and U01NS106513); Deputy Editor for JAMA Neurology; clinical trial steering/executive committees for Medtronic, Janssen, and Javelin Medical; endpoint adjudication committees for AstraZeneca, Novo Nordisk, and Boehringer Ingelheim; and household ownership interests in TETMedical, Spectrum Plastics Group, and Burke Porter Group. S.E.K. reports grants from Genentech, Medtronic, DiaMedica, and Bayer; consulting fees from AbbVie and Shionogi; fees from AstraZeneca for participation in a Data Safety Monitoring Board; and royalties from UpToDate. E.K. has received funding from European Union's Horizon 2020 research and innovation programme under grant agreement no 754517; speaker honoraria/travel grants: Bayer, Pfizer, Amgen, Elpen, Innovis, and Sanofi. B.B.N. reports no conflicts of interest. C.P. reports no conflicts of interest. L.S. reports no conflicts of interest. R.B.S. has received funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme under the grant agreement no 648131, from the European Union's Horizon 2020 research and innovation programme under the grant agreement no 847770 (AFFECT-EU) and German Center for Cardiovascular Research (DZHK e.V.) (81Z1710103 and 81Z0710114), German Ministry of Research and Education (BMBF 01ZX1408A) and ERACoSysMed3 (031L0239), and Wolfgang Seefried project funding German Heart Foundation and has received lecture fees and advisory board fees from BMS/Pfizer outside this work. E.S. reports institutional lecture fees from Bayer, Bristol-Myers Squibb-Pfizer, Boehringer Ingelheim, Johnson & Johnson, and Merck Sharp & Dohme. G.Y.H.L. reports being a consultant and speaker for BMS/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos. No fees are received personally. G.Y.H.L. is co-principal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no 899871. D.A.G. reports institutional research grants from Bayer, AstraZeneca, Werfen, and Medtronic and speaker fees from AstraZeneca. M.P. is the Italian national principal investigator of the AFFIRMO project on multi-morbidity in AF, which has received funding from the European Union's Horizon 2020 research and innovation programme under grant agreement no 899871. A.H., J.K., R.L., S.N., and J.M.R.-C. declared no disclosure of interest for this contribution.

### Data Availability

No data were generated or analysed for this manuscript.
# Funding

All authors declare no funding for this contribution.

# References

1. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. *Lancet Neurol* 2014;13:429-38. https://doi.org/10.1016/S1474-4422(13)70310-7

2. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. *Stroke* 2017;48:867-72. https://doi.org/10.1161/strokeaha.116.016414

3. Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Manios E, Spengos K, et al. Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis. *Stroke* 2015;46:176-81. https://doi.org/10.1161/strokeaha.114.007240

4. Ntaios G. Embolic stroke of undetermined source: JACC review topic of the week. *J Am Coll Cardiol* 2020;75:333-40. https://doi.org/10.1016/j.jacc.2019.11.024

5. Diener HC, Easton JD, Hart RG, Kasner S, Kamel H, Ntaios G. Review and update of the concept of embolic stroke of undetermined source. *Nat Rev Neurol* 2022;18:455-65. https://doi.org/10.1038/s41582-022-00663-4

6. Ntaios G, Hart RG. Embolic stroke. *Circulation* 2017;136:2403-5. https://doi.org/10.1161/circulationa.117.030509

7. Ntaios G, Pearce LA, Veltkamp R, Sharma M, Kasner SE, Korompoki E, et al. Potential embolic sources and outcomes in embolic stroke of undetermined source in the NAVIGATE-ESUS trial. *Stroke* 2020;51:1797-804. https://doi.org/10.1161/STROKEAHA.119.028669

8. Ntaios G, Perlepe K, Lambrou D, Sirimargo G, Strambo D, Eskandari A, et al. Prevalence and overlap of potential embolic sources in patients with embolic stroke of undetermined source. *J Am Heart Assoc* 2019;8:e012858. https://doi.org/10.1161/jaha.119.012858

9. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJM. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. *Lancet* 2004;363:915-24. doi: https://doi.org/10.1016/S0140-6736(04)15785-1

10. Saba L, Saam T, Jager HR, Yuan C, Hatsukami TS, Saloner D, et al. Imaging biomarkers of vulnerable carotid plaques for stroke risk prediction and their potential clinical implications. *Lancet Neurol* 2019;18:559-72. https://doi.org/10.1016/s1474-4422(19)30035-3

11. Ntaios G, Wintermark M, Michel P. Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source. *Eur Heart J* 2021;42:1789-96. https://doi.org/10.1093/eurheartj/eha218

12. Kamtchum-Tatuene J, Wilman A, Saqqur M, Shuaib A, Jickling GC. Carotid plaque with high-risk features in embolic stroke of undetermined source: systematic review and meta-analysis. *Stroke* 2020;51:311-4. https://doi.org/10.1161/strokeaha.119.027272

13. Ntaios G, Swaminathan B, Berkowitz SD, Gagliardi RJ, Lang W, Siegler JE, et al. Efficacy and safety of rivaroxaban versus aspirin in embolic stroke of undetermined source and carotid atherosclerosis. *Stroke* 2019;50:2477-85. https://doi.org/10.1161/strokeaha.119.025168

14. Ntaios G, Perlepe K, Sirimargo G, Strambo D, Eskandari A, Karagkiozi E, et al. Carotid plaques and detection of atrial fibrillation in embolic stroke of undetermined source. *Neurology* 2019;92:e2644-52. https://doi.org/10.1012/wnl.0000000000007611

15. Kopczak A, Schindler A, Bayer-Karpinska A, Koch ML, Sepp D, Zeller J, et al. Complicated carotid artery plaques as a cause of cryptogenic stroke. *J Am Coll Cardiol* 2020;76:2212-22. https://doi.org/10.1016/j.jacc.2020.09.532

16. Schindler A, Schinner R, Altaf N, Hosseini AA, Simpson RJ, Esposito-Bauer L, et al. Prediction of stroke risk by detection of hemorrhage in carotid plaques: meta-analysis of individual patient data. *JACC Cardiovasc Imaging* 2020;13:395-406. https://doi.org/10.1016/j.jcmg.2019.03.028

17. Lusby RJ, Ferrell LD, Ehrenfeld WK, Stoney RJ, Wylie EJ. Carotid plaque hemorrhage. Its role in production of cerebral ischemia. *Arch Surg* 1982;117:1479-88. https://doi.org/10.1001/archsurg.1982.01380350069010

18. Takaya N, Yuan C, Chu B, Saam T, Polissar NL, Jarvik GP, et al. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. *Circulation* 2005;111:2768-75. https://doi.org/10.1161/CIRCULATIONAHA.104.504167

19. Kwee RM, van Oostenbrugge RJ, Mess WH, Prins MH, van der Geest RJ, ter Berg JW, et al. MRI of carotid atherosclerosis to identify TIA and stroke patients who are at risk of a recurrence. *J Magn Reson Imaging* 2013;37:1189-94. https://doi.org/10.1002/jmri.23918

20. Yuan C, Zhang SX, Polissar NL, Echelard D, Ortiz G, Davis JW, et al. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. *Circulation* 2002;105:181-5. https://doi.org/10.1161/hc0202.102121

21. Sadat U, Teng Z, Young VE, Walsh SR, Li ZY, Graves MJ, et al. Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent

ischaemic cerebrovascular events—a longitudinal in vivo magnetic resonance imaging-based finite element study. *Eur J Vasc Endovasc Surg* 2010;40:485-91. https://doi.org/10.1016/j.ejvs.2010.07.015

22. Bhatti AF, Leon LR Jr, Labropoulos N, Rubinas TL, Rodriguez H, Kalman PG, et al. Free-floating thrombus of the carotid artery: literature review and case reports. *J Vasc Surg* 2007;45:199-205. https://doi.org/10.1016/j.jvs.2006.09.057

23. McNally JS, McLaughlin MS, Hinckley PJ, Treiman SM, Stoddard GJ, Parker DL, et al. Intraluminal thrombus, intraplaque hemorrhage, plaque thickness, and current smoking optimally predict carotid stroke. *Stroke* 2015;46:84-90. https://doi.org/10.1161/STROKEAHA.114.006286

24. Eesa M, Hill MD, Al-Khathaami A, Al-Zawahmah M, Sharma P, Menon BK, et al. Role of CT angiographic plaque morphologic characteristics in addition to stenosis in predicting the symptomatic side in carotid artery disease. *AJNR Am J Neuroradiol* 2010;31:1254-60. https://doi.org/10.3174/ajnr.A2078

25. Saba L, Anzidei M, Marincola BC, Piga M, Raz E, Bassareo PP, et al. Imaging of the carotid artery vulnerable plaque. *Cardiovasc Intervent Radiol* 2014;37:572-85. https://doi.org/10.1007/s00270-013-0711-2

26. Prabhakaran S, Rundek T, Ramas R, Elkind MS, Paik MC, Boden-Albala B, et al. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. *Stroke* 2006;37:2696-701. https://doi.org/10.1161/01.STR.000244780.82190.a4

27. Sitzer M, Muller W, Siebler M, Hort W, Kniemeyer HW, Jancke L, et al. Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. *Stroke* 1995;26:1231-3. https://doi.org/10.1161/01.str.26.7.1231

28. Ferguson GG, Eliasziw M, Barr HW, Clagett GP, Barnes RW, Wallace MC, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. *Stroke* 1999;30:1751-8. https://doi.org/10.1161/01.str.30.9.1751

29. Eliasziw M, Streifler JY, Fox AJ, Hachinski VC, Ferguson GG, Barnett HJ. Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial. *Stroke* 1994;25:304-8. https://doi.org/10.1161/01.str.25.2.304

30. Homburg PJ, Rozie S, van Gils MJ, van den Bouwhuijsen QJ, Niessen WJ, Dippel DW, et al. Association between carotid artery plaque ulceration and plaque composition evaluated with multidetector CT angiography. *Stroke* 2011;42:367-72. https://doi.org/10.1161/STROKEAHA.110.597369

31. Xu D, Hippe DS, Underhill HR, Oikawa-Wakayama M, Dong L, Yamada K, et al. Prediction of high-risk plaque development and plaque progression with the carotid atherosclerosis score. *JACC Cardiovasc Imaging* 2014;7:366-73. https://doi.org/10.1016/j.jcmg.2013.09.022

32. Mono ML, Karameshev A, Slotboom J, Remonda L, Galimanis A, Jung S, et al. Plaque characteristics of asymptomatic carotid stenosis and risk of stroke. *Cerebrovasc Dis* 2012;34:343-50. https://doi.org/10.1159/000343227

33. Gupta A, Baradarhan R, Schweitzer AD, Kamel H, Pandya A, Delgado D, et al. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. *Stroke* 2013;44:3071-7. https://doi.org/10.1161/STROKEAHA.113.002551

34. Coutinho JM, Derkatch S, Potvin AR, Tomlinson G, Kiehl TR, Silver FL, et al. Nonstenotic carotid plaque on CT angiography in patients with cryptogenic stroke. *Neurology* 2016;87:665-72. https://doi.org/10.1212/WNL.00000000000002978

35. Zhao X, Hippe DS, Li R, Canton GM, Sui B, Song Y, et al. Prevalence and characteristics of carotid artery high-risk atherosclerotic plaques in Chinese patients with cerebrovascular symptoms: a Chinese atherosclerosis risk evaluation II study. *J Am Heart Assoc* 2017;6:e005831. https://doi.org/10.1161/JAHA.117.005831

36. Yang J, Pan X, Zhang B, Yan Y, Huang Y, Woolf AK, et al. Superficial and multiple calcifications and ulceration associate with intraplaque hemorrhage in the carotid atherosclerotic plaque. *Eur Radiol* 2018;28:4968-77. https://doi.org/10.1007/s00330-018-5535-7

37. Benson JC, Nardi V, Madhavan AA, Bois MC, Saba L, Savastano L, et al. Reassessing the carotid artery plaque "rim sign" on CTA: a new analysis with histopathologic confirmation. *AJNR Am J Neuroradiol* 2022;43:429-34. https://doi.org/10.3174/ajnr.A7443

38. Eisenmenger LB, Aldred BW, Kim SE, Stoddard GJ, de Havenon A, Treiman GS, et al. Prediction of carotid intraplaque hemorrhage using adventitial calcification and plaque thickness on CTA. *AJNR Am J Neuroradiol* 2016;37:1496-503. https://doi.org/10.3174/ajnr.A4765

39. Saba L, Chen H, Cau R, Rubeis GD, Zhu G, Pisu F, et al. Impact analysis of different CT configurations of carotid artery plaque calcifications on cerebrovascular events. *AJNR Am J Neuroradiol* 2022;43:272-9. https://doi.org/10.3174/ajnr.A7401

40. Saba L, Lai ML, Montisci R, Tamponi E, Sanfilippo R, Faa G, et al. Association between carotid plaque enhancement shown by multidetector CT angiography and histologically validated microvessel density. *Eur Radiol* 2012;22:2237-45. https://doi.org/10.1007/s00330-012-2467-5

41. Song Y, Dang Y, Wang J, Cai H, Feng J, Zhang H, et al. Carotid intraplaque neovascularization predicts ischemic stroke recurrence in patients with carotid atherosclerosis. *Gerontology* 2021;67:144-51. https://doi.org/10.1159/000511360
# Funding

All authors declare no funding for this contribution.

# References

1. Hart RG, Diener HC, Coutts SB, Easton JD, Granger CB, O'Donnell MJ, et al. Embolic strokes of undetermined source: the case for a new clinical construct. *Lancet Neurol* 2014;13:429-38. https://doi.org/10.1016/S1474-4422(13)70310-7

2. Hart RG, Catanese L, Perera KS, Ntaios G, Connolly SJ. Embolic stroke of undetermined source: a systematic review and clinical update. *Stroke* 2017;48:867-72. https://doi.org/10.1161/strokeaha.116.016414

3. Ntaios G, Papavasileiou V, Milionis H, Makaritsis K, Manios E, Spengos K, et al. Embolic strokes of undetermined source in the Athens stroke registry: a descriptive analysis. *Stroke* 2015;46:176-81. https://doi.org/10.1161/strokeaha.114.007240

4. Ntaios G. Embolic stroke of undetermined source: JACC review topic of the week. *J Am Coll Cardiol* 2020;75:333-40. https://doi.org/10.1016/j.jacc.2019.11.024

5. Diener HC, Easton JD, Hart RG, Kasner S, Kamel H, Ntaios G. Review and update of the concept of embolic stroke of undetermined source. *Nat Rev Neurol* 2022;18:455-65. https://doi.org/10.1038/s41582-022-00663-4

6. Ntaios G, Hart RG. Embolic stroke. *Circulation* 2017;136:2403-5. https://doi.org/10.1161/circulationa.117.030509

7. Ntaios G, Pearce LA, Veltkamp R, Sharma M, Kasner SE, Korompoki E, et al. Potential embolic sources and outcomes in embolic stroke of undetermined source in the NAVIGATE-ESUS trial. *Stroke* 2020;51:1797-804. https://doi.org/10.1161/STROKEAHA.119.028669

8. Ntaios G, Perlepe K, Lambrou D, Sirimargo G, Strambo D, Eskandari A, et al. Prevalence and overlap of potential embolic sources in patients with embolic stroke of undetermined source. *J Am Heart Assoc* 2019;8:e012858. https://doi.org/10.1161/jaha.119.012858

9. Rothwell PM, Eliasziw M, Gutnikov SA, Warlow CP, Barnett HJM. Endarterectomy for symptomatic carotid stenosis in relation to clinical subgroups and timing of surgery. *Lancet* 2004;363:915-24. doi: https://doi.org/10.1016/S0140-6736(04)15785-1

10. Saba L, Saam T, Jager HR, Yuan C, Hatsukami TS, Saloner D, et al. Imaging biomarkers of vulnerable carotid plaques for stroke risk prediction and their potential clinical implications. *Lancet Neurol* 2019;18:559-72. https://doi.org/10.1016/s1474-4422(19)30035-3

11. Ntaios G, Wintermark M, Michel P. Supracardiac atherosclerosis in embolic stroke of undetermined source: the underestimated source. *Eur Heart J* 2021;42:1789-96. https://doi.org/10.1093/eurheartj/eha218

12. Kamtchum-Tatuene J, Wilman A, Saqqur M, Shuaib A, Jickling GC. Carotid plaque with high-risk features in embolic stroke of undetermined source: systematic review and meta-analysis. *Stroke* 2020;51:311-4. https://doi.org/10.1161/strokeaha.119.027272

13. Ntaios G, Swaminathan B, Berkowitz SD, Gagliardi RJ, Lang W, Siegler JE, et al. Efficacy and safety of rivaroxaban versus aspirin in embolic stroke of undetermined source and carotid atherosclerosis. *Stroke* 2019;50:2477-85. https://doi.org/10.1161/strokeaha.119.025168

14. Ntaios G, Perlepe K, Sirimargo G, Strambo D, Eskandari A, Karagkiozi E, et al. Carotid plaques and detection of atrial fibrillation in embolic stroke of undetermined source. *Neurology* 2019;92:e2644-52. https://doi.org/10.1012/wnl.0000000000007611

15. Kopczak A, Schindler A, Bayer-Karpinska A, Koch ML, Sepp D, Zeller J, et al. Complicated carotid artery plaques as a cause of cryptogenic stroke. *J Am Coll Cardiol* 2020;76:2212-22. https://doi.org/10.1016/j.jacc.2020.09.532

16. Schindler A, Schinner R, Altaf N, Hosseini AA, Simpson RJ, Esposito-Bauer L, et al. Prediction of stroke risk by detection of hemorrhage in carotid plaques: meta-analysis of individual patient data. *JACC Cardiovasc Imaging* 2020;13:395-406. https://doi.org/10.1016/j.jcmg.2019.03.028

17. Lusby RJ, Ferrell LD, Ehrenfeld WK, Stoney RJ, Wylie EJ. Carotid plaque hemorrhage. Its role in production of cerebral ischemia. *Arch Surg* 1982;117:1479-88. https://doi.org/10.1001/archsurg.1982.01380350069010

18. Takaya N, Yuan C, Chu B, Saam T, Polissar NL, Jarvik GP, et al. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: a high-resolution magnetic resonance imaging study. *Circulation* 2005;111:2768-75. https://doi.org/10.1161/CIRCULATIONAHA.104.504167

19. Kwee RM, van Oostenbrugge RJ, Mess WH, Prins MH, van der Geest RJ, ter Berg JW, et al. MRI of carotid atherosclerosis to identify TIA and stroke patients who are at risk of a recurrence. *J Magn Reson Imaging* 2013;37:1189-94. https://doi.org/10.1002/jmri.23918

20. Yuan C, Zhang SX, Polissar NL, Echelard D, Ortiz G, Davis JW, et al. Identification of fibrous cap rupture with magnetic resonance imaging is highly associated with recent transient ischemic attack or stroke. *Circulation* 2002;105:181-5. https://doi.org/10.1161/hc0202.102121

21. Sadat U, Teng Z, Young VE, Walsh SR, Li ZY, Graves MJ, et al. Association between biomechanical structural stresses of atherosclerotic carotid plaques and subsequent

ischaemic cerebrovascular events—a longitudinal in vivo magnetic resonance imaging-based finite element study. *Eur J Vasc Endovasc Surg* 2010;40:485-91. https://doi.org/10.1016/j.ejvs.2010.07.015

22. Bhatti AF, Leon LR Jr, Labropoulos N, Rubinas TL, Rodriguez H, Kalman PG, et al. Free-floating thrombus of the carotid artery: literature review and case reports. *J Vasc Surg* 2007;45:199-205. https://doi.org/10.1016/j.jvs.2006.09.057

23. McNally JS, McLaughlin MS, Hinckley PJ, Treiman SM, Stoddard GJ, Parker DL, et al. Intraluminal thrombus, intraplaque hemorrhage, plaque thickness, and current smoking optimally predict carotid stroke. *Stroke* 2015;46:84-90. https://doi.org/10.1161/STROKEAHA.114.006286

24. Eesa M, Hill MD, Al-Khathaami A, Al-Zawahmah M, Sharma P, Menon BK, et al. Role of CT angiographic plaque morphologic characteristics in addition to stenosis in predicting the symptomatic side in carotid artery disease. *AJNR Am J Neuroradiol* 2010;31:1254-60. https://doi.org/10.3174/ajnr.A2078

25. Saba L, Anzidei M, Marincola BC, Piga M, Raz E, Bassareo PP, et al. Imaging of the carotid artery vulnerable plaque. *Cardiovasc Intervent Radiol* 2014;37:572-85. https://doi.org/10.1007/s00270-013-0711-2

26. Prabhakaran S, Rundek T, Ramas R, Elkind MS, Paik MC, Boden-Albala B, et al. Carotid plaque surface irregularity predicts ischemic stroke: the northern Manhattan study. *Stroke* 2006;37:2696-701. https://doi.org/10.1161/01.STR.000244780.82190.a4

27. Sitzer M, Muller W, Siebler M, Hort W, Kniemeyer HW, Jancke L, et al. Plaque ulceration and lumen thrombus are the main sources of cerebral microemboli in high-grade internal carotid artery stenosis. *Stroke* 1995;26:1231-3. https://doi.org/10.1161/01.str.26.7.1231

28. Ferguson GG, Eliasziw M, Barr HW, Clagett GP, Barnes RW, Wallace MC, et al. The North American Symptomatic Carotid Endarterectomy Trial: surgical results in 1415 patients. *Stroke* 1999;30:1751-8. https://doi.org/10.1161/01.str.30.9.1751

29. Eliasziw M, Streifler JY, Fox AJ, Hachinski VC, Ferguson GG, Barnett HJ. Significance of plaque ulceration in symptomatic patients with high-grade carotid stenosis. North American Symptomatic Carotid Endarterectomy Trial. *Stroke* 1994;25:304-8. https://doi.org/10.1161/01.str.25.2.304

30. Homburg PJ, Rozie S, van Gils MJ, van den Bouwhuijsen QJ, Niessen WJ, Dippel DW, et al. Association between carotid artery plaque ulceration and plaque composition evaluated with multidetector CT angiography. *Stroke* 2011;42:367-72. https://doi.org/10.1161/STROKEAHA.110.597369

31. Xu D, Hippe DS, Underhill HR, Oikawa-Wakayama M, Dong L, Yamada K, et al. Prediction of high-risk plaque development and plaque progression with the carotid atherosclerosis score. *JACC Cardiovasc Imaging* 2014;7:366-73. https://doi.org/10.1016/j.jcmg.2013.09.022

32. Mono ML, Karameshev A, Slotboom J, Remonda L, Galimanis A, Jung S, et al. Plaque characteristics of asymptomatic carotid stenosis and risk of stroke. *Cerebrovasc Dis* 2012;34:343-50. https://doi.org/10.1159/000343227

33. Gupta A, Baradarhan R, Schweitzer AD, Kamel H, Pandya A, Delgado D, et al. Carotid plaque MRI and stroke risk: a systematic review and meta-analysis. *Stroke* 2013;44:3071-7. https://doi.org/10.1161/STROKEAHA.113.002551

34. Coutinho JM, Derkatch S, Potvin AR, Tomlinson G, Kiehl TR, Silver FL, et al. Nonstenotic carotid plaque on CT angiography in patients with cryptogenic stroke. *Neurology* 2016;87:665-72. https://doi.org/10.1212/WNL.0000000000002978

35. Zhao X, Hippe DS, Li R, Canton GM, Sui B, Song Y, et al. Prevalence and characteristics of carotid artery high-risk atherosclerotic plaques in Chinese patients with cerebrovascular symptoms: a Chinese atherosclerosis risk evaluation II study. *J Am Heart Assoc* 2017;6:e005831. https://doi.org/10.1161/JAHA.117.005831

36. Yang J, Pan X, Zhang B, Yan Y, Huang Y, Woolf AK, et al. Superficial and multiple calcifications and ulceration associate with intraplaque hemorrhage in the carotid atherosclerotic plaque. *Eur Radiol* 2018;28:4968-77. https://doi.org/10.1007/s00330-018-5535-7

37. Benson JC, Nardi V, Madhavan AA, Bois MC, Saba L, Savastano L, et al. Reassessing the carotid artery plaque "rim sign" on CTA: a new analysis with histopathologic confirmation. *AJNR Am J Neuroradiol* 2022;43:429-34. https://doi.org/10.3174/ajnr.A7443

38. Eisenmenger LB, Aldred BW, Kim SE, Stoddard GJ, de Havenon A, Treiman GS, et al. Prediction of carotid intraplaque hemorrhage using adventitial calcification and plaque thickness on CTA. *AJNR Am J Neuroradiol* 2016;37:1496-503. https://doi.org/10.3174/ajnr.A4765

39. Saba L, Chen H, Cau R, Rubeis GD, Zhu G, Pisu F, et al. Impact analysis of different CT configurations of carotid artery plaque calcifications on cerebrovascular events. *AJNR Am J Neuroradiol* 2022;43:272-9. https://doi.org/10.3174/ajnr.A7401

40. Saba L, Lai ML, Montisci R, Tamponi E, Sanfilippo R, Faa G, et al. Association between carotid plaque enhancement shown by multidetector CT angiography and histologically validated microvessel density. *Eur Radiol* 2012;22:2237-45. https://doi.org/10.1007/s00330-012-2467-5

41. Song Y, Dang Y, Wang J, Cai H, Feng J, Zhang H, et al. Carotid intraplaque neovascularization predicts ischemic stroke recurrence in patients with carotid atherosclerosis. *Gerontology* 2021;67:144-51. https://doi.org/10.1159/000511360
42. Qiao Y, Etesami M, Astor BC, Zeiler SR, Trout HH III, Wasserman BA. Carotid plaque neovascularization and hemorrhage detected by MR imaging are associated with recent cerebrovascular ischemic events. *AJNR Am J Neuroradiol* 2012;**33**:755–60. https://doi.org/10.3174/ajnr.A2863

43. Romero JM, Babiarz LS, Forero NP, Murphy EK, Schaefer PW, Gonzalez RG, et al. Arterial wall enhancement overlying carotid plaque on CT angiography correlates with symptoms in patients with high grade stenosis. *Stroke* 2009;**40**:1894–6. https://doi.org/10.1161/STROKEAHA.108.529008

44. Poredos P, Gregoric ID, Jezovnik MK. Inflammation of carotid plaques and risk of cerebrovascular events. *Ann Transl Med* 2020;**8**:1281. https://doi.org/10.21037/atm-2020-cass-15

45. Saba L, Cau R, Murgia A, Nicolaides AN, Wintermark M, Castillo M, et al. Carotid plaque-RADS: a novel stroke risk classification system. *JACC Cardiovasc Imaging* 2024;**17**:62–75. https://doi.org/10.1016/j.jcmg.2023.09.005

46. Kamel H, Merkler AE, Iadecola C, Gupta A, Navi BB. Tailoring the approach to embolic stroke of undetermined source: a review. *JAMA Neurol* 2019;**76**:855–61. https://doi.org/10.1001/jamaneurol.2019.0591

47. Ntaios G, Papavasileiou V, Sagris D, Makaritsis K, Vemmos K, Steiner T, et al. Closure of patent foramen ovale versus medical therapy in patients with cryptogenic stroke or transient ischemic attack. Updated systematic review and meta-analysis. *Stroke* 2018;**49**:412–8. https://doi.org/10.1161/strokeaHA.117.020030

48. Kent DM, Saver JL, Kasner SE, Nelson J, Carroll JD, Chatellier G, et al. Heterogeneity of treatment effects in an analysis of pooled individual patient data from randomized trials of device closure of patent foramen ovale after stroke. *JAMA* 2021;**326**:2277–86. https://doi.org/10.1001/jama.2021.20956

49. Pristipino C, Sievert H, D'Ascenzo F, Mas JL, Meier B, Scacciatella P, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. *Eurointervention* 2019;**14**:1389–402. https://doi.org/10.4244/EJL-D-18-00622

50. Elgendy AY, Saver JL, Amin Z, Boudoulas KD, Carroll JD, Elgendy IY, et al. Proposal for updated nomenclature and classification of potential causative mechanism in patent foramen ovale-associated stroke. *JAMA Neurol* 2020;**77**:878–86. https://doi.org/10.1001/jamaneurol.2020.0458

51. Turc G, Lee JY, Brochet E, Kim JS, Song JK, Mas JL, et al. Atrial septal aneurysm, shunt size, and recurrent stroke risk in patients with patent foramen ovale. *J Am Coll Cardiol* 2020;**75**:2312–20. https://doi.org/10.1016/j.jacc.2020.02.068

52. Leung DY, Davidson PM, Cranney GB, Walsh WF. Thromboembolic risks of left atrial thrombus detected by transesophageal echocardiogram. *Am J Cardiol* 1997;**79**:626–9. https://doi.org/10.1016/s0002-9149(96)00828-4

53. Lurie A, Wang J, Hinnegan KJ, McIntyre WF, Belley-Côté EP, Amit G, et al. Prevalence of left atrial thrombus in anticoagulated patients with atrial fibrillation. *J Am Coll Cardiol* 2021;**77**:2875–86. doi:10.1016/j.jacc.2021.04.036

54. Noubiap JJ, Abgaedeng TA, Nloadoumgue AL, Nyaga UF, Kengne AP. Atrial thrombus detection on transoesophageal echocardiography in patients with atrial fibrillation undergoing cardioversion or catheter ablation: a pooled analysis of rates and predictors. *J Cardiovasc Electrophysiol* 2021;**32**:2179–88. https://doi.org/10.1111/jce.15082

55. Omran H, Rang B, Schmidt H, Illen S, Schimpf R, Maccarter D, et al. Incidence of left atrial thrombi in patients in sinus rhythm and with a recent neurologic deficit. *Am Heart J* 2000;**140**:658–62. https://doi.org/10.1067/mhj.2000.109213

56. Mac Grory B, Chang A, Atalay MK, Yaghi S. Left atrial appendage thrombus and embolic stroke. *Stroke* 2018;**49**:e286–9. https://doi.org/10.1161/STROKEAHA.118.022674

57. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. *J Am Coll Cardiol* 1994;**23**:961–9. https://doi.org/10.1016/0735-1097(94)90644-0

58. Talner CN. Report of the New England Regional Infant Cardiac Program, by Donald C. Fyler, MD, pediatrics, 1980; 65(suppl):375–461. *Pediatrics* 1998;**102**:258–9.

59. Hart RG, Pearce LA, Aguilar ML. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. *Ann Intern Med* 2007;**146**:857–67. https://doi.org/10.7326/0003-4819-146-12-200706190-00007

60. Sposato LA, Cipriano LE, Saposnik G, Ruiz Vargas E, Riccio PM, Hachinski V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. *Lancet Neurol* 2015;**14**:377–87. https://doi.org/10.1016/S1474-4422(15)70027-x

61. Schnabel RB, Haeusler KG, Healey JS, Freedman B, Boriani G, Brachmann J, et al. Searching for atrial fibrillation poststroke: a white paper of the AF-SCREEN international collaboration. *Circulation* 2019;**140**:1834–50. https://doi.org/10.1161/circulationaha.119.040267

62. Healey JS, Lopes RD, Granger CB, Alings M, Rivard L, McIntyre WF, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. *N Engl J Med* 2024;**390**:107–17. https://doi.org/10.1056/NEJMoa2310234

63. Kirchhof P, Toennis T, Goette A, Camm AJ, Diener HC, Becher N, et al. Anticoagulation with edoxaban in patients with atrial high-rate episodes. *N Engl J Med* 2023;**389**:1167–79. https://doi.org/10.1056/NEJMoa2303062

64. Van Gelder IC, Healey JS, Cripps H, Wang J, Hohnloser SH, Gold MR, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. *Eur Heart J* 2017;**38**:1339–44. https://doi.org/10.1093/eurheartj/ehx042

65. Singer DE, Ziegler PD, Koehler JL, Sarkar S, Passman RS. Temporal association between episodes of atrial fibrillation and risk of ischemic stroke. *JAMA Cardiol* 2021;**6**:1364–9. https://doi.org/10.1001/jamacardio.2021.3702

66. Singer AJ, Quinn A, Dasgupta N, Thode HC Jr. Management and outcomes of bleeding events in patients in the emergency department taking warfarin or a non-vitamin K antagonist oral anticoagulant. *J Emerg Med* 2017;**52**:1–7 e1. https://doi.org/10.1016/j.jemered.2016.09.028

67. McIntyre WF, Benz AP, Becher N, Healey JS, Granger CB, Rivard L, et al. Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: a study-level meta-analysis of the NOAH-AFNET 6 and ARTESiA trials. *Circulation* 2023. https://doi.org/10.1161/CIRCULATIONAHA.123.067512

68. Becher N, Toennis T, Bertaglia E, Blomström-Lundqvist C, Brandes A, Cabanelas N, et al. Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h. *Eur Heart J* 2023;**45**:837–849. https://doi.org/10.1093/eurheartj/ehd771.

69. Perlepe K, Sirimarco G, Strambo D, Eskandari A, Karagkiozi E, Vemmou A, et al. Left atrial diameter thresholds and new incident atrial fibrillation in embolic stroke of undetermined source. *Eur J Intern Med* 2020;**75**:30–4. https://doi.org/10.1016/j.ejim.2020.01.002

70. Di Tullio MR, Sacco RL, Sciacca RR, Homma S. Left atrial size and the risk of ischemic stroke in an ethnically mixed population. *Stroke* 1999;**30**:2019–24. https://doi.org/10.1161/01.str.30.10.2019

71. Yaghi S, Moon YP, Mora-Mclaughlin C, Willey JZ, Cheung K, Di Tullio MR, et al. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. *Stroke* 2015;**46**:1488–93. https://doi.org/10.1161/STROKEAHA.115.008711

72. Kamel H, O'Neal WT, Okin PM, Loehr LR, Alonso A, Soliman EZ. Electrocardiographic left atrial abnormality and stroke subtype in the atherosclerosis risk in communities study. *Ann Neurol* 2015;**78**:670–8. https://doi.org/10.1002/ana.24482

73. Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial fibrillation and mechanisms of stroke: time for a new model. *Stroke* 2016;**47**:895–900. https://doi.org/10.1161/STROKEAHA.115.012004

74. Healey JS, Gladstone DJ, Swaminathan B, Eckstein J, Mundl H, Epstein AE, et al. Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial. *JAMA Neurol* 2019;**76**:764–73. https://doi.org/10.1001/jamaneurol.2019.0617.

75. Kamel H, Longstreth WT Jr, Tirschwell DL, Kronmal RA, Marshall RS, Broderick JP, et al; ARCADIA Investigators. Apixaban to prevent recurrence after cryptogenic stroke in patients with atrial cardiopathy: the ARCADIA randomized clinical trial. *JAMA* 2024;**331**:573–581. https://doi.org/10.1001/jama.2023.27188

76. Yang M, Kondo T, Butt JH, Abraham WT, Anand IS, Desai AS, et al. Stroke in patients with heart failure and reduced or preserved ejection fraction. *Eur Heart J* 2023;**44**:2998–3013. https://doi.org/10.1093/eurheartj/ehd338

77. Cohen A, Donal E, Delgado V, Pepi M, Tsang T, Gerber B, et al. EACVI recommendations on cardiovascular imaging for the detection of embolic sources: endorsed by the Canadian Society of Echocardiography. *Eur Heart J Cardiovasc Imaging* 2021;**22**:e24–57. https://doi.org/10.1093/ehjci/jeab008

78. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. *N Engl J Med* 2012;**366**:1859–69. https://doi.org/10.1056/NEJMoa1202299

79. Li W, Seo J, Kokkinidis DG, Palaiodimos L, Nagraj S, Korompoki E, et al. Efficacy and safety of vitamin-K antagonists and direct oral anticoagulants for stroke prevention in patients with heart failure and sinus rhythm: an updated systematic review and meta-analysis of randomized clinical trials. *Int J Stroke* 2023;**18**:392–9. https://doi.org/10.1177/17474930221109149

80. El-Am EA, Dispenzieri A, Grogan M, Nkomo VT. Reply: cardiac amyloidosis, atrial arrhythmias, thrombus, and stroke: a vexing problem. *J Am Coll Cardiol* 2019;**73**:2911–3. https://doi.org/10.1016/j.jacc.2019.04.005

81. Habib G, Harron P, Eicher JC, Giorgi R, Donal E, Laperche T, et al. Isolated left ventricular non-compaction in adults: clinical and echocardiographic features in 105 patients. Results from a French registry. *Eur J Heart Fail* 2011;**13**:177–85. https://doi.org/10.1093/eurjhf/hfq225

82. Levine GN, McEvoy JW, Fang JC, Ibeh C, McCarthy CP, Misra A, et al. Management of patients at risk for and with left ventricular thrombus: a scientific statement from the American Heart Association. *Circulation* 2022;**146**:e205–23. https://doi.org/10.1161/CIR.00000000000001092

83. Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: executive summary. *Heart Rhythm* 2019;**16**:e373–407. https://doi.org/10.1016/j.hrthm.2019.09.019
42. Qiao Y, Etesami M, Astor BC, Zeiler SR, Trout HH III, Wasserman BA. Carotid plaque neovascularization and hemorrhage detected by MR imaging are associated with recent cerebrovascular ischemic events. *AJNR Am J Neuroradiol* 2012;33:755-60. https://doi.org/10.3174/ajnr.A2863

43. Romero JM, Babiarz LS, Forero NP, Murphy EK, Schaefer PW, Gonzalez RG, et al. Arterial wall enhancement overlying carotid plaque on CT angiography correlates with symptoms in patients with high grade stenosis. *Stroke* 2009;40:1894-6. https://doi.org/10.1161/STROKEAHA.108.529008

44. Poredos P, Gregoric ID, Jezovnik MK. Inflammation of carotid plaques and risk of cerebrovascular events. *Ann Transl Med* 2020;8:1281. https://doi.org/10.21037/atm-2020-cass-15

45. Saba L, Cau R, Murgia A, Nicolaides AN, Wintermark M, Castillo M, et al. Carotid plaque-RADS: a novel stroke risk classification system. *JACC Cardiovasc Imaging* 2024;17:62-75. https://doi.org/10.1016/j.jcmg.2023.09.005

46. Kamel H, Merkler AE, Iadecola C, Gupta A, Navi BB. Tailoring the approach to embolic stroke of undetermined source: a review. *JAMA Neurol* 2019;76:855-61. https://doi.org/10.1001/jamaneurol.2019.0591

47. Ntaios G, Papavasileiou V, Sagris D, Makaritsis K, Vemmos K, Steiner T, et al. Closure of patent foramen ovale versus medical therapy in patients with cryptogenic stroke or transient ischemic attack. Updated systematic review and meta-analysis. *Stroke* 2018;49:412-8. https://doi.org/10.1161/strokeaHA.117.020030

48. Kent DM, Saver JL, Kasner SE, Nelson J, Carroll JD, Chatellier G, et al. Heterogeneity of treatment effects in an analysis of pooled individual patient data from randomized trials of device closure of patent foramen ovale after stroke. *JAMA* 2021;326:2277-86. https://doi.org/10.1001/jama.2021.20956

49. Pristipino C, Sievert H, D'Ascenzo F, Mas JL, Meier B, Scacciatella P, et al. European position paper on the management of patients with patent foramen ovale. General approach and left circulation thromboembolism. *Eurointervention* 2019;14:1389-402. https://doi.org/10.4244/EJL-D-18-00622

50. Elgendy AY, Saver JL, Amin Z, Boudoulas KD, Carroll JD, Elgendy IY, et al. Proposal for updated nomenclature and classification of potential causative mechanism in patent foramen ovale-associated stroke. *JAMA Neurol* 2020;77:878-86. https://doi.org/10.1001/jamaneurol.2020.0458

51. Turc G, Lee JY, Brochet E, Kim JS, Song JK, Mas JL, et al. Atrial septal aneurysm, shunt size, and recurrent stroke risk in patients with patent foramen ovale. *J Am Coll Cardiol* 2020;75:2312-20. https://doi.org/10.1016/j.jacc.2020.02.068

52. Leung DY, Davidson PM, Cranney GB, Walsh WF. Thromboembolic risks of left atrial thrombus detected by transesophageal echocardiogram. *Am J Cardiol* 1997;79:626-9. https://doi.org/10.1016/s0002-9149(96)00828-4

53. Lurie A, Wang J, Hinnegan KJ, McIntyre WF, Belley-Côté EP, Amit G, et al. Prevalence of left atrial thrombus in anticoagulated patients with atrial fibrillation. *J Am Coll Cardiol* 2021;77:2875-86. doi:10.1016/j.jacc.2021.04.036

54. Noubiap JJ, Abgaedeng TA, Nloadoumgue AL, Nyaga UF, Kengne AP. Atrial thrombus detection on transoesophageal echocardiography in patients with atrial fibrillation undergoing cardioversion or catheter ablation: a pooled analysis of rates and predictors. *J Cardiovasc Electrophysiol* 2021;32:2179-88. https://doi.org/10.1111/jce.15082

55. Omran H, Rang B, Schmidt H, Illen S, Schimpf R, Maccarter D, et al. Incidence of left atrial thrombi in patients in sinus rhythm and with a recent neurologic deficit. *Am Heart J* 2000;**140**:658-62. https://doi.org/10.1067/mhj.2000.109213

56. Mac Grory B, Chang A, Atalay MK, Yaghi S. Left atrial appendage thrombus and embolic stroke. *Stroke* 2018;49:e286-9. https://doi.org/10.1161/STROKEAHA.118.022674

57. Fatkin D, Kelly RP, Feneley MP. Relations between left atrial appendage blood flow velocity, spontaneous echocardiographic contrast and thromboembolic risk in vivo. *J Am Coll Cardiol* 1994;23:961-9. https://doi.org/10.1016/0735-1097(94)90644-0

58. Talner CN. Report of the New England Regional Infant Cardiac Program, by Donald C. Fyler, MD, pediatrics, 1980; 65(suppl):375-461. *Pediatrics* 1998;102:258-9.

59. Hart RG, Pearce LA, Aguilar ML. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. *Ann Intern Med* 2007;**146**:857-67. https://doi.org/10.7326/0003-4819-146-12-200706190-00007

60. Sposato LA, Cipriano LE, Saposnik G, Ruiz Vargas E, Riccio PM, Hachinski V. Diagnosis of atrial fibrillation after stroke and transient ischaemic attack: a systematic review and meta-analysis. *Lancet Neurol* 2015;**14**:377-87. https://doi.org/10.1016/S1474-4422(15)70027-x

61. Schnabel RB, Haeusler KG, Healey JS, Freedman B, Boriani G, Brachmann J, et al. Searching for atrial fibrillation poststroke: a white paper of the AF-SCREEN international collaboration. *Circulation* 2019;140:1834-50. https://doi.org/10.1161/circulationaha.119.040267

62. Healey JS, Lopes RD, Granger CB, Alings M, Rivard L, McIntyre WF, et al. Apixaban for stroke prevention in subclinical atrial fibrillation. *N Engl J Med* 2024;**390**:107-17. https://doi.org/10.1056/NEJMoa2310234

63. Kirchhof P, Toennis T, Goette A, Camm AJ, Diener HC, Becher N, et al. Anticoagulation with edoxaban in patients with atrial high-rate episodes. *N Engl J Med* 2023;**389**:1167-79. https://doi.org/10.1056/NEJMoa2303062

64. Van Gelder IC, Healey JS, Cripps H, Wang J, Hohnloser SH, Gold MR, et al. Duration of device-detected subclinical atrial fibrillation and occurrence of stroke in ASSERT. *Eur Heart J* 2017;**38**:1339-44. https://doi.org/10.1093/eurheartj/ehx042

65. Singer DE, Ziegler PD, Koehler JL, Sarkar S, Passman RS. Temporal association between episodes of atrial fibrillation and risk of ischemic stroke. *JAMA Cardiol* 2021;6:1364-9. https://doi.org/10.1001/jamacardio.2021.3702

66. Singer AJ, Quinn A, Dasgupta N, Thode HC Jr. Management and outcomes of bleeding events in patients in the emergency department taking warfarin or a non-vitamin K antagonist oral anticoagulant. *J Emerg Med* 2017;52:1-7 e1. https://doi.org/10.1016/j.emermed.2016.09.028

67. McIntyre WF, Benz AP, Becher N, Healey JS, Granger CB, Rivard L, et al. Direct oral anticoagulants for stroke prevention in patients with device-detected atrial fibrillation: a study-level meta-analysis of the NOAH-AFNET 6 and ARTESiA trials. *Circulation* 2023. https://doi.org/10.1161/CIRCULATIONAHA.123.067512

68. Becher N, Toennis T, Bertaglia E, Blomström-Lundqvist C, Brandes A, Cabanelas N, et al. Anticoagulation with edoxaban in patients with long atrial high-rate episodes ≥24 h. *Eur Heart J* 2023;45:837-849. https://doi.org/10.1093/eurheartj/ehd771.

69. Perlepe K, Sirimarco G, Strambo D, Eskandari A, Karagkiozi E, Vemmou A, et al. Left atrial diameter thresholds and new incident atrial fibrillation in embolic stroke of undetermined source. *Eur J Intern Med* 2020;**75**:30-4. https://doi.org/10.1016/j.ejim.2020.01.002

70. Di Tullio MR, Sacco RL, Sciacca RR, Homma S. Left atrial size and the risk of ischemic stroke in an ethnically mixed population. *Stroke* 1999;**30**:2019-24. https://doi.org/10.1161/01.str.30.10.2019

71. Yaghi S, Moon YP, Mora-Mclaughlin C, Willey JZ, Cheung K, Di Tullio MR, et al. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. *Stroke* 2015;**46**:1488-93. https://doi.org/10.1161/STROKEAHA.115.008711

72. Kamel H, O'Neal WT, Okin PM, Loehr LR, Alonso A, Soliman EZ. Electrocardiographic left atrial abnormality and stroke subtype in the atherosclerosis risk in communities study. *Ann Neurol* 2015;**78**:670-8. https://doi.org/10.1002/ana.24482

73. Kamel H, Okin PM, Elkind MS, Iadecola C. Atrial fibrillation and mechanisms of stroke: time for a new model. *Stroke* 2016;**47**:895-900. https://doi.org/10.1161/STROKEAHA.115.012004

74. Healey JS, Gladstone DJ, Swaminathan B, Eckstein J, Mundl H, Epstein AE, et al. Recurrent stroke with rivaroxaban compared with aspirin according to predictors of atrial fibrillation: secondary analysis of the NAVIGATE ESUS randomized clinical trial. *JAMA Neurol* 2019;**76**:764-73. https://doi.org/10.1001/jamaneurol.2019.0617.

75. Kamel H, Longstreth WT Jr, Tirschwell DL, Kronmal RA, Marshall RS, Broderick JP, et al; ARCADIA Investigators. Apixaban to prevent recurrence after cryptogenic stroke in patients with atrial cardiopathy: the ARCADIA randomized clinical trial. *JAMA* 2024;**331**:573-581. https://doi.org/10.1001/jama.2023.27188

76. Yang M, Kondo T, Butt JH, Abraham WT, Anand IS, Desai AS, et al. Stroke in patients with heart failure and reduced or preserved ejection fraction. *Eur Heart J* 2023;**44**:2998-3013. https://doi.org/10.1093/eurheartj/ehd338

77. Cohen A, Donal E, Delgado V, Pepi M, Tsang T, Gerber B, et al. EACVI recommendations on cardiovascular imaging for the detection of embolic sources: endorsed by the Canadian Society of Echocardiography. *Eur Heart J Cardiovasc Imaging* 2021;**22**:e24-57. https://doi.org/10.1093/ehjci/jeab008

78. Homma S, Thompson JL, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. *N Engl J Med* 2012;**366**:1859-69. https://doi.org/10.1056/NEJMoa1202299

79. Li W, Seo J, Kokkinidis DG, Palaiodimos L, Nagraj S, Korompoki E, et al. Efficacy and safety of vitamin-K antagonists and direct oral anticoagulants for stroke prevention in patients with heart failure and sinus rhythm: an updated systematic review and meta-analysis of randomized clinical trials. *Int J Stroke* 2023;**18**:392-9. https://doi.org/10.1177/17474930221109149

80. El-Am EA, Dispenzieri A, Grogan M, Nkomo VT. Reply: cardiac amyloidosis, atrial arrhythmias, thrombus, and stroke: a vexing problem. *J Am Coll Cardiol* 2019;**73**:2911-3. https://doi.org/10.1016/j.jacc.2019.04.005

81. Habib G, Harron P, Eicher JC, Giorgi R, Donal E, Laperche T, et al. Isolated left ventricular non-compaction in adults: clinical and echocardiographic features in 105 patients. Results from a French registry. *Eur J Heart Fail* 2011;**13**:177-85. https://doi.org/10.1093/eurjhf/hfq225

82. Levine GN, McEvoy JW, Fang JC, Ibeh C, McCarthy CP, Misra A, et al. Management of patients at risk for and with left ventricular thrombus: a scientific statement from the American Heart Association. *Circulation* 2022;**146**:e205-23. https://doi.org/10.1161/CIR.00000000000001092

83. Towbin JA, McKenna WJ, Abrams DJ, Ackerman MJ, Calkins H, Darrieux FCC, et al. 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy: executive summary. *Heart Rhythm* 2019;**16**:e373-407. https://doi.org/10.1016/j.hrthm.2019.09.019
84. Chen L, Yan S, He Y, Zhong W, Gong X, Lou M, et al. Prediction of acute myocardial infarction in Asian patients with acute ischemic stroke: the CTRAN score. JACC Asia 2022;2:845-52. https://doi.org/10.1016/j.jacasi.2022.08.008

85. Boivin-Proulx LA, Ieroncig F, Demers SP, Nozza A, Soltani M, Ghersi I, et al. Contemporary incidence and predictors of left ventricular thrombus in patients with anterior acute myocardial infarction. Clin Res Cardiol 2023;112:558-65. https://doi.org/10.1007/s00392-023-02158-8

86. Thuny F, Di Salvo G, Belliard O, Avierinos JF, Pergola V, Rosenberg V, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005;112:69-75. https://doi.org/10.1161/CIRCULATIONAHA.104.493155

87. Arregle F, Martel H, Philip M, Gouriet F, Casalta JP, Riberi A, et al. Infective endocarditis with neurological complications: delaying cardiac surgery is associated with worse outcome. Arch Cardiovasc Dis 2021;114:527-36. https://doi.org/10.1016/j.acvd.2021.01.004

88. Quintero-Martinez JA, Hindy JR, El Zein S, Michelena HI, Nkomo VT, DeSimone DC, et al. Contemporary demographics, diagnostics and outcomes in non-bacterial thrombotic endocarditis. Heart 2022;108:heartjnl-2022-320970. https://doi.org/10.1136/heartjnl-2022-320970

89. Breithardt G, Baumgartner H, Berkowitz SD, Hellkamp AS, Piccini JP, Stevens SR, et al. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur Heart J 2014;35:3377-85. https://doi.org/10.1093/eurheartj/ehu305

90. Steiner DK, Sogaard P, Jensen M, Bjerregatta Larsen T, Lip GYH, Nielsen PB. Risk of stroke or systemic embolism in patients with degenerative mitral stenosis with or without atrial fibrillation: a cohort study. Int J Cardiol Heart Vasc 2022;43:101126. https://doi.org/10.1016/j.ijcha.2022.101126

91. Okura H, Nakada Y, Nogi M, Ishihara S, Okamura A, Okayama S, et al. Prevalence of mitral annular calcification and its association with mitral valvular disease. Echocardiography 2021;38:1907-12. https://doi.org/10.1111/echo.15236

92. Suhai Fl, Varga A, Szilveszter B, Nagy-Vecsey M, Apor A, Nagy AI, et al. Predictors and neurological consequences of periprocedural cerebrovascular events following transcatheter aortic valve implantation with self-expanding valves. Front Cardiovasc Med 2022;9:951943. https://doi.org/10.3389/fcmv.2022.951943

93. Ishizuka K, Hoshino T, Ashihara K, Mruyama K, Toi S, Mizuno S, et al. Associations of mitral and aortic valve calcifications with complex aortic atheroma in patients with embolic stroke of undetermined source. J Stroke Cerebrovasc Dis 2018;27:697-702. https://doi.org/10.1016/j.jstrotecerebrovasdis.2017.09.057

94. Leitman M, Tyomkin V, Peleg E, Shmueli R, Krakover R, Vered Z. Clinical significance and prevalence of valvular strands during routine echo examinations. Eur Heart J Cardiovascular Imaging 2014;15:1226-30. https://doi.org/10.1093/ehjci/jeu110

95. Salehi Omran S, Chaker S, Lerario MP, Merkler AE, Navi BB, Kamel H. Relationship between Lamb's excrescences and embolic strokes of undetermined source. Eur Stroke J 2020;5:169-73. https://doi.org/10.1177/2396987319901201

96. Navi BB, Iadecola C. Ischemic stroke in cancer patients: a review of an underappreciated pathology. Neurol 2018;83:873-83. https://doi.org/10.1002/ana.25227

97. Navi BB, Singer S, Merkler AE, Cheng NT, Stone JB, Kamel H, et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014;83:26-33. https://doi.org/10.1212/WNL.0000000000000539

98. Navi BB, Reiner AS, Kamel H, Iadecola C, Okin PM, Tagawa ST, et al. Arterial thromboembolic events preceding the diagnosis of cancer in older persons. Blood 2019;133:781-9. https://doi.org/10.1182/blood-2018-06-860874

99. Selvik HA, Bjerkreim AT, Thomassen L, Waje-Andreassen U, Naess H, Kvistad CE. When to screen ischaemic stroke patients for cancer. Cerebrovasc Dis 2018;45:42-7. https://doi.org/10.1159/000484668

100. Gon Y, Sakaguchi M, Takasugi J, Kawano T, Kanki H, Watanabe A, et al. Plasma d-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. Eur J Neurol 2017;24:503-8. https://doi.org/10.1111/ene.13234

101. Cocho D, Gendre J, Boltes A, Espinosa J, Ricciardi AC, Pons J, et al. Predictors of occult cancer in acute ischemic stroke patients. J Stroke Cerebrovasc Dis 2015;24:1324-8. https://doi.org/10.1016/j.jstrokecerebrovasdis.2015.02.006

102. Beyeler M, Birner B, Branca M, Meinel T, Vynckier J, Buffle E, et al. Development of a score for prediction of occult malignancy in stroke patients (occult-5 score). J Stroke Cerebrovasc Dis 2022;31:106609. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106609

103. Navi BB, Reiner AS, Kamel H, Iadecola C, Elkind MS, Panageas KS, et al. Association between incident cancer and subsequent stroke. Ann Neurol 2015;77:291-300. https://doi.org/10.1002/ana.24325

104. Otite FO, Somani S, Aneni E, Akano E, Patel SD, Anikpezie N, et al. Trends in age and sex-specific prevalence of cancer and cancer subtypes in acute ischemic stroke from 2007-2019. J Stroke Cerebrovasc Dis 2022;31:106818. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106818

105. Navi BB, Kasner SE, Elkind MSV, Cushman M, Bang OY, DeAngelis LM. Cancer and embolic stroke of undetermined source. Stroke 2021;52:1121-30. https://doi.org/10.1161/STROKEAHA.120.032002

106. Navi BB, Sherman CP, Genova R, Mathias R, Lansdale KN, LeMoss NM, et al. Mechanisms of ischemic stroke in patients with cancer: a prospective study. Ann Neurol 2021;90:159-69. https://doi.org/10.1002/ana.26129

107. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16-35. https://doi.org/10.1097/00005792-198501000-00002

108. Hurrell H, Roberts-Thomson R, Prendergast BD. Non-infective endocarditis. Heart 2020;106:1023-9. https://doi.org/10.1136/heartjnl-2019-315204

109. Merkler AE, Navi BB, Singer S, Cheng NT, Stone JB, Kamel H, et al. Diagnostic yield of echocardiography in cancer patients with ischemic stroke. J Neurooncol 2015;123:115-21. https://doi.org/10.1007/s11060-015-1768-3

110. Park H, Kim J, Ha J, Hwang IG, Song TJ, Yoo J, et al. Histological features of intracranial thrombi in stroke patients with cancer. Ann Neurol 2019;86:143-9. https://doi.org/10.1002/ana.25495

111. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001;86:1327-30.

112. Bang OY, Chung JW, Cho YH, Oh MJ, Seo WK, Kim GM, et al. Circulating DNAs, a marker of neutrophil extracellular traposis and cancer-related stroke: the OASIS-cancer study. Stroke 2019;50:2944-7. https://doi.org/10.1161/STROKEAHA.119.062373

113. Gon Y, Okazaki S, Terasaki Y, Sasaki T, Yoshimine T, Sakaguchi M, et al. Characteristics of cryptogenic stroke in cancer patients. Ann Clin Transl Neurol 2016;3:280-7. https://doi.org/10.1002/actn.3.291

114. Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012;43:3029-34. https://doi.org/10.1161/STROKEAHA.112.658625

115. Nam KW, Kim CK, Kim TJ, An SJ, Demchuk AM, Kim Y, et al. d-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer. Eur J Neurol 2017;24:205-11. https://doi.org/10.1111/ene.13184

116. Finelli PF, Nouh A. Three-territory DWI acute infarcts: diagnostic value in cancer-associated hypercoagulation stroke (Troussseau syndrome). AJNR Am J Neuroradiol 2016;37:2033-6. https://doi.org/10.3174/ajnr.A4846

117. Navi BB, Zhang C, Sherman CP, Genova R, LeMoss NM, Kamel H, et al. Ischemic stroke with cancer: hematologic and embolic biomarkers and clinical outcomes. J Thromb Haemost 2020;22:2046-57. https://doi.org/10.1111/jth.15779

118. Seok JM, Kim SG, Kim JW, Chung CS, Kim GM, Lee KH, et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010;68:213-9. https://doi.org/10.1002/ana.22050

119. Rioux B, Touma L, Nehme A, Gore G, Keezer MR, Gioia LC. Frequency and predictors of occult cancer in ischemic stroke: a systematic review and meta-analysis. Int J Stroke 2021;16:12-9. https://doi.org/10.1177/1747493020971104

120. Hasegawa Y, Setoguchi T, Sakaida T, luchi T. Utility of a scoring system for differentiating cancer-associated stroke from cryptogenic stroke in patients with cancer. Neurol Sci 2020;41:1245-50. https://doi.org/10.1007/s10072-019-04231-5

121. Nezu T, Hosomi N, Naito H, Aoki S, Torii T, Kurashige T, et al. Clinical characteristics and tumor markers in ischemic stroke patients with active cancer. Intern Emerg Med 2022;17:735-41. https://doi.org/10.1007/s11739-021-02862-1

122. Abdelsam M, Abu-Hegazy M, El-Hadaad HA, Wahba H, Egila H, Esmael A. Pathophysiology, mechanism, and outcome of ischemic stroke in cancer patients. J Stroke Cerebrovasc Dis 2020;29:105299. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105299

123. Navi BB, Kawaguchi K, Hriljac I, Lavi E, DeAngelis LM, Jamieson DG. Multifocal stroke from tumor emboli. Arch Neurol 2009;66:1174-5. https://doi.org/10.1001/archneurol.2009.172

124. Kitano T, Sasaki T, Gon Y, Todo K, Okazaki S, Kitamura T, et al. The effect of chemotherapy on stroke risk in cancer patients. Thromb Haemost 2020;120:714-23. https://doi.org/10.1055/s-0040-1708484

125. Parikh NS, Burch JE, Kamel H, DeAngelis LM, Navi BB. Recurrent thromboembolic events after ischemic stroke in patients with primary brain tumors. J Stroke Cerebrovasc Dis 2017;26:2396-403. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.031

126. Ntaios G, Omran SS. Diagnostic challenges and uncertainties of embolic strokes of undetermined source in young adults. JAMA Neurol 2022;79:444-7. https://doi.org/10.1001/jamaneurol.2022.00058

127. Ntaios G, Perlepe K, Lambrou D, Sirimarco G, Strambo D, Eskandari A, et al. Identification of patients with embolic stroke of undetermined source and low risk of new incident atrial fibrillation: the AF-ESUS score. Int J Stroke 2021;16:29-38. https://doi.org/10.1177/1747493020925281
84. Chen L, Yan S, He Y, Zhong W, Gong X, Lou M, et al. Prediction of acute myocardial infarction in Asian patients with acute ischemic stroke: the CTRAN score. JACC Asia 2022;2:845-52. https://doi.org/10.1016/j.jacasi.2022.08.008

85. Boivin-Proulx LA, Ieroncig F, Demers SP, Nozza A, Soltani M, Ghersi I, et al. Contemporary incidence and predictors of left ventricular thrombus in patients with anterior acute myocardial infarction. Clin Res Cardiol 2023;112:558-65. https://doi.org/10.1007/s00392-023-02158-8

86. Thuny F, Di Salvo G, Belliard O, Avierinos JF, Pergola V, Rosenberg V, et al. Risk of embolism and death in infective endocarditis: prognostic value of echocardiography: a prospective multicenter study. Circulation 2005;112:69-75. https://doi.org/10.1161/CIRCULATIONAHA.104.493155

87. Arregle F, Martel H, Philip M, Gouriet F, Casalta JP, Riberi A, et al. Infective endocarditis with neurological complications: delaying cardiac surgery is associated with worse outcome. Arch Cardiovasc Dis 2021;114:527-36. https://doi.org/10.1016/j.acvd.2021.01.004

88. Quintero-Martinez JA, Hindy JR, El Zein S, Michelena HI, Nkomo VT, DeSimone DC, et al. Contemporary demographics, diagnostics and outcomes in non-bacterial thrombotic endocarditis. Heart 2022;108:heartjnl-2022-320970. https://doi.org/10.1136/heartjnl-2022-320970

89. Breithardt G, Baumgartner H, Berkowitz SD, Hellkamp AS, Piccini JP, Stevens SR, et al. Clinical characteristics and outcomes with rivaroxaban vs. warfarin in patients with non-valvular atrial fibrillation but underlying native mitral and aortic valve disease participating in the ROCKET AF trial. Eur Heart J 2014;35:3377-85. https://doi.org/10.1093/eurheartj/ehu305

90. Steiner DK, Sogaard P, Jensen M, Bjerregatta Larsen T, Lip GYH, Nielsen PB. Risk of stroke or systemic embolism in patients with degenerative mitral stenosis with or without atrial fibrillation: a cohort study. Int J Cardiol Heart Vasc 2022;43:101126. https://doi.org/10.1016/j.ijcha.2022.101126

91. Okura H, Nakada Y, Nogi M, Ishihara S, Okamura A, Okayama S, et al. Prevalence of mitral annular calcification and its association with mitral valvular disease. Echocardiography 2021;38:1907-12. https://doi.org/10.1111/echo.15236

92. Suhai Fl, Varga A, Szilveszter B, Nagy-Vecsey M, Apor A, Nagy AI, et al. Predictors and neurological consequences of periprocedural cerebrovascular events following transcatheter aortic valve implantation with self-expanding valves. Front Cardiovasc Med 2022;9:951943. https://doi.org/10.3389/fcmv.2022.951943

93. Ishizuka K, Hoshino T, Ashihara K, Mruyama K, Toi S, Mizuno S, et al. Associations of mitral and aortic valve calcifications with complex aortic atheroma in patients with embolic stroke of undetermined source. J Stroke Cerebrovasc Dis 2018;27:697-702. https://doi.org/10.1016/j.jstrotecerebrovasdis.2017.09.057

94. Leitman M, Tyomkin V, Peleg E, Shmueli R, Krakover R, Vered Z. Clinical significance and prevalence of valvular strands during routine echo examinations. Eur Heart J Cardiovascular Imaging 2014;15:1226-30. https://doi.org/10.1093/ehjci/jeu110

95. Salehi Omran S, Chaker S, Lerario MP, Merkler AE, Navi BB, Kamel H. Relationship between Lamb's excrescences and embolic strokes of undetermined source. Eur Stroke J 2020;5:169-73. https://doi.org/10.1177/2396987319901201

96. Navi BB, Iadecola C. Ischemic stroke in cancer patients: a review of an underappreciated pathology. Neurol 2018;83:873-83. https://doi.org/10.1002/ana.25227

97. Navi BB, Singer S, Merkler AE, Cheng NT, Stone JB, Kamel H, et al. Recurrent thromboembolic events after ischemic stroke in patients with cancer. Neurology 2014;83:26-33. https://doi.org/10.1212/WNL.0000000000000539

98. Navi BB, Reiner AS, Kamel H, Iadecola C, Okin PM, Tagawa ST, et al. Arterial thromboembolic events preceding the diagnosis of cancer in older persons. Blood 2019;133:781-9. https://doi.org/10.1182/blood-2018-06-860874

99. Selvik HA, Bjerkreim AT, Thomassen L, Waje-Andreassen U, Naess H, Kvistad CE. When to screen ischaemic stroke patients for cancer. Cerebrovasc Dis 2018;45:42-7. https://doi.org/10.1159/000484668

100. Gon Y, Sakaguchi M, Takasugi J, Kawano T, Kanki H, Watanabe A, et al. Plasma d-dimer levels and ischaemic lesions in multiple vascular regions can predict occult cancer in patients with cryptogenic stroke. Eur J Neurol 2017;24:503-8. https://doi.org/10.1111/ene.13234

101. Cocho D, Gendre J, Boltes A, Espinosa J, Ricciardi AC, Pons J, et al. Predictors of occult cancer in acute ischemic stroke patients. J Stroke Cerebrovasc Dis 2015;24:1324-8. https://doi.org/10.1016/j.jstrotecerebrovasdis.2015.02.006

102. Beyeler M, Birner B, Branca M, Meinel T, Vynckier J, Buffle E, et al. Development of a score for prediction of occult malignancy in stroke patients (occult-5 score). J Stroke Cerebrovasc Dis 2022;31:106609. https://doi.org/10.1016/j.jstrokecerebrovasdis.2022.106609

103. Navi BB, Reiner AS, Kamel H, Iadecola C, Elkind MS, Panageas KS, et al. Association between incident cancer and subsequent stroke. Ann Neurol 2015;77:291-300. https://doi.org/10.1002/ana.24325

104. Otite FO, Somani S, Aneni E, Akano E, Patel SD, Anikpezie N, et al. Trends in age and sex-specific prevalence of cancer and cancer subtypes in acute ischemic stroke from 2007-2019. J Stroke Cerebrovasc Dis 2022;31:106818. https://doi.org/10.1016/j.jstrotecerebrovasdis.2022.106818

105. Navi BB, Kasner SE, Elkind MSV, Cushman M, Bang OY, DeAngelis LM. Cancer and embolic stroke of undetermined source. Stroke 2021;52:1121-30. https://doi.org/10.1161/STROKEAHA.120.032002

106. Navi BB, Sherman CP, Genova R, Mathias R, Lansdale KN, LeMoss NM, et al. Mechanisms of ischemic stroke in patients with cancer: a prospective study. Ann Neurol 2021;90:159-69. https://doi.org/10.1002/ana.26129

107. Graus F, Rogers LR, Posner JB. Cerebrovascular complications in patients with cancer. Medicine (Baltimore) 1985;64:16-35. https://doi.org/10.1097/00005792-198501000-00002

108. Hurrell H, Roberts-Thomson R, Prendergast BD. Non-infective endocarditis. Heart 2020;106:1023-9. https://doi.org/10.1136/heartjnl-2019-315204

109. Merkler AE, Navi BB, Singer S, Cheng NT, Stone JB, Kamel H, et al. Diagnostic yield of echocardiography in cancer patients with ischemic stroke. J Neurooncol 2015;123:115-21. https://doi.org/10.1007/s11060-015-1768-3

110. Park H, Kim J, Ha J, Hwang IG, Song TJ, Yoo J, et al. Histological features of intracranial thrombi in stroke patients with cancer. Ann Neurol 2019;86:143-9. https://doi.org/10.1002/ana.25495

111. Taylor FB Jr, Toh CH, Hoots WK, Wada H, Levi M; Scientific Subcommittee on Disseminated Intravascular Coagulation (DIC) of the International Society on Thrombosis and Haemostasis (ISTH). Towards definition, clinical and laboratory criteria, and a scoring system for disseminated intravascular coagulation. Thromb Haemost 2001;86:1327-30.

112. Bang OY, Chung JW, Cho YH, Oh MJ, Seo WK, Kim GM, et al. Circulating DNAs, a marker of neutrophil extracellular traposis and cancer-related stroke: the OASIS-cancer study. Stroke 2019;50:2944-7. https://doi.org/10.1161/STROKEAHA.119.062373

113. Gon Y, Okazaki S, Terasaki Y, Sasaki T, Yoshimine T, Sakaguchi M, et al. Characteristics of cryptogenic stroke in cancer patients. Ann Clin Transl Neurol 2016;3:280-7. https://doi.org/10.1002/actn.3.291

114. Schwarzbach CJ, Schaefer A, Ebert A, Held V, Bolognese M, Kablau M, et al. Stroke and cancer: the importance of cancer-associated hypercoagulation as a possible stroke etiology. Stroke 2012;43:3029-34. https://doi.org/10.1161/STROKEAHA.112.658625

115. Nam KW, Kim CK, Kim TJ, An SJ, Demchuk AM, Kim Y, et al. d-dimer as a predictor of early neurologic deterioration in cryptogenic stroke with active cancer. Eur J Neurol 2017;24:205-11. https://doi.org/10.1111/ene.13184

116. Finelli PF, Nouh A. Three-territory DWI acute infarcts: diagnostic value in cancer-associated hypercoagulation stroke (Troussseau syndrome). AJNR Am J Neuroradiol 2016;37:2033-6. https://doi.org/10.3174/ajnr.A4846

117. Navi BB, Zhang C, Sherman CP, Genova R, LeMoss NM, Kamel H, et al. Ischemic stroke with cancer: hematologic and embolic biomarkers and clinical outcomes. J Thromb Haemost 2020;22:2046-57. https://doi.org/10.1111/jth.15779

118. Seok JM, Kim SG, Kim JW, Chung CS, Kim GM, Lee KH, et al. Coagulopathy and embolic signal in cancer patients with ischemic stroke. Ann Neurol 2010;68:213-9. https://doi.org/10.1002/ana.22050

119. Rioux B, Touma L, Nehme A, Gore G, Keezer MR, Gioia LC. Frequency and predictors of occult cancer in ischemic stroke: a systematic review and meta-analysis. Int J Stroke 2021;16:12-9. https://doi.org/10.1177/1747493020971104

120. Hasegawa Y, Setoguchi T, Sakaida T, luchi T. Utility of a scoring system for differentiating cancer-associated stroke from cryptogenic stroke in patients with cancer. Neurol Sci 2020;41:1245-50. https://doi.org/10.1007/s10072-019-04231-5

121. Nezu T, Hosomi N, Naito H, Aoki S, Torii T, Kurashige T, et al. Clinical characteristics and tumor markers in ischemic stroke patients with active cancer. Intern Emerg Med 2022;17:735-41. https://doi.org/10.1007/s11739-021-02862-1

122. Abdelsam M, Abu-Hegazy M, El-Hadaad HA, Wahba H, Egila H, Esmael A. Pathophysiology, mechanism, and outcome of ischemic stroke in cancer patients. J Stroke Cerebrovasc Dis 2020;29:105299. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.105299

123. Navi BB, Kawaguchi K, Hriljac I, Lavi E, DeAngelis LM, Jamieson DG. Multifocal stroke from tumor emboli. Arch Neurol 2009;66:1174-5. https://doi.org/10.1001/archneurol.2009.172

124. Kitano T, Sasaki T, Gon Y, Todo K, Okazaki S, Kitamura T, et al. The effect of chemotherapy on stroke risk in cancer patients. Thromb Haemost 2020;120:714-23. https://doi.org/10.1055/s-0040-1708484

125. Parikh NS, Burch JE, Kamel H, DeAngelis LM, Navi BB. Recurrent thromboembolic events after ischemic stroke in patients with primary brain tumors. J Stroke Cerebrovasc Dis 2017;26:2396-403. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.05.031

126. Ntaios G, Omran SS. Diagnostic challenges and uncertainties of embolic strokes of undetermined source in young adults. JAMA Neurol 2022;79:444-7. https://doi.org/10.1001/jamaneurol.2022.00058

127. Ntaios G, Perlepe K, Lambrou D, Sirimarco G, Strambo D, Eskandari A, et al. Identification of patients with embolic stroke of undetermined source and low risk of new incident atrial fibrillation: the AF-ESUS score. Int J Stroke 2021;16:29-38. https://doi.org/10.1177/1747493020925281
128. Kitsiou A, Sagris D, Schäbitz WR, Ntaios G. Validation of the AF-ESUS score to identify patients with embolic stroke of undetermined source and low risk of device-detected atrial fibrillation. *Eur J Intern Med* 2021;**89**:135–6. https://doi.org/10.1016/j.ejim.2021.04.003

129. Papanagiotou P, Ntaios G. Endovascular thrombectomy in acute ischemic stroke. *Circ Cardiovasc Interv* 2018;**11**:e005362. https://doi.org/10.1161/circinterventions.117.005362

130. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. *N Engl J Med* 2018;**378**:2191–201. https://doi.org/10.1056/NEJMoa1802686

131. Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. *N Engl J Med* 2019;**380**:1906–17. https://doi.org/10.1056/NEJMoa1813959

132. Poli S, Meissner C, Baezner HJ, Kraft A, Hillenbrand F, Hobohm C, et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS) randomized trial—update of patient characteristics and study timeline after interim analysis. *Eur Heart J* 2021;**42**:ehab724.2070. https://doi.org/10.1093/eurheartj/ehab724.2070
128. Kitsiou A, Sagris D, Schäbitz WR, Ntaios G. Validation of the AF-ESUS score to identify patients with embolic stroke of undetermined source and low risk of device-detected atrial fibrillation. *Eur J Intern Med* 2021;**89**:135–6. https://doi.org/10.1016/j.ejim.2021.04.003

129. Papanagiotou P, Ntaios G. Endovascular thrombectomy in acute ischemic stroke. *Circ Cardiovasc Interv* 2018;**11**:e005362. https://doi.org/10.1161/circinterventions.117.005362

130. Hart RG, Sharma M, Mundl H, Kasner SE, Bangdiwala SI, Berkowitz SD, et al. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. *N Engl J Med* 2018;**378**:2191–201. https://doi.org/10.1056/NEJMoa1802686

131. Diener HC, Sacco RL, Easton JD, Granger CB, Bernstein RA, Uchiyama S, et al. Dabigatran for prevention of stroke after embolic stroke of undetermined source. *N Engl J Med* 2019;**380**:1906–17. https://doi.org/10.1056/NEJMoa1813959

132. Poli S, Meissner C, Baezner HJ, Kraft A, Hillenbrand F, Hobohm C, et al. Apixaban for treatment of embolic stroke of undetermined source (ATTICUS) randomized trial—update of patient characteristics and study timeline after interim analysis. *Eur Heart J* 2021;**42**:ehab724.2070. https://doi.org/10.1093/eurheartj/ehab724.2070