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Introduction
Cryptogenic stroke accounts for approximately 30% of all ischemic strokes1. Recently, atrial cardiopathy has been shown to be associated with ischemic stroke, particularly those of embolic subtypes2,3.
Several studies suggest that not only atrial fibrillation (AF) but also left atrial diameter and other markers of atrial cardiopathy may be implicated in the pathogenesis of cryptogenic stroke4. Left atrial enlargement (LAE) has been shown to be associated with incident AF and incident ischemic stroke risk after adjusting for several confounders, including AF. An analysis of NOMASS5 showed that moderate to severe LAE is an independent predictor of recurrent stroke risk and is particularly related to embolism (adjusted HR 2.38 95% CI 1.03-7.81). Some studies suggest a mechanistic relationship between LAE and ischemic stroke.
Recently, several scores have been proposed to easily and cost-effectively predict paroxysmal AF on outpatient cardiac monitoring after an Embolic Stroke of Undetermined Source (ESUS)6,7. For instance, the Brown ESUS AF score incorporates moderate severe LAE and age to assign a score from 0 to 4 with an area under the curve of 0.725 to predict paroxysmal AF7. This score still needs to be externally validated.
We sought to examine LAE and age and its relationship with recurrence and AF development in patients with ESUS using the Brown ESUS AF score.
Materials and methods
ESUS cohort
We analyzed data from 64 patients with confirmed diagnoses of ESUS treated in our hospital from November 2015 to March 2018. We used patient data prospectively included in our stroke database. Our registry includes consecutive outpatients with an acute first-ever confirmed ischemic stroke admitted to the stroke clinic in Mexico City. Every patient in our clinic undergoes a thorough evaluation in search of stroke etiology that comprises brain magnetic resonance imaging (MRI), duplex ultrasound of the neck, transcranial Doppler, and/or computed tomography (CT) angiography of the head and neck arteries, 24-h Holter monitoring, and transthoracic echocardiogram (TE). This study was approved by the local Research and Ethics Committee.
We included patients 18 years old or older with confirmed ischemic stroke by CT or MRI who fulfilled the ESUS criteria8. Patients with any identifiable cause of stroke or in whom initial assessments had not been completed were excluded from the study. The diagnosis of ESUS was made according to the ESUS criteria proposed by Hart et al. (1). Ischemic stroke detected by CT or MRI that is not lacunar; (2) absence of extracranial or intracranial atherosclerosis causing ≥50% luminal stenosis in arteries supplying the area of ischemia; (3) no major risk cardioembolic source of embolism and; (4) no other specific cause of stroke identified)8. Every patient underwent a comprehensive clinical investigation in search of stroke etiology, including neuroimaging, either CT or MRI, intracranial and extracranial vessel imaging, TE, and 24-h Holter monitoring.
Echocardiogram
In all cases, the TE conducted during the index event was evaluated and interpreted by the same certified cardiologist. The left atrial diameter was determined by the auricular area. All measurements were interpreted and recorded on the printed report by the cardiologist using the classification of mild, moderate, or severe LAE according to established parameters9.
Patients were categorized into a high (human resource planning [HRP]) or low-risk (non-HRP) group based on their Brown ESUS AF score (Table 1). Patients were given a score from 0 to 4 according to their age and LAE. The score is composed of two items. The first is age: patients under 64 years of age score 0 points, patients aged 65-74 years score 1 point, and patients over 75 years old score 2 points. The second variable is LAE: patients with mild LAE score 0 points, and patients with moderate-severe LAE score 2 points. Table 1 shows how the score is composed.
Table 1 The Brown embolic stroke of undetermined source atrial fibrillation score
| Variable | Score |
|---|---|
| Age | |
| − 18-64 years | 0 points |
| − 65-74 years | +1 points |
| − ≥ 75 years | +2 points |
| Left atrial enlargement | |
| − Mild | 0 |
| − Moderate - severe | +2 |
Patients who scored > 2 were considered HRP. The HRP group was re-evaluated with a new 24-h Holter monitoring in a period of time of 6 months between the first scanning and the second to identify incident AF.
During follow-up, we evaluated stroke recurrence or death. Recurrence was defined as any recurrent stroke occurring during follow-up in any vascular territory, including TIA. Functional outcome was evaluated with the modified ranking scale (mRs); good functional outcome was defined as mRs > 2.
Statistical analysis
The statistical analysis was conducted using SPSS (Statistical Package for the Social Sciences, version 23.0, IBM Inc., Armonk, NY). Demographic variables and risk factors for stroke were included in the study. Values for continuous variables were expressed according to their pattern of normality, as evaluated by the ShapiroWilk test. Variables that were normally distributed were expressed as the mean and SD, while variables that were not normally distributed were expressed as the median and IQ ranges. Categorical nominal variables were expressed as whole numbers and percentages. Association analysis was performed using Students t-test or MannWhitney Wilcoxon.
A univariate analysis of the independent variables (LAE and age over 65 years) was conducted, with the addition of covariates (sex, hypertension, diabetes, and dyslipidemia), to examine the relationship to appearance of AF and recurrence using a Chi-Square or Fishers statistic accordingly, respectively. A multivariate regression analysis was performed in search of further associations with respect to the variables of interest.
Results
We identified 228 consecutive stroke patients in our clinics database from November 2015 to March 2018. Sixty-four (28%) were diagnosed with ESUS. Thirty-three (51.6%) were men. The median age was 62 years (range: 22-85 years). Nineteen patients (29.7%) were under 50 years of age. The median initial NIHSS score was 3 points (range: 0-27). Forty patients (77%) had good clinical outcomes (mRs ≤ 2). There was a significant difference in the number of female patients in the HRP group versus non-HRP group. These patients were followed up for a period of time with a median of 20 months (Range of 4-39 months). Table 2 describes the baseline characteristics.
Table 2 Baseline characteristics
| Variable | High-risk n = 12 (18.8%) | Low-risk n = 52 (81.3%) | Total n = 64 (100%) | p value |
|---|---|---|---|---|
| Demographics | ||||
| Age | ||||
| 65 | 1 (8.3%) | 35 (65.4%) | 36 (54.7%) | 0.001 |
| 65-74 | 2 (16.7%) | 18 (34.6%) | 20 (31.3%) | 0.312 |
| 75 | 9 (75%) | 0 (0.0%) | 0 (14.5%) | 0.000 |
| Female | 10 (83.3%) | 21 (40.4%) | 31 (48%) | 0.007 |
| Clinical | ||||
| HTN | 9 (75%) | 32 (61.5%) | 41 (64.1%) | 0.357 |
| Diabetes Mellitus | 2 (16.7%) | 17 (33.3%) | 19 (30.2%) | 0.258 |
| Tobacco | 2 (16.7%) | 18 (34.6%) | 20 (31.3%) | 0.427 |
| Dyslipidemia | 1 (8.3%) | 5 (9.6%) | 6 (9.4%) | 0.891 |
| Cardiopathy | 1 (8.3%) | 0 (0.0%) | 1 (1.6%) | 0.628 |
| Clinical course | ||||
| NIHSS (range) | 2.5 (0-18) | 3.5 (0-27) | 0.464 | |
| mRs 2 discharge | 11 (91.4%) | 41 (78.4%) | 52 (82.5%) | 0.355 |
| mRs 2-3 months | 11 (91.4%) | 41 (78.4%) | 52 (82.5%) | 0.355 |
| mRs 2-6 months | 11 (91.4%) | 43 79.6%) | 54 (85.7%) | 0.513 |
HTN: hypertension; NIHSS: National Institutes of Health Stroke Scale; mRs: modified rankin scale.
Twelve patients (18.8%) were categorized as HRP, while 52 (81.3%) were non-HRP. In the non-HRP group, 34 patients (53%) had a Brown ESUS AF score of 0, and 18 (28%) had a score of 1. For the HRP group, seven patients (10.9%) scored 3 points, 2 (3.1%) scored 2 points, and 3 patients (4.6%) scored the maximum score of 4 points. Table 3 shows the complete distribution of the scores.
Table 3 Left atrial enlargement, age, and corresponding brown embolic stroke of undetermined source atrial fibrillation score
| Variable | n (%) | Brown score |
|---|---|---|
| Left atrial enlargement | ||
| Absent | 46 (72) | +0 |
| Mild | 12 (19) | +0 |
| Moderate | 4 (6) | +2 |
| Severe | 2 (3) | +2 |
| Age (years) | ||
| 65 | 35 (54) | +0 |
| 65-74 | 20 (31) | +1 |
| 75 | 9 (14) | +2 |
There were two deaths during follow-up in the HRP group versus 0 in the non-HRP (16.6% vs. 0%, p ≤ 0.001); one of these deaths was recurrence related, while the other was due to systemic complications of sepsis 18 months after the index event. The remaining ten patients were re-evaluated with a new 24-h Holter monitoring, but we did not document AF in any of these cases.
We found a significant tendency toward recurrence among HRP vs. non-HRP, 3 (25%) versus 2 (3.8%) (OR: 8.3 95% CI 1.2-57, p = 0.042). A univariate analysis was performed on the variables that could have been associated with recurrence. No significant difference was found for history of arterial hypertension (p = 0.341), diabetes mellitus (p = 0.629), tobacco use (p = 0.709), ischemic heart disease (p = 0.769), or hypercholesterolemia (p = 0.454). Looking at the variables of interest, age and LAE, only severe atrial enlargement (OR: 14.5; 95% CI 0.78-277, p = 0.02) and age 75 years (OR: 12.7; 95% CI 1.7-92.2, p = 0.03) showed an association with recurrence. A multivariate regression was performed, but no association was found.
Discussion
Patients with ESUS represent a heterogeneous group with a high probability of their stroke having a cardiac embolic source and a higher risk of stroke recurrence3,10. In a recent population-based study, LAE has been shown to be associated with incident AF and incident ischemic stroke5,11. Our findings reinforce the argument that LAE should be considered a risk factor for recurrent ischemic stroke and suggest that left atrial thromboembolism can occur independently of documentation of AF12.
The baseline characteristics of our cohort are compatible with those reported in the literature; ESUS patients tend to be younger and have less severe strokes3,13,14. Nevertheless, we observed that women are at higher risk (OR: 7.3 95% CI 1.4-37.1, p = 0.007), a finding that correlates with other prognostic scales such as CHA2 DS2 -VASC, in which female sex confers risk of recurrence15.
A significant tendency was found between HRP and stroke recurrence compared with non-HRP (OR: 8.3 95% CI 1.2-57, p=0.042); this relationship was conditioned by age > 75 years and severe atrial dilation as demonstrated in the univariate analysis. Although our patients may have presented subclinical AF, the important aspect of our findings is that the risk of recurrence can be predicted with documentation of LAE on a conventional echo. Therefore, we did not find a relation between LAE, age, and AF development, which can be readily explained by our AF monitoring strategy, which was only a 24-h Holter monitor, known to have a low diagnostic yield for paroxysmal AF2. Subclinical AF is suggested to play an important role in ESUS pathogenesis, and proper screening for AF in these patients is mandatory16. Unfortunately, the reality for most countries in Latin America is that prolonged monitoring, external, or implantable, is very scarce, so searching for better strategies to further select patients who would benefit the most from more strict follow-up protocols is essential. Patients with LAE have been shown to have reduced left atrial contractility, leading to reductions in left atrial volume and kinetic energy. The resultant dysfunctional left atrium leads to atrial thromboembolism. Furthermore, LAE can promote stasis, endothelial dysfunction, and thrombus formation17. In addition, patients with LAE are more likely to have well-known stroke risk factors, which possibly increased their risk of developing stroke.
Our findings suggest that the detection of LAE in patients with ESUS allows the identification of patients at high risk of recurrence in which some pharmacological therapies could be beneficial. In a subanalysis of ESUS NAVIGATE patients with ESUS and enlarged left atrium, there was a lower recurrence rate in the rivaroxaban group, though these results must be taken with caution since they are a positive subgroup in an overall negative trial; however, they show some promising evidence that better-selected ESUS patients may indeed benefit from anticoagulants18.
This study was not intended to function as an external validation for the Brown Score since we do not have the option at our center to place our patients on prolonged cardiac monitoring. The score is simple to apply, and it does not require any additional evaluation beyond the standard etiology screening. Better strategies for AF detection that is both feasible and cost effective need to be structured for this group of patients. LAE could be a valuable biomarker to select patients with high risk of stroke recurrence, and further studies need to be performed to fully assess this suggestion. Some limitations of our study must be recognized. First, the small number of patients included is a limitation, considering that this is a selected group of patients with specific ESUS criteria in which no other probable cause of IC was demonstrated. A second limitation is that our sample came from a single neurological center.
