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Abstract

Introduction:

Embolic stroke of undetermined source (ESUS) is a common medical challenge regarding secondary prevention strategy. Cardiac imaging is the cornerstone of embolic stroke workup, in an effort to diagnose high risk cardio-embolic sources. Cardiac computed tomography angiography (CCTA) is an emerging imaging modality with high diagnostic performance for intra-cardiac thrombus detection. The yield of CCTA implementation in addition to standard care in ESUS workup is unknown. Thus, the aim of this study was to assess the utility of CCTA in detecting intra-cardiac thrombi in the routine ESUS workup.

Patients and methods:

This is a retrospective observational analysis of ESUS cases managed in vascular neurology unit between 2019 and 2021. Within this ESUS registry, consecutive patients undergoing CCTA were included and carefully analyzed.

Results:

During the study period 1066 Ischemic stroke (IS) cases were treated and evaluated. 266/1066 (25%) met ESUS criteria and 129/266 (48%) underwent CCTA. Intra-cardiac thrombus was detected by CCTA in 22/129 (17%; 95% CI, 11.5%−23.5%) patients: left ventricular thrombus (LVT) in 13 (10.1%) patients, left atrial appendage (LAA) thrombus in 8 (6.2%) patients, and left atrial (LA) thrombus in 1 (0.8%) patient. Only 5/22 (23%) of these thrombi were suspected, but could not be confirmed, in trans-thoracic echocardiogram (TTE). Among CCTA-undergoing patients, 27/129 (21%; 95% CI, 14%−28%) were found to have an indication (including pulmonary embolism) for commencing anticoagulation (AC) treatment, rather than anti-platelets. In favor of CCTA implementation, 22/266 (8.2%; 95% CI, 4.9%−11.5%) patients within the entire ESUS cohort were diagnosed with intra-cardiac thrombus, otherwise missed.

Conclusion:

CCTA improves the detection of intra-cardiac thrombi in addition to standard care in ESUS patients. The implementation of CCTA in routine ESUS workup can change secondary prevention strategy in a considerable proportion of patients.

Graphical abstract

Keywords

Embolic stroke of undetermined source (ESUS)cardiac-CT intra-cardiac thrombus

Introduction

Embolic stroke of undetermined source (ESUS) is an evolving stroke subtype that poses great clinical challenge for secondary prevention strategy.¹ One main aim of ESUS workup is to detect cardiac sources of embolism, such as intra-cardiac thrombi that indicates commencing anti-coagulants (AC).² However, according to current stroke prevention guidelines, the use of advanced cardiac imaging is not obligatory and might be reasonable (class IIb recommendation) in ESUS cases,¹ as data supporting this strategy is scarce.

While echocardiography is still the mainstay of post-stroke cardiac imaging,³ reports on cardiac computed tomography angiography (CCTA) in ischemic stroke (IS) of presumed cardiac source, have been increasingly published in recent years,⁴ and CCTA has become a promising imaging modality for more reliable detection of intra-cardiac thrombi.⁵ Relying on the preliminary published experience of implementing CCTA in IS workup,^6–8 our hospital’s vascular neurology unit adopted this strategy as a supplemental imaging modality in ESUS workup, since 2019. According to this diagnostic strategy, ESUS cases that are not considered for transesophageal echocardiography (TEE) as standard of care, would undergo CCTA as advanced cardiac imaging for major cardio-embolic source detection.

In the present study, we evaluated the impact of CCTA in the diagnosis of intra-cardiac thrombus, in a consecutive group of patients hospitalized with the diagnosis of ESUS. In addition, we tested the impact of CCTA findings on medical management.

Methods

Study design: A retrospective observational study.

Study population: Data of all patients hospitalized due to IS in the stroke unit or neurology department in Beilinson hospital, Israel, between April 1st 2019 and October 1st 2021, were included. The data was extracted from the institutional medical records registrar, relying on discharge diagnosis of all subtypes of IS. Patients with transient ischemic attack (TIA) were excluded. All imaging and medical records were reviewed by an expert stroke neurologist in order to determine whether the IS could be labeled as ESUS. According to accepted criteria,⁹ that were used in the two completed major ESUS trials,^10,11 ESUS was defined as a non-lacunar stroke, with absence of past or present atrial fibrillation (AF) in baseline electrocardiogram (ECG) and in-hospital continuous cardiac telemetry monitoring of at least 20 h duration, absence of other proven cardiac source of embolism by non-contrast transthoracic echocardiogram (NCTTE), and absence of ipsilateral arterial luminal stenosis of more than 50% on vascular imaging. Patients who met these accepted published criteria for diagnosis of ESUS,⁹ formed an ESUS registry. Within this registry, patients who underwent CCTA as part of their stroke workup, formed a consecutive designated cohort that was used for this study. Medical records of ESUS patients who did not undergo CCTA were also reviewed, in order to evaluate the clinical considerations for not performing CCTA in ESUS cases, or preferring transesophageal echocardiography (TEE) over CCTA.

Data collection: Demographic and clinical data were collected via computerized medical records. Covariates of interest were selected upon previous knowledge regarding their relationship with stroke and cardiac pathologies such as ischemic heart disease (IHD) and atrial fibrillation (AF). Baseline characteristics included age, sex, smoking (never/pervious/current) and major comorbidities: hypertension (HTN), diabetes mellitus (DM), ischemic heart disease (IHD), congestive heart failure (CHF), peripheral vascular disease (PVD), chronic renal failure (CRF), and previous stroke.

Acquisition protocol: All scans were performed using a 256-slice CT system (Brilliance iCT, Philips Healthcare, Cleveland, Ohio) with a gantry rotation time of 330 ms. Data were acquired with a collimation of 256 ×0.625 mm, tube current was 485 mA at 100 kV, and pitch value was 0.2. The scan direction was cranio-caudal and the scan volume ranged from aortic arch to below the diaphragmatic pace of the heart. Beta-blockers were used at the discretion of the cardiac imager.

Intravenous injection of 60–85 ml of nonionic contrast agent (Iopromide 370; Bayer Schering, Berlin, Germany) was administered at a flow rate of 5 ml/s and was followed by a 40-ml saline chase bolus. Data acquisition consisted of two acquisitions. The first acquisition was automatically initiated using a bolus tracking with a region of interest placed in the descending aorta and a threshold level of 180 Hounsfield units, and the second acquisition was automatically initiated 60 s after administration of the contrast agent. Acquisition was performed during an inspiratory breath-hold while the electrocardiogram was recorded simultaneously to allow retrospective gating of data.

Image reconstruction and data analysis: The three-dimensional reconstructed dataset of the contrast-enhanced CT scan was reconstructed using iterative model reconstruction level 1 and transmitted to a dedicated CT workstation (Philips Intellispace Portal, version 11.0) for data analysis, which was performed by one reader, who was blinded to patient details. All images were reconstructed with a slice thickness of 0.67 mm and a slice increment of 0.34 mm.

Statistical analysis: Categorical variables are presented as numbers (%), continuous variables with normal distribution – as mean ± standard deviation (SD), otherwise – as medians with 25 and 75 percentiles. The baseline characteristics of the study patients, stratified by the presence or absence of intra-cardiac thrombus, were compared using the Mann-Whitney-Wilcoxon test for continuous variables, and chi-square test for categorical variables. p-Value of <0.05 was considered as statistically significant. Statistical analysis was performed with a statistical software package (SPSS, version 17.0, SPSS, Chicago, Illinois).

Ethics approval: This single-center registry has been approved by the Ethics Committee of Rabin Medical Center. Due to its retrospective nature, informed consent was waived.

Results

During the study period, 1066 IS patients were hospitalized to the stroke unit and/or neurology department at our center, forming our consecutive IS cohort. Figure 1 provides a graphical representation of diagnostic flow-chart of all patients diagnosed with IS during the study period. 266/1066 (25%) of IS cases (69.7 ± 15.7 years, 120 [44%] females) met ESUS criteria. CCTA was performed in 129/266 (48%) of ESUS patients (73.6 ± 9.9 years, 58 [45%] females). Most of these patients had at least one comorbidity, the most common ones being HTN (76%), DM (41%) and IHD (33%). Moreover, 41/129 (32%) patients had a history of prior stroke. The theoretical CHADS VASC score was 3.9 ± 1.9. Patients’ baseline characteristics are presented in Table 1.

Figure 1.

Diagnostic flow-chart of all patients diagnosed with ischemic stroke during the study period.

Table 1.

Patients’ characteristics.

	Total (N = 129)	No thrombus detected (n = 107)	Thrombus detected (n = 22)	p Value
Sex (%)				0.5
Female	58 (45)	50 (47)	8 (36)
Male	71 (55)	57 (53)	14 (64)
Age (mean ± SD)	73.6 ± 9.9	73.8 ± 10.4	73.1 ± 8.7	0.7
Comorbidities (%)
Hypertension	98 (76)	82 (76)	16 (72)	0.8
Diabetes	53 (41)	45 (42)	8 (36)	0.8
Ischemic heart disease	43 (33)	30 (28)	13 (59)	0.01
Previous stroke	41 (32)	34 (32)	7 (4)	0.2
Congestive heart failure	15 (12)	6 (6)	9 (40)	<0.0001
PVD	10 (8)	8 (7)	2 (9)	0.7
Charlson comorbidity index score (mean ± SD)	4.4 ± 1.7	4.4 ± 1.8	4.6 ± 1.5	0.6
Smoking status (%)
Never	83 (64)	72 (67)	11 (50)	0.1
Past	17 (13)	14 (13)	3 (14)	0.1
Current	29 (22)	21 (20)	8 (36)	0.09
CHADS2 VASC (mean ± SD)	3.9 ± 1.9	3.8 ± 1.9	4.3 ± 1.7	0.3
Echocardiography
EF%				<0.0001
Mean ± SD	55 ± 11	57 ± 10	46 ± 12
Median	60	60	45
Apical hypokinesia	26 (20)	13 (12)	13 (59)	<0.0001

EF: ejection fraction; PVD: peripheral vascular disease; SD: standard deviation.

CCTA detected intra-cardiac thrombus in 22/129 (17%; 95% CI, 11.5%−23.5%) of ESUS patients. Left ventricular thrombus (LVT) was detected in 13 (10.1%) patients; LAA thrombus in 8 (6.2%) patients; and LA thrombus in 1 (0.8%) patient. As shown in Table 1, patients in whom intra-cardiac thrombus was detected by CCTA had higher prevalence of IHD and congestive heart failure (CHD) compared with patients in whom thrombus was not detected; this was reflected also by significantly lower ejection fraction (EF%) and higher prevalence of apical hypo-kinesia, demonstrated on TTE. Figure 2 provides selected images of intra-cardiac thrombi detected on cardiac CT scans.

Figure 2.

Selected images of intra-cardiac thrombi detected on cardiac CT scans. Representative left atrial appendage thrombus assessed on contrast enhanced CT images (a) and post-contrast CT scan (b). Representative left ventricular apical thrombus assessed on contrast enhanced CT images (c) and post-contrast CT scan (d).

Twenty-six (20%) patients in the ESUS-CCTA cohort had apical hypo/akinesia demonstrated on NCTTE. All the 13 LVT detected by CCTA were located in the apex with a concomitant apical wall motion abnormality demonstrated on NCCTE. NCTTE raised suspicion of LV thrombus in 5/13 (38%) of these cases, but could not confirm this diagnosis. Five of 13 (38%) of LVT were measured >20 mm on the longest plain on CCTA, 6/13 (46%) 10–20 mm, and 2/13 (15%) were <10 mm. All 13 patients with LVT had evidence of previous myocardial infarction on CCTA, however, the presence of IHD was previously unknown in two of them.

CCTA revealed pulmonary embolism (PE) in seven patients (in two cases, PE and LV thrombus were detected concurrently). Another important finding of CCTA was hyper-attenuated leaflet thickening (HALT), representing subclinical leaflet thrombosis (SLT), on aortic prosthetic valve in two patients (in one case, concurrent with LAA thrombus). Altogether, anticoagulation was found to be indicated in 27/129 (21%; 95% CI, 14%−28%) of ESUS patients undergoing CCTA, otherwise treated with anti-aggregation.

Considering the entire ESUS cohort, CCTA implementation strategy led to intra-cardiac thrombus detection in 22/266 (8.2%; 95% CI, 4.9%−11.5%) patients.

Within our ESUS registry, 137/266 (52%) patients did not undergo CCTA. As shown in Figure 1, the main reason for not performing CCTA was the preference of TEE in 57/137 (42%) of these patients. Table 2 compares baseline characteristics of this TEE group with CCTA group. TEE was implemented in 41/57 (72%) patients, who were younger than 60 years, for which patent foramen ovale (PFO) closure would be contemplated, if diagnosed. As shown in Table 2, PFO was detected in 17/57 (30%) of the TEE group versus 6/129 (5%) of the CCTA group (p < 0.0001). TEE was also preferred over CCTA in patients suspected to have a valvular source of embolism such as infectious (4/57 patients) or non-infectious (9/57 patients) endocarditis for which TEE is still considered the standard of care. In 3/57 of TEE-undergoing patients, the reason for preferring TEE over CCTA was not specified.

Table 2.

Baseline characteristics of patients undergoing CCTA vs. TEE, and detection of intra-cardiac thrombus or PFO among these groups.

	CCTA (N = 129)	TEE (N = 57)	p Value
Sex (%)			0.5
Female	58 (45)	23 (41)
Male	71 (55)	34 (60)
Age (mean ±SD)	73 ± 9	53 ± 15	<0.0001
Comorbidities (%)
Hypertension	98 (76)	23 (40)	<0.0001
Diabetes	53 (41)	14 (25)	0.02
Ischemic heart disease	43 (33)	5 (9)	<0.0001
Previous stroke	41 (32)	2 (3)	<0.0001
Congestive heart failure	15 (12)	3 (5)	0.15
PVD	10 (8)	5 (9)	0.86
Smoking status (%)			0.46
Never	83 (64)	41 (72)
Past	17 (13)	7 (12)
Current	29 (22)	9 (16)
Main intra-cardiac findings (%)
PFO	6 (5)	17 (30)	<0.0001
Intra cardiac thrombus	22 (17)	0	<0.0001

CCTA: cardiac computed tomography angiography; PFO: patent foramen ovale; PVD: peripheral vascular disease; SD: standard deviation; TEE: transesophageal echocardiography.

Of the entire ESUS cohort, 186/266 (70%) patients underwent advanced cardiac imaging (CCTA or TEE) as part of their ESUS workup.

Discussion

In this study, a consecutive cohort of patients with ESUS underwent CCTA in addition to standard of care in order to better evaluate the prevalence of intra-cardiac thrombus as a possible cardio-embolic source. The major findings of this study are as follows: (1) performing CCTA in addition to screening NCTTE improves the detection of intra-cardiac thrombi, and (2) the use of CCTA in routine ESUS workup can change secondary prevention strategy in a considerable proportion of patients.

ESUS workup: The ESUS construct was originally proposed in order to establish an optimal secondary prevention strategy, assuming that the majority of the cases are related to covert AF.^12,13 However, on prolonged cardiac rhythm monitoring, even with the use of implantable loop recorder, only up to 30% of ESUS patients are diagnosed with AF.^14,15 This fact correlates with recent clinical trials that failed to demonstrate superiority of direct oral anticoagulation (DOAC) over aspirin for secondary stroke prevention in ESUS cases.^10,11 The most likely explanation for these results is the heterogeneity of stroke mechanisms in trials cohorts.

Initial diagnostic work-up of non-lacunar stroke includes imaging of the cervical and intracranial arteries, screening NCTTE, 12 lead ECG and at least 24 h of continuous heart-rhythm monitoring.¹⁶ After this evaluation, approximately 17% of all IS (which are approximately 22% of non-lacunar strokes) are considered as ESUS according to the accepted definition in stroke literature.^1,9 Once an ESUS diagnosis is made, further investigation is considered on a case-by-case basis and should include long-term cardiac monitoring, TEE, cervical vessel wall and plaque imaging, hypercoagulable testing and malignancy screening.¹⁷ In this setting, post stroke intra-cardiac thrombus detection, is of considerable clinical importance, as it indicates commencing AC treatment.^1,2,18

NCTTE is used as the basic screening cardiac imaging for IS and is therefore a pre-requisite for ESUS definition. TEE is considered as a more advanced and sensitive modality for post stroke cardiac imaging, particularly for PFO or valvular sources of embolism, but the general yield of both modalities in stroke patients is uncertain.^19–21 TTE is preferred for detecting LV thrombi, especially if contrast enhanced echocardiography is performed,²² while LA/LAA thrombi are best detected by TEE.⁴ In recent years, studies reporting the use of CCTA for IS workup, as a supplementary imaging modality for detection of intra-cardiac thrombi, have been increasingly published.⁵ However, in the majority of these studies, IS patients who underwent CCTA, were those with suspected cardio-embolic source, especially known AF.^23,24 The clinical considerations and rational of implementing CCTA in AF patients (for which anticoagulation is indicated regardless of CCTA findings) in these studies, was not explicitly specified, but rather expressed as a general aim to define predictors of stroke recurrence. To our knowledge, this analysis of consecutive cohort of ESUS patients, is the first to assess the widespread implementation of CCTA in routine ESUS workup. One retrospective analysis, revealed 5/74 (6.7%) intra-cardiac thrombi detection rate among those who met ESUS criteria and underwent CCTA in a Chinese cohort of re-perfused IS patients.²⁵ In the consecutive ESUS cohort of our study, a significantly higher rate of intra-cardiac thrombi was detected, emphasizing the importance of CCTA use in ESUS workup. The significant difference between intra-cardiac thrombi detection rates in these two cohorts may be attributed to the different prevalence of atherosclerosis, being the most common IS subtype in China.^26,27

LA/LAA thrombi detection: CCTA was shown to be an accurate and reliable alternative to TEE for the detection of LA/LAA thrombi in patients with AF, avoiding the discomfort and risks associated with TEE.²⁸ Compared to TEE as the gold standard for LA/LAA thrombi detection, mean sensitivity and specificity of CCTA are 96% and 92% respectively, and in some prospective single-center studies, have reached 100% and 99% respectively.²⁹ Accordingly, also among IS patients, CCTA sensitivity and specificity for LA/LAA thrombi detection are 96% and 100%, respectively.³⁰ In our study, LA/LAA thrombi were detected in 9/129 (7.0%) of ESUS patients who underwent CCTA. As TEE is not the standard of care for all ESUS cases, and because none of these thrombi were detected by NCTTE in our cohort, these patients would otherwise be discharged without commencing AC treatment. The LA/LAA thrombi diagnosed in our cohort may be attributed to left atrial dysfunction, also known as atrial-cardiopathy, associated with higher rates of stroke recurrence.^31,32 As atrial-cardiopathy markers among ESUS patients have not yet been proven as an indication for anticoagulation,¹⁷ currently only LA/LAA thrombi detection justifies and indicates commencing AC treatment, and therefore their detection should be pursued efficiently. In contrast to TEE as a rather invasive, uncomfortable, and more expensive procedure, CCTA is a non-invasive and less operator-depended modality. Moreover, CCTA might be more atrial-thrombi-specific as it can better distinguish between spontaneous echo contrast (SEC) and LAA thrombus.³³

LV thrombi detection: Unrecognized myocardial infarction (MI) and severe LV systolic dysfunction (LVSD), are considered important causes of ESUS.¹⁷ Therefore, in the setting of IS, severe LVSD may be considered as an indication for AC.^1,34 On the other hand, LV regional wall motion abnormalities (RWMA) and impaired LV contractility, that are commonly found in ESUS patients, are not currently considered as high-risk sources of cardiac embolism. These abnormalities may have the propensity for thrombus formation, but ESUS patients carrying them, are not routinely prescribed AC. The association between RWMA and IS recurrence has been previously debated without clear conclusion.^35–37 In current practice, regional or moderate global LV dysfunction is not considered as an indication for AC. Interestingly, a recent subgroup analysis of LVSD cases from the NAVIGATE-ESUS study (defined as regional and/or global LVSD), has suggested that in this subgroup, AC is superior to aspirin in reducing the risk of recurrent stroke.³⁸ Yet, only a diagnosis of LVT is currently considered as a definite indication for commencing AC treatment in IS patients.

TTE is an operator dependent technique, also influenced by individual patient’s characteristics such as chest wall anatomy. LVT can be detected by TTE with relatively low sensitivity of 21%–33%, that can be increased to 61% when contrast-enhanced TTE (CTTE) is performed.²⁹ CTTE allows significantly improved assessment of the presence or absence of LV thrombus.^22,39,40 Among LV dysfunction patients, CTTE has the greatest impact over NCTTE, for LVT detection.⁴¹ However, in common practice, CTTE is not included in routine IS/ESUS workup,^17,42 and therefore is not considered standard of care. TTE has difficulty in visualizing LV thrombi, with lowest sensitivity (10%) for thrombi smaller than 10 mm, and highest sensitivity (46%) for thrombi larger than 20mm. This relatively low sensitivity for LV thrombi detection is related to the limited near field resolution, wherein adherent mural thrombi resemble the adjacent myocardium.⁴³ Among the 13 LVT detected in our cohort by CCTA, NCTTE raised suspicion of LVT in 5/13 (38%) of them, but could not confirm this diagnosis. In these cases, TTE demonstrated a substantial apical a-kinetic area, but the thrombus was indistinguishable from the adjacent myocardium so a confirmed diagnosis of LVT could not be reached.

TEE is considered the least sensitive modality for LVT detection.^4,20

Cardiac MRI (CMRI) is the most sensitive and specific imaging modality for LVT detection in IS patients, and thus considered as the gold standard for this purpose.^4,29,43 Unfortunately, CMRI has not been routinely adopted in ESUS workup due to its current cost and availability.

CCTA demonstrates LVT as a hypodense mass within enhanced LV cavity, with significantly lower attenuation in comparison with the myocardium. CCTA diagnose LVT and distinguishes it from myocardial wall with sensitivity, specificity and positive and negative predictive values of 94%, 97%, 94%, and 97%, respectively.⁴⁴ Currently, there are few validated data on the role of cardiac CT in the detection of LVT in comparison with MRI.²⁹ However, in the setting of IS, CCTA may be superior to TTE regarding LV thrombi detection.²³ LVT is associated with increased risk of stroke and systemic embolism and indicates commencing anti-coagulation treatment for at least 3 months. Furthermore, embolic events appear to occur even after the resolution of LVT, suggesting that this therapy should be considered for a longer period in some cases.⁴⁵

LV thrombus detection in our ESUS cohort (10%) suggests that this diagnostic strategy is justified, as it changed the medical management in these cases. According to our findings, NCTTE is not sensitive enough and therefore insufficient for comprehensive ESUS workup. One possible conclusion from our study is that the presence of global or regional LV dysfunction in the setting of ESUS, particularly apical wall motion abnormality, may justify advanced cardiac imaging (CCTA or CMRI) or at least CTTE, in order to improve LVT detection. Further studies are needed to assess this hypothesis.

Overall, while CTTE is LV sensitive and TEE is LA/LAA sensitive, CCTA serves as a more comprehensive cardiac imaging for ESUS, addressing both diagnostic challenges at the same time.

ESUS subgroups: In lack of a single secondary prevention strategy for ESUS, differential-diagnosis oriented approach enables the identification of ESUS subgroups that might benefit from anticoagulation treatment or advanced imaging.^17,46 This diagnostic approach is manifested in our ESUS cohort, with the preference of TEE in younger patients eligible for PFO closure, along with the implementation of CCTA in older and high-risk patients. Our findings suggest that ESUS subgroups, such as apical wall motion abnormality, or cardiac bio-markers of atrial-cardiopathy, can benefit from CCTA as a modality that can identify both ventricular and atrial thrombi with high sensitivity and specificity.

Another finding of CCTA in our cohort was hyper-attenuated leaflet thickening (HALT), representing subclinical leaflet thrombosis (SLT),⁴⁷ on aortic prosthetic valve in two patients (in one case, concurrent with LAA thrombus). While SLT is relatively frequent after TAVR (occurring in 15%−30% of patients),⁴⁸ and its clinical significance in means of valve functionality is debatable, this pathology was shown to be associated with increased stroke risk.⁴⁹ Oral anticoagulation (OAC) treatment after SLT diagnosis is associated with significantly higher odds of SLT resolution compared with no OAC treatment (OR: 0.01; 95% CI: 0.00–0.06; p < 0.00001),⁴⁹ but its duration has not been determined. Whether post-TAVR/intra-cardiac implanted device patients presenting with ESUS should routinely undergo CCTA, in pursue of this diagnosis, is unknown. Further studies are needed to assess this hypothesis.

ESUS criteria: In light of the negativity/neutrality of the two major ESUS trials,^10,11 and with acknowledgment of more specified ESUS subgroups, modified stricter ESUS criteria might be more suitable for clinical practice and future studies. One recently published suggestion for such criteria, is expressed by the A.H.E.A.D mnemonics,⁵⁰ where E stands for ECG and Echo, and represents a more comprehensive exclusion of high risk cardio-embolic sources, including intra-cardiac thrombi. The results of our study imply that CCTA can be suitable, as advanced cardiac imaging in selected patients, for such a stricter and comprehensive ESUS definition.

Limitations

The retrospective design of this single-center cohort study is the main limitation of this study. Accordingly, the decision of whether or not a patient would undergo advanced cardiac imaging, either CCTA or TEE, was not randomized nor blinded, and therefore introduces selection bias.

Of the entire ESUS cohort, 80/266 (30%) did not undergo advanced cardiac imaging (neither CCTA nor TEE). The main reason for not performing advanced cardiac imaging, in 49/80 (61%) of these patients, was lack of patient cooperation due to neurological or medical condition (aphasia, altered mental status, reduced consciousness, respiratory or hemodynamic instability, or general fragility). Lack of patients’ cooperation limited the possibility of implementing CCTA, as this may cause significant artifacts in the exam. Moreover, altered mental status or aphasia impaired patients’ capability to provide informed consent for TEE, as an invasive procedure. In 9/80 (11%) patients, another factor limiting the use of CCTA was the relative contra-indication of acute or chronic kidney injury or single functioning kidney. Finally, as CCTA is a valuable and sometimes scarce resource for coronary artery disease workup (cardiology, internal medicine, emergency medicine etc.), it was not available for 22/80 (28%) patients during their hospitalization in the stroke unit or vascular neurology ward, and therefore was not performed. Accordingly, only 70% of the ESUS cohort underwent advanced cardiac imaging, and this impairs the generalization of our findings and moderates their impact.

Our study is unable to perform a direct comparison between CCTA and TEE as none of the patients included in our cohort were examined by both modalities. The comparison between CCTA and TEE undergoing patients (Table 2) does not lead to any comparative conclusions, as the baseline characteristics of these two groups are distinctly and significantly different, and retrospectively reflect the workup strategy in the study period.

Since CCTA was not compared to another imaging modality for similar patient group, we could not define the incremental intra-cardiac thrombus detection rate of CCTA, but rather the net clinical impact of implementing it in ESUS workup, expressed as added AC indications and intra-cardiac thrombus detections.

Furthermore, as contrast-enhanced TTE is not routinely used in IS workup, all patients in our cohort underwent NCTTE, impairing LVT detection by echocardiography.

Conclusion

The implementation of CCTA in routine ESUS workup can change secondary prevention pharmacologic strategy in a considerable proportion of patients, by providing an indication for anti-coagulation rather than conventional antiplatelet regimen. Future studies are needed to evaluate the impact of changes in medical management on the outcome of ESUS patients.

Footnotes

Author contributions

RB conceived the study and wrote the first draft of the manuscript, INA was involved in protocol development and equally contributed to this study. AH, RK, and EA were involved in protocol development. RM, SP and JN were involved in data acquisition and analysis, GS, AS, and AH were involved in imaging analysis. All authors reviewed and edited the manuscript and approved the final version of the manuscript.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Informed consent

Informed consent was not sought for the present study because of its retrospective observational nature.

Ethical approval

Ethical approval for this study was obtained from the Ethics Committee of Rabin Medical Center.

ORCID iD

Rani Barnea

References

Kleindorfer

Towfighi

Chaturvedi

, et al 2021 Guideline for the Prevention of stroke in patients with stroke and transient ischemic attack: a guideline from the American Heart Association/American Stroke Association. Stroke. Epub ahead of print 24 May 2021. DOI: 10.1161/STR.0000000000000375

Powers

Rabinstein

Ackerson

, et al Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2019; 50: e344–e418.

Giruparajah

Bosch

Vanassche

, et al Global survey of the diagnostic evaluation and management of cryptogenic ischemic stroke. Int J Stroke 2015; 10: 1031–1036.

Camen

Haeusler

Schnabel

. Cardiac imaging after ischemic stroke or transient ischemic attack. Curr Neurol Neurosci Rep 2020; 20: 36.

Hur

Choi

. Cardiac CT imaging for ischemic stroke: current and evolving clinical applications. Radiology 2017; 283: 14–28.

Ajlan

Bagdadi

Alama

, et al Impact of implementing cardiac CT in evaluating patients suspected of cardioembolic stroke. J Comput Assist Tomogr 2016; 40: 380–386.

Hur

Kim

Lee

, et al Left atrial appendage thrombi in stroke patients: detection with two-phase cardiac CT angiography versus transesophageal echocardiography. Radiology 2009; 251: 683–690.

Taina

Vanninen

Sipola

, et al Cardiac CT differentiates left atrial appendage thrombi from circulatory stasis in acute stroke patients. Vivo Athens Greece 2016; 30: 671–676.

Hart

Catanese

Perera

, et al Embolic stroke of undetermined source: a systematic review and clinical update. Stroke 2017; 48: 867–872.

10.

Diener

Sacco

Easton

, et al Dabigatran for prevention of stroke after embolic stroke of undetermined source. N Engl J Med 2019; 380: 1906–1917.

11.

Hart

Connolly

Mundl

. Rivaroxaban for stroke prevention after embolic stroke of undetermined source. N Engl J Med 2018; 379: 987–2201.

12.

Hart

Diener

Coutts

, et al Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014; 13: 429–438.

13.

Schäbitz

Köhrmann

Schellinger

, et al

Embolic stroke of undetermined source: gateway to a new stroke entity?

Am J Med 2020; 133: 795–801.

14.

Israel

Kitsiou

Kalyani

, et al Detection of atrial fibrillation in patients with embolic stroke of undetermined source by prolonged monitoring with implantable loop recorders. Thromb Haemost 2017; 117: 1962–1969.

15.

Verma

Ziegler

Liu

, et al Incidence of atrial fibrillation among patients with an embolic stroke of undetermined source: insights from insertable cardiac monitors. Int J Stroke 2019; 14: 146–153.

16.

Kamel

. The evolving concept of cryptogenic stroke. Continuum 2020; 26: 353–362.

17.

Kamel

Merkler

Iadecola

, et al Tailoring the approach to embolic stroke of undetermined source: a Review. JAMA Neurol 2019; 76: 855–861.

18.

European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm

, et al Guidelines for the management of atrial fibrillation: the task force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369–2429.

19.

Holmes

Rathbone

Littlewood

, et al Routine echocardiography in the management of stroke and transient ischaemic attack: a systematic review and economic evaluation. Health Technol Assess 2014; 18: 1–176.

20.

McGrath

Paikin

Motlagh

, et al Transesophageal echocardiography in patients with cryptogenic ischemic stroke: a systematic review. Am Heart J 2014; 168: 706–712.

21.

Powers

. Clinical utility of echocardiography in secondary ischemic stroke prevention. Handb Clin Neurol 2021; 177: 359–375.

22.

Mulvagh

Rakowski

Vannan

, et al American Society of Echocardiography consensus statement on the clinical applications of ultrasonic contrast agents in echocardiography. J Am Soc Echocardiogr 2008; 21: 1179–1201; quiz 1281.

23.

Groeneveld

Guglielmi

Leeflang

MMG

, et al CT angiography vs echocardiography for detection of cardiac thrombi in ischemic stroke: a systematic review and meta-analysis. J Neurol 2020; 267: 1793.

24.

Apfaltrer

Lavra

De Cecco

, et al Predictive value of cardiac CTA, cardiac MRI, and transthoracic echocardiography for cardioembolic stroke recurrence. AJR Am J Roentgenol. Epub ahead of print 16 September 2020. DOI: 10.2214/AJR.20.23903

25.

Yan

Zhou

Han

, et al Potential role of 2-Phase cardiac CT in patients with embolic stroke of undetermined source. Am J Med 2020; 133: e290–e293.

26.

Xin

Cheng

Yang

, et al Comparison study of ASCO and TOAST classification system in Chinese minor stroke patients. Cerebrovasc Dis 2019; 47: 95–100.

27.

Zhao

Liu

Wang

, et al Epidemiology of cardiovascular disease in China: current features and implications. Nat Rev Cardiol 2019; 16: 203–212.

28.

Romero

Husain

Kelesidis

, et al Detection of left atrial appendage thrombus by cardiac computed tomography in patients with atrial fibrillation: a meta-analysis. Circ Cardiovasc Imaging 2013; 6: 185–194.

29.

Cohen

Donal

Delgado

, et al EACVI recommendations on cardiovascular imaging for the detection of embolic sources: endorsed by the Canadian Society of Echocardiography. Eur Heart J 2021; 22: e24–e57.

30.

Hur

Kim

Lee

, et al Dual-enhanced cardiac CT for detection of left atrial appendage thrombus in patients with stroke: a prospective comparison study with transesophageal echocardiography. Stroke 2011; 42: 2471–2477.

31.

Kamel

Okin

Longstreth

Jr , et al Atrial cardiopathy: a broadened concept of left atrial thromboembolism beyond atrial fibrillation. Future Cardiol 2015; 11: 323–331.

32.

Edwards

Healey

Fang

, et al Atrial cardiopathy in the absence of atrial fibrillation increases risk of ischemic stroke, incident atrial fibrillation, and mortality and improves stroke risk prediction. J Am Heart Assoc 2020; 9: e013227.

33.

Kim

Chun

Choi

, et al Differentiation between spontaneous echocardiographic contrast and left atrial appendage thrombus in patients with suspected embolic stroke using two-phase multidetector computed tomography. Am J Cardiol 2010; 106: 1174–1181.

34.

Beggs

SAS

Rørth

Gardner

, et al Anticoagulation therapy in heart failure and sinus rhythm: a systematic review and meta-analysis. Heart 2019; 105: 1325–1334.

35.

Choi

Cha

Jung

, et al Left ventricular wall motion abnormality is associated with cryptogenic stroke. Int J Stroke 2020; 15: 188–196.

36.

Choi

Cha

Jung

, et al Left ventricular wall motion abnormalities are associated with stroke recurrence. Neurology 2017; 88: 586–594.

37.

Ramasamy

Yaghi

Salehi Omran

, et al Association between left ventricular ejection fraction, wall motion abnormality, and embolic stroke of undetermined source. J Am Heart Assoc 2019; 8: e011593.

38.

Merkler

Pearce

Kasner

, et al Left ventricular dysfunction among patients with embolic stroke of undetermined source and the effect of rivaroxaban vs aspirin: A subgroup analysis of the NAVIGATE ESUS randomized clinical trial. JAMA Neurol 2021; 78: 1454–1460.

39.

Kurt

Shaikh

Peterson

, et al Impact of contrast echocardiography on evaluation of ventricular function and clinical management in a large prospective cohort. J Am Coll Cardiol 2009; 53: 802–810.

40.

Senior

Becher

Monaghan

, et al Contrast echocardiography: evidence-based recommendations by European Association of Echocardiography. Eur J Echocardiogr 2009; 10: 194–212.

41.

Zhao

O’Quinn

Ambrose

, et al Contrast-enhanced echocardiography has the greatest impact in patients with reduced ejection fractions. J Am Soc Echocardiogr 2018; 31: 289–296.

42.

Ntaios

. Embolic stroke of undetermined source: JACC review topic of the Week. J Am Coll Cardiol 2020; 75: 333–340.

43.

Srichai

Junor

Rodriguez

, et al Clinical, imaging, and pathological characteristics of left ventricular thrombus: a comparison of contrast-enhanced magnetic resonance imaging, transthoracic echocardiography, and transesophageal echocardiography with surgical or pathological validation. Am Heart J 2006; 152: 75–84.

44.

Bittencourt

Achenbach

Marwan

, et al Left ventricular thrombus attenuation characterization in cardiac computed tomography angiography. J Cardiovasc Comput Tomogr 2012; 6: 121–126.

45.

Cruz Rodriguez

Okajima

Greenberg

. Management of left ventricular thrombus: a narrative review. Ann Transl Med 2021; 9: 520.

46.

Greeve

Schäbitz

. Embolic stroke of undetermined source: identification of patient subgroups for oral anticoagulation treatment. Neural Regen Res 2022; 17: 1005–1006.

47.

Chakravarty

Søndergaard

Friedman

, et al Subclinical leaflet thrombosis in surgical and transcatheter bioprosthetic aortic valves: an observational study. Lancet 2017; 389: 2383–2392.

48.

Calabrò

Gragnano

Niccoli

, et al Antithrombotic therapy in patients undergoing transcatheter interventions for structural heart disease. Circulation 2021; 144: 1323–1343.

49.

Bogyi

Schernthaner

Loewe

, et al Subclinical leaflet thrombosis after transcatheter aortic valve replacement: a meta-analysis. JACC Cardiovasc Interv 2021; 14: 2643–2656.

50.

Rose

Kasner

. Forge AHEAD with stricter criteria in future trials of embolic stroke of undetermined source. Neural Regen Res 2022; 17: 1009–1010.

Cardiac CT for intra-cardiac thrombus detection in embolic stroke of undetermined source (ESUS)

Abstract

Introduction:

Patients and methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Results

Discussion

Limitations

Conclusion

Footnotes

Author contributions

Declaration of conflicting interests

Funding

Informed consent

Ethical approval

ORCID iD

References