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J Stroke > Volume 26(2); 2024 > Article
Rizzo, Schwarz, Bonelli, Di Pietro, Di Pietro, Aruta, Motto, De Chiara, Moreo, and Agostoni: The Role of Atrial Cardiopathy as a Potential Cause of Embolic Stroke of Undetermined Source
Dear Sir:
Atrial cardiopathy (AC), which refers to left atrial (LA) structural and functional disorders (independent of atrial fibrillation [AF]) [1,2], is increasingly considered a potential mechanism for embolic stroke of undetermined source (ESUS) [3]. AC has been independently associated with silent AF detection and stroke recurrence [4,5], suggesting an etiopathogenic role. Most studies on AC in ESUS were conducted before the recently proposed ESUS construct update [6]. Given the heterogeneous definition of ESUS, etiological misclassification may have limited our understanding of the link between AC and ESUS. After applying the proposed ESUS construct update, we first assessed whether any differences existed in the prevalence of AC in patients with ESUS classified according to the traditional versus revised criteria. After focusing on the revised classification, we investigated the clinical and radiological differences between ESUS with AC (AC(+)/ESUS) versus without AC (AC(-)/ESUS). Additionally, we investigated the association between AC and stroke severity and outcome and the role of AC in stroke recurrence and AF detected after stroke (AFDAS) [7].
This retrospective single-center study included all consecutive patients with acute ischemic stroke (AIS) diagnosed as ESUS (according to standard criteria) [8]. These patients were admitted to our stroke unit between January 2018 and December 2022. All diagnostic evaluations were reviewed for each patient, and recently proposed changes to the ESUS construct [6] were applied to redefine the ESUS classification. We excluded patients with (1) high-risk patent foramen ovale (PFO), (2) high-risk non-stenosing (<50%) ipsilateral supracardiac atherosclerosis, and (3) probable cancer-related hypercoagulability (see Supplementary Methods for details).
AC was defined as LA enlargement (LAE), measured using the LA volume index (LAVI) based on the standard criteria: LAVI >34 mL/m2. The entire cohort was divided based on the presence of AC (AC(+)/ESUS if LAVI >34 mL/m2) versus its absence (AC(−)/ESUS if LAVI ≤34 mL/m2). AC was also categorized according to severity as mild (LAVI 35-41 mL/m2) or moderate/severe (LAVI ≥42 mL/m2) [9].
Radiological data, including the analysis of stroke lesions by location and site, were also collected. Stroke severity (measured by the baseline National Institutes of Health Stroke Scale [NIHSS] score) and functional status at 90 days (modified Rankin Scale [mRS] score of 0-2 and 0-3) were considered as clinical outcomes. Stroke recurrence and AFDAS were considered long-term follow-up outcomes.
Statistical analysis was performed using Stata statistical software (Version 17; StataCorp., College Station, TX, USA), with the significance level set at P<0.05. Univariate and multivariate logistic (or ordered logistic) regression analyses were performed to evaluate the association between AC (considered both continuous [LAVI] and dichotomous variables [AC(+) vs. AC(-); moderate/severe AC vs. mild AC/AC(-)]) and stroke severity, 90-day mRS score, stroke recurrence, and AFDAS. This study was approved by the local ethics committee (Comitato Etico Milano Area 3, n. 346-18052022), and informed consent was obtained from patients upon admission. Detailed information regarding the study population, diagnostic evaluations, and statistical analyses can be found in Supplementary Methods.
Among the 414 eligible ESUS patients (with available LAVI measurements), 116 (28%) were reclassified and excluded per the ESUS construct update, resulting in a final sample of 298 ESUS patients (Supplementary Figure 1). The prevalence of AC was higher in ESUS cases classified according to the revised criteria than in those classified according to the traditional criteria (42.0% vs. 36.2%) and significantly different from excluded ESUS cases (42.0% vs. 21.5%; P<0.001) (Table 1). The excluded patients with ESUS had a lower LAVI, were younger with fewer vascular risk factors, experienced milder strokes, and had better 3-month outcomes (Supplementary Table 1). The general characteristics of the final ESUS cohort (revised criteria) are presented in Table 2. Patients with AC(+)/ESUS were older and had more hypertension, coronary artery disease, and non-stenosing ipsilateral supra-cardiac atherosclerosis. Additionally, they suffered more frequently from cortico-subcortical strokes and had fewer small-isolated cortical lesions compared to patients with AC(-)/ESUS.
Over a median follow-up of 20 months (interquartile range [IQR] 8-32; available for 290 patients), recurrent stroke occurred in 17 patients (5.9%) and AFDAS in 28 patients (9.7%). The median time between the index and recurrent stroke was 5 months (IQR 3-20). In both univariate and multivariate logistic regression analyses, no significant associations were observed between the AC parameters (presence, severity, and LAVI), stroke severity, 90-day mRS, and stroke recurrence. The AFDAS was independently associated with all AC parameters (Table 3). Further analyses and results are reported in the Supplementary Results, including Kaplan-Meier survival analysis for the risk of stroke recurrence (Supplementary Figure 2).
In our study, we found that, following the recent ESUS update, patients classified as non-ESUS exhibited a significantly different echocardiographic profile than ESUS patients, with a higher AC incidence in the latter group (42.0%). This finding highlights the substantial heterogeneity in the echocardiographic profiles within these two groups and underscores the importance of precise ESUS patient classification.
The prevalence of AC varies in published studies, depending on the criteria used for its definition. Various AC biomarkers, categorized as electrophysiological, structural, hemodynamic, and serological, have been associated with stroke risk [2]. Our study defined AC as LAE by measuring the LAVI, which is now considered a superior indicator of LA dimensions compared to LA diameter. The LAVI has been demonstrated to be better associated with new-onset AF [4] and stroke recurrence [10] in patients with ESUS.
Consistent with previous studies, our findings indicate that patients with AC tended to be older and have a higher atherosclerotic burden. This finding aligns with the pathogenetic evidence indicating that LAE results from progressive cardiac wall remodeling due to aging, inflammation, oxidative stress, and stretching from pressure and volume overloads [1,2].
Additionally, the infarction pattern differs; AC(+)/ESUS exhibits more cortical-subcortical infarcts and fewer small isolated cortical lesions, suggesting a potential connection to the formation of larger thrombi in the larger left atria. Our study revealed no significant differences in stroke recurrence rates. However, given the limited sample size and recurrence rates, our results may be underpowered to draw meaningful conclusions. Notably, we found that AC was independently associated with AFDAS. This finding aligns with those of previous studies [4,7] and supports the adoption of the LAVI in future trials assessing the role of anticoagulant therapy in selected patients with ESUS at high risk of AFDAS.
Our study had several strengths. First, we focused on a carefully “selected” ESUS population, following the recently proposed update, and utilized LAVI measurement as a superior marker of LAE. However, acknowledging certain limitations is important. This was a retrospective, observational, single-center study. We restricted our analysis to structural cardiopathy, defining AC as LAE without measuring other markers of LA dysfunction. Further studies should include serological and electrophysiological biomarkers to ensure a more comprehensive evaluation of AC in ESUS. Finally, the initiation of anticoagulation therapy might have occurred after AFDAS, potentially influencing the observed stroke recurrence rate.
Despite these limitations, our study provides valuable insights for a deeper understanding of the role of AC in ESUS. Although we found an independent association between AC and AFDAS, no significant associations were observed with stroke severity, 90-day outcome, and stroke recurrence. Considering the recent failure of the ARCADIA trial (NCT03192215), our results may prove instrumental in the design of future trials aimed at demonstrating the benefits of anticoagulation therapy in these patients.

Supplementary materials

Supplementary materials related to this article can be found online at https://doi.org/10.5853/jos.2024.00031.
Supplementary Table 1.
Differences in clinical, radiological and echocardiographic characteristics between ESUS patients classified per traditional versus revised criteria
jos-2024-00031-Supplementary-Table-1.pdf
Supplementary Figure 1.
Study flowchart. ESUS, embolic stroke of undetermined source; LAVI, left atrial volume index; PFO, patent foramen ovale.
jos-2024-00031-Supplementary-Fig-1,2.pdf
Supplementary Figure 2.
Kaplan-Meier survival analysis for risk of ischemic stroke recurrence according to the presence of atrial cardiopathy. AC, atrial cardiopathy; ESUS, embolic stroke of undetermined source.
jos-2024-00031-Supplementary-Fig-1,2.pdf

Notes

Funding statement
None
Conflicts of interest
The authors have no financial conflicts of interest.
Author contribution
Conceptualization: ACR, GS, AM, ECA. Study design: ACR, GS. Methodology: ACR, GS, AB, BDC, AM, ECA. Data collection: ACR, GS, AB, ADP, MDP, FA, BDC. Investigation: ACR, GS, AB, BDC. Statistical analysis: ACR, GS. Writing—original draft: ACR, GS. Writing—review & editing: ACR, GS, AB, BDC, AM, ECA, CM. Approval of final manuscript: all authors.

Table 1.
Differences in echocardiographic characteristics between ESUS patients classified according to traditional and revised ESUS criteria
TTE characteristics Entire ESUS cohort (n=414, 100%) ESUS included (n=298, 72%) ESUS excluded (n=116, 28%) P
AC 150 (36.2) 125 (42.0) 25 (21.5) <0.001
AC moderate/severe 75 (18.1) 64 (21.5) 11 (9.5) <0.001
LAVI (mL/m2) 30 (24-38) 32 (25-40) 27 (21-33) <0.001
LVDD grade 2-3 46 (11.1) 39 (13.1) 7 (6.0) 0.040
LVEF (%) 59 (56-63) [n=397] 59 (56-62) [n=285] 60 (57-63) [n=112] 0.122
LVEF ≤50% 31 (7.5) 24 (8.0) 7 (6.0) 0.483
Values are presented as n (%) or median (interquartile range).
ESUS, embolic stroke of undetermined source; TTE, transthoracic echocardiography; AC, atrial cardiopathy; LAVI, left atrial volume index; LVDD, left ventricular diastolic dysfunction; LVEF, left ventricular ejection fraction.
Table 2.
Differences in clinical, radiological, and echocardiographic characteristics between ESUS patients with versus without AC (defined as LAVI >34 mL/m2)
Entire ESUS cohort (n=298, 100%) AC(+)/ESUS (n=125, 42%) AC(-)/ESUS (n=173, 58%) P
Baseline characteristics
 Age (yr) 71 (61-80) 76 (69-82) 68 (57-76) <0.001
 Female sex 136 (45.6) 63 (50.4) 73 (42.2) 0.161
 Pre-mRS score 0 (0-0) 0 (0-0) 0 (0-0) 0.096
 NIHSS score 5 (2-11) 6 (3-10) 5 (2-12) 0.567
 Prior stroke 36 (12.1) 14 (11.2) 22 (12.7) 0.692
 Current smoking 73 (24.5) 24 (19.2) 49 (28.3) 0.071
 Hypertension 234 (78.5) 114 (91.2) 120 (69.4) <0.001
 Diabetes 59 (19.8) 30 (24.0) 29 (16.8) 0.122
 Dyslipidemia 176 (59.1) 67 (53.6) 109 (63.0) 0.103
 Obesity 63 (21.1) 27 (21.6) 36 (20.8) 0.869
 CAD 52 (17.4) 33 (26.4) 19 (11.0) 0.001
 Supra-cardiac atherosclerosis 136 (45.6) 69 (55.2) 67 (38.7) 0.005
Acute reperfusion therapy
 IVT 85 (28.5) 40 (32.0) 46 (26.6) 0.309
 EVT +/- IVT 108 (36.2) 44 (35.2) 63 (36.4) 0.829
 None 152 (51.0) 59 (47.2) 93 (53.8) 0.264
Stroke pattern and location
 Anterior circulation 232 (77.8) 97 (77.6) 135 (78.0) 0.929
 Posterior circulation 80 (26.8) 34 (27.2) 46 (26.6) 0.907
 Multi-territory 21 (7.0) 10 (8.0) 11 (6.4) 0.585
 Cortical (small isolated lesions) 19 (6.4) 2 (1.6) 17 (9.8) 0.004
 Cortical-subcortical 252 (84.5) 112 (89.6) 140 (80.9) 0.041
 Deep (white/grey) matter 27 (9.1) 11 (8.8) 16 (9.2) 0.894
 Intracranial vessel occlusion 192 (64.4) 84 (67.2) 108 (62.4) 0.396
 LVO 102 (34.2) 44 (35.2) 58 (33.5) 0.764
 MeVO 90 (30.2) 40 (32.0) 50 (28.9) 0.565
TTE characteristics
 LAVI (mL/m2) 32 (25-40) 42 (38-48) 26 (22-30) <0.001
 AC moderate/severe 64 (21.5) 64 (51.2) NA
 LVDD grade 2-3 39 (13.1) 37 (29.6) 2 (1.2) <0.001
 LVEF (%) 59 (56-62) [n=285] 58 (55-62) [n=120] 60 (57-63) [n=165] 0.019
 LVEF ≤50% 24 (8.0) 12 (9.6) 12 (6.9) 0.404
90-day outcome
 mRS score 1 (0-3) [n=295] 1 (0-3) [n=124] 1 (0-2) [n=171] 0.742
 mRS 0-2 215 (72.9) 86 (68.8) 129 (74.6) 0.487
 mRS 0-3 251 (85.1) 107 (86.3) 144 (84.2) 0.621
 Death 15 (5.0) 5 (4.0) 10 (5.8) 0.747
Long-term follow-up
 Follow-up (mo) 20 (8-32) [n=290] 20 (8-32) [n=123] 20 (8-33) [n=167] 0.848
 Implantable loop recorder 52 (17.9) 22 (17.9) 30 (18.0) 0.986
 AFDAS 28 (9.7) 21 (17.1) 7 (4.2) <0.001
 Stroke recurrence 17 (5.9) 10 (8.1) 7 (4.2) 0.158
Values are presented as n (%) or median (interquartile range).
ESUS, embolic stroke of undetermined source; AC, atrial cardiopathy; LAVI, left atrial volume index; mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale; CAD, coronary artery disease; IVT, intravenous thrombolysis; EVT, endovascular treatment; LVO, large vessel occlusion; MeVO, medium vessel occlusion; TTE, transthoracic echocardiography; LVDD, left ventricular diastolic dysfunction; LVEF, left ventricular ejection fraction; AFDAS, atrial fibrillation detected after stroke.
Table 3.
Univariate and multivariate logistic regression analysis for the association between AC related variables and stroke severity, 90-day functional outcome, and follow-up variables
Univariate analysis
Multivariate analysis
OR (95% CI) P aOR (95% CI) P
Stroke severity*
 +1 point in baseline NIHSS score
  LAVI 1.01 (0.99-1.02) 0.501 1.01 (0.99-1.03) 0.226
  AC 1.12 (0.75-1.67) 0.569 1.17 (0.78-1.75) 0.442
  Moderate/severe AC 1.01 (0.63-1.62) 0.973 0.92 (0.56-1.49) 0.731
 Baseline NIHSS score >5
  LAVI 1.01 (0.99-1.03) 0.515 1.01 (0.98-1.03) 0.525
  AC 1.17 (0.74-1.86) 0.493 1.11 (0.63-1.95) 0.715
  Moderate/severe AC 1.10 (0.63-1.92) 0.732 0.92 (0.47-1.83) 0.821
90-day functional outcome
 90-day mRS 0-2
  LAVI 1.00 (0.98-1.02) 0.912 1.02 (0.99-1.05) 0.203
  AC 0.92 (0.53-1.57) 0.750 2.48 (0.97-6.31) 0.056
  Moderate/severe AC 1.14 (0.59-2.21) 0.699 1.77 (0.76-4.13) 0.184
 90-day mRS 0-3
  LAVI 1.00 (0.98-1.03) 0.525 1.04 (0.99-1.08) 0.101
  AC 1.18 (0.61-2.28) 0.621 1.60 (0.77-3.30) 0.205
  Moderate/severe AC 1.26 (0.55-2.88) 0.578 1.94 (0.65-5.76) 0.234
Follow-up
 AFDAS
  LAVI 1.05 (1.02-1.08) 0.001 1.04 (1.01-1.08) 0.009
  AC 4.71 (1.93-11.47) 0.001 4.63 (1.77-12.14) 0.002
  Moderate/severe AC 3.77 (1.68-8.43) 0.001 3.15 (1.30-7.64) 0.011
 Stroke recurrence
  LAVI 1.03 (0.99-1.07) 0.097 1.03 (0.99-1.07) 0.169
  AC 2.02 (0.75-5.47) 0.165 1.56 (0.53-4.64) 0.420
  Moderate/severe AC 1.14 (0.36-3.63) 0.824 0.88 (0.25-3.03) 0.834
AC, atrial cardiopathy; OR, odds ratio; CI, confidence interval; aOR, adjusted odds ratio; NIHSS, National Institutes of Health Stroke Scale; LAVI, left atrial volume index; mRS, modified Rankin Scale; AFDAS, atrial fibrillation detected after stroke; LVO, large vessel occlusion; MeVO, medium vessel occlusion; AIS, acute ischemic stroke; IVT, intravenous thrombolysis; EVT, endovascular treatment.
* Multivariate analysis adjusted for: site of vessel occlusion (no occlusion/LVO/MeVO) and vascular territory (anterior circulation/posterior circulation/multiterritory);
Multivariate analysis adjusted for: age, female sex, baseline NIHSS score, pre-AIS mRS score >2, site of vessel occlusion (no occlusion/LVO/MeVO) and vascular territory (anterior circulation/posterior circulation/multi-territory), arterial hypertension, diabetes, coronary artery disease, dyslipidemia, acutephase treatment (IVT alone/EVT alone/IVT+EVT);
Multivariate analysis adjusted for: age, female sex, arterial hypertension, diabetes, coronary artery disease, dyslipidemia, obesity, implantable loop recorder.

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