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Left Atrial Enlargement is Associated with Stroke Severity with Cardioembolic and Cryptogenic Subtypes in a Chinese Population
ARTICLE IN PRESS
Left Atrial Enlargement is Associated with Stroke Severity with Cardioembolic and Cryptogenic Subtypes in a Chinese Population Jie Xue, MD,# Xu shen Xu, MD,# Xiao qiong Zhu, MD,# Zhi zhang Li, MD, Xiao-guang Zhang, MD, Yan-ting Ma, MD, Wen-hao Yang, MD, Ling-yun Liu, PhD, and Yun-hua Yue, PhD
Background: Left atrial enlargement is associated with increased risk for stroke. However, few studies that evaluated the correlation between left atrial size and ischemic stroke severity. In this study, we aim to evaluate the association between left atrial size and stroke severity, especially with cardioembolic and cryptogenic stroke in the Chinese population. Methods: A total of 1271 patients with acute ischemic stroke were included in this study. Echocardiographic left atrial diameter was measured and indexed to height. Stroke severity was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Moderate-to-severe neurologic deficit was defined as NIHSS greater than or equal to 5. Patients were divided into mild, moderate, or severe abnormal left atrial size by tertile distribution. Binary logistic regression analysis was used to identify independent predictors of severe stroke after adjustment. Results: Among all enrolled patients, 328 (25.8%) were classified into moderate-to severe stroke severity (NIHSS 5). In the multivariable model, compared with the lowest tertile of left atrial size, the odds ratio for moderate-to-severe neurologic deficit was 0.902 (95% CI, 0.644-1.264, P = .550) when left atrial size was the highest tertile. Of all patients, 190 patients were further categorized as cardioembolic and cryptogenic subtypes, and 70 (36.8%) were classified into moderate-to-severe stroke severity. After adjusting for confounders, compared with the lowest tertile, the top tertile of left atrial size was significantly associated with moderate-to-severe stroke (3.156, 95% CI, 1.1438.711, P = .027). Conclusion: Left atrial enlargement was associated with more severe initial neurologic deficits of embolic subtypes (cardioembolic and cryptogenic stroke) in patients with acute ischemic stroke. Key Words: Left atrial size—stroke severity—NIHSS—cardioembolic and cryptogenic stroke © 2020 Elsevier Inc. All rights reserved.
Introduction
From the Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China. Received December 8, 2019; revision received February 10, 2020; accepted February 13, 2020. Financial disclosure: None. Address correspondence to Yun-hua Yue, PhD and Ling-yun Liu, PhD, Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China. Emails: [email protected], [email protected]. # These authors contributed equally to this work. 1052-3057/$ - see front matter © 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104767
Ischemic stroke is the leading cause of death and adult disability in the world.1 In China, the annual stroke mortality rate reached approximately 157 per 100,000 people.2 Although a variety of risk factors have been identified for ischemic stroke, the severity of ischemic stroke can be very different. Therefore, it is important to predict the severity of stroke. Left atrium is 1 of the 4 chambers of the heart and increased left atrial (LA) size is shown to be correlated with higher risk of atrial fibrillation (AF),3-5 cardiovascular events6,7 and all-cause mortality.8,9 It has been newly reported that left ventricular hypertrophy was associated with more severe stroke and higher in-hospital mortality
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in patients with acute ischemic stroke.10 However, the relationship between LA size and the severity of ischemic stroke was less reported. Kim et al11 found that LA enlargement was correlated with stroke severity in ischemic stroke patients with AF.11 In previous study, we have found LA enlargement is an independent predictor of the composite of recurrent cardioembolic or cryptogenic stroke, suggesting that these 2 stroke subtypes may share a common embolic mechanism.12 The purpose of this study was to investigate the association between LA size and stroke severity of patients with acute ischemic stroke. We hypothesized that LA size would be an independent predictor of stroke severity, especially with cardioembolic and cryptogenic stroke.
Participants and Methods Study Population This is a hospital-based observational study performed in the Department of Neurology at Yangpu Hospital Tongji University School of Medicine. Patients who met all of the following inclusion criteria were enrolled: (1) age greater than or equal to 18 years; (2) a diagnosis of acute ischemic stroke. A total of 1271 patients with acute ischemic stroke were enrolled in the present study between December 2015 and September 2018. Ischemic stroke etiologic subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (Trial of Org 10172 in Acute Stroke Treatment) criteria.13 The study was approved by the ethics committee of the Yangpu Hospital Tongji University School of Medicine. Clinical information obtained included age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, diabetes mellitus, hyperlipidemia, coronary heart disease, AF, smoking, and alcohol drinking.
Echocardiography Measurements Transthoracic echocardiography was performed in the left lateral decubitus position using standard imaging planes, based on the recommendations of the American Society of Echocardiography.14 Left atrial diameter was measured using 2-dimensional echocardiography, from the posterior aortic wall to the posterior LA wall, in the parastemal longaxis view at the end-ventricular systole. LA diameter was measured and indexed to height (LA diameter/H) according to previous studies.8,12 Left ventricular (LV) ejection fraction was estimated using the Teichholz formula or the Simpson rule. The data of the echocardiographic measurements was recorded during hospitalization. The data of the echocardiographic measurements were blinded to the neurologists who evaluated the stroke subtypes.
Stroke Severity Stroke severity was assessed based on the National Institutes of Health Stroke Scale (NIHSS).15 The NIHSS score was assessed for all patients at admission. Ischemic
stroke severity fall into mild versus moderate-to-severe neurologic deficit using an NIHSS score cutoff of 5 based on a previous study.10
Statistical Analysis Statistical analysis were performed using the SPSS 22 software package for Windows (SPSS Inc., Chicago, IL, RRID: SCR_002865). Data are presented as mean § SD or median (interquartile range) for continuous variables and percentages for categorical variables. Distribution normality was analyzed with the Kolmogorov-Smirnov test. A 2-sided probability value less than .05 was used to assess statistical significance. Spearman’s rank correlation was performed for linear regression between LA diameter/H and NIHSS score as continuous variables. In the absence of any established standards for LA diameter/H, patients were divided into mild, moderate, or severe abnormal LA diameter /H by tertile distribution. Binary logistic regression analysis was used to identify independent predictors of severe stroke at admission. The same grouping methods were used in cardioembolic and cryptogenic subtypes. LA diameter/H was also used in the analysis as continuous variables and 95% confidence intervals (95% CI) were estimated. Covariates considered for inclusion in the multivariate analyses included demographics characteristics (age, sex, BMI), clinical risk factors (systolic BP, diastolic BP, diabetes mellitus, hyperlipidemia, coronary heart disease, AF, smoking, and alcohol drinking), echocardiographic LV ejection fraction based on a previous study.10
Results Baseline Characteristics Baseline characteristics of participants in the acute ischemic stroke group and different stroke subtypes are shown in Table 1. The median age of the patients was 69.0 years old (61.0-82.0) and 483 (38%) were female. The median BMI was 24.0 kg/m2 (22.0-26.1). Moderate-tosevere strokes on admission were found in 328 patients (25.8%) in all patients. And 70 (36.8%) patients in cardioembolic and cryptogenic group were classified as moderate-to-severe stroke.
Association between LA Size and Stroke Severity of Any Subtype Table 2 shows the risk factors estimated for ischemic stroke and stroke severity with and without adjustment for demographic information, clinical, and echocardiographic covariates in all patients. In the univariate analysis, AF is positively associated with moderate-to-severe stroke severity (P = .008). And older patients were likely to have higher NIHSS score, but the correlation was not statistically significant (P = .056). However, the highest tertile of LA diameter/ H is not associated with moderate-to-severe stroke severity (0.973, 95% CI, 0.715-1.323, P = .859) when compared with the lowest tertile of LA diameter/H. In the multivariable
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Table 1. Baseline demographics and clinical data in all patients different stroke subtypes at admission Total (1271) Age (years) Gender (female) BMI (kg/m2) Systolic BP, mmHg Diastolic BP, mmHg Diabetes (n) Hyperlipidemia (n) Coronary heart disease (n) AF (n) Smoking (n) Alcohol drinking (n) LA diameter/H T1 T2 T3 LV ejection fraction NIHSS NIHSS 5 Stroke etiologic subtypes Atherosclerotic Cardioembolic Lacunar Cryptogenic
Cardioembolic and Cryptogenic subtypes (190)
Atherosclerotic and Lacunar subtypes (1081)
P value
71.0 (61.8-84.0) 83 (43.7) 23.1 (20.7-26.0) 140 (130-151) 80 (74-87) 20 (10.5) 19 (10.0) 22 (11.6) 60 (31.6) 71 (37.4) 22 (17.3) 21.7 (19.1-26.0) 18.0 (16.9-18.8) 21.3 (20.6-23.0) 27.8 (26.3-31.6) 67 (62-71) 3 (1-6) 70 (36.8)
68.0 (61.0-81.0) 400 (37.0) 24.2 (22.2-26.2) 148 (136-160) 82 (78-90) 479 (44.3) 284 (26.3) 127 (11.7) 27 (2.5) 420 (38.9) 150 (13.9) 20.6 (18.8-22.5) 17.9 (16.8-18.8) 20.6 (20.0-21.0) 23.3 (22.5-25.0) 67 (62-71) 3 (1-4) 258 (23.9)
.109 .089 .001 <.001 .002 <.001 <.001 1.000 <.001 .747 .423 <.001
69.0 (61.0-82.0) 483 (38.0) 24.0 (22.0-26.1) 146 (135-160) 82 (78-90) 499 (39.3) 303 (23.8) 149 (11.7) 87 (6.8) 491 (38.6) 172 (13.5) 20.6 (18.8-22.9) 17.9 (16.8-18.8) 20.6 (20.0-21.2) 23.9 (22.8-25.9) 67 (62-71) 3 (1-5) 328 (25.8) 555 (43.7) 64 (5) 526 (41.4) 126 (9.9)
.793 .022 <.001
555 (51.3) 64 (33.7) 526 (48.7) 126 (66.3)
Abbreviations: AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; LA diameter/H, left atrial diameter/Height; LV, left ventricular; T1, LA diameter/H at first tertile, T2, LA diameter/H at second tertile, T3, LA diameter/H at third tertile. Data are presented as medians (IQR) or as number (percentage).
model adjusting for demographics characteristics (age, sex, BMI), clinical risk factors (systolic BP, diastolic BP, diabetes mellitus, hyperlipidemia, coronary heart disease, AF, smoking, and alcohol drinking), echocardiographic LV ejection fraction, compared with the lowest tertile of LA diameter/ H, the odds ratio for moderate-to-severe neurologic deficit was 0.902 (95% CI, 0.644-1.264, P = .550) when LA diameter/H was the highest tertile. Similar results were found when LA diameter/H was used as continuous variable for analysis. There was also no significant correlation between LA diameter/H and NIHSS score in all patients (r = 0.032, P = .254; Fig 1). The independent predictors of moderate-tosevere stroke were age, female gender and AF.
Association between LA Size and Stroke Severity of Cardioembolic and Cryptogenic Subtypes For cardioembolic and cryptogenic subtypes, we showed the risk factors for ischemic stroke severity with and without adjustment for demographic information, clinical, and echocardiographic covariates in Table 3. In the univariate analysis, the highest tertile of LA diameter/H is positively associated with moderate-to-severe stroke severity (2.187, 95% CI, 1.031-4.643, P = .041) when compared with the lowest tertile of LA diameter/H. After adjusting for demographics characteristics (age, sex, BMI), clinical risk factors (systolic BP, diastolic BP, diabetes mellitus, hyperlipidemia,
coronary heart disease, AF, smoking, and alcohol drinking), echocardiographic LV ejection fraction, patients in the top tertiles had higher odds ratio for moderate-to-severe stroke (3.156, 95% CI, 1.143-8.711, P = .027). BMI was also found as an independent predictors of moderate-to-severe stroke in cardioembolic and cryptogenic subtypes (0.886, 95% CI, 0.808-0.971, P = .010). In a secondary analysis, using LA diameter/H as a continuous variable, the association attenuated in the univariate and multivariable model after adjustment (unadjusted OR 1.059 per 1 mm/m change in LA diameter/H, 95% CI, 1.003-1.119, P = .040; adjusted OR 1.091 per 1 mm/m change in LA diameter/H, 95% CI, 1.010-1.178, P = .028). Moreover, there was a positive correlation between LA diameter/H and NIHSS score in cardioembolic and cryptogenic subtypes (r = 0.219, P< .01; Fig 2).
Discussion In this study performed in patients with acute ischemic stroke, LA diameter/H was not associated with stroke severity in patients of all stroke subtypes. However, in a further analysis, the highest tertile of LA diameter/H was associated with moderate-to-severe stroke in the composite of cardioembolic and cryptogenic subtypes in a multivariable model when compared with the lowest tertile of LA diameter/H, suggesting that LA diameter/H was a predictor of
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Table 2. Factors associated with severe stroke in univariate and multivariate analysis in all stroke subtypes Univariate analysis
Age Gender (female) BMI Systolic BP Diastolic BP Diabetes Hyperlipidemia Coronary heart disease AF Smoking Alcohol drinking LA diameter/H T1 T2 T3 Per 1 mm/m increase LV ejection fraction
Multivariate analysis
Odds ratio
95% Confidence interval
P value
Odds ratio
95% Confidence interval
P value
1.010 1.229 0.977 1.003 0.997 1.145 1.076 1.104 0.543 0.978 0.914
1.000-1.021 0.945-1.598 0.943-1.012 0.996-1.009 0.988-1.007 0.883-1.483 0.799-1.449 0.742-1.644 0.345-0.854 0.756-1.265 0.636-1.312
.056 .124 .194 .421 .595 .308 .631 .625 .008 .865 .624
1.012 1.430 0.986 1.005 0.997 1.098 0.960 1.164 0.509 1.069 0.914
1.000-1.024 1.034-1.978 0.950-1.024 0.997-1.012 0.985-1.008 0.841-1.433 0.705-1.309 0.767-1.767 0.312-0.832 0.763-1.499 0.607-1.378
.046 .030 .469 .211 .553 .493 .798 .474 .007 .698 .669
Ref 1.016 0.973 1.013 1.116
0.747-1.382 0.715-1.323 0.979-1.048 0.191-6.501
.919 .859 .455 .903
Ref 0.945 0.902 0.998 1.459
0.689-1.297 0.644-1.264 0.960-1.038 0.239-8.892
.726 .550 .932 .682
Abbreviations: AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; LA diameter/H, left atrial diameter/Height; LV, left ventricular; T1, LA diameter/H at first tertile, T2, LA diameter/H at second tertile, T3, LA diameter/H at third tertile.
Figure 1. Correlation between LA diameter/H and NIHSS score in all patients; r [spearman] = 0.032, P= .254. Abbreviations: LA diameter/H, left atrial diameter/Height.
moderate-to-severe stroke. This association persisted even when using LA diameter/H as a continuous variable. A number of studies have assessed the value of LA size for predicting stroke based on the general population, but the conclusions vary. Nagarajarao et al8 reported that LA diameter/H was an independent predictor of stroke in a
population of 1886 African Americans, but relationship did not remain significant after adjustment for LV hypertrophy and LV ejection fraction. Barnes et al16 found that LA size, as evaluated by LA volume, was associated with ischemic stroke in an elderly cohort with sinus rhythm. On the contrary, the relationship between LA
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Table 3. Factors associated with severe stroke in univariate and multivariate analysis in cardioembolic and cryptogenic subtypes Univariate analysis
Age Gender (female) BMI Systolic BP Diastolic BP Diabetes Hyperlipidemia Coronary heart disease AF Smoking Alcohol drinking LA diameter/H T1 T2 T3 Per 1 mm/m increase LV ejection fraction
Multivariate analysis
Odds ratio
95% Confidence interval
P value
Odds ratio
95% Confidence interval
P value
1.016 0.962 0.925 1.004 0.993 0.545 1.717 0.439 0.821 0.922 1.024
0.993-1.040 0.531-1.742 0.855-1.001 0.988-1.019 0.958-1.029 0.215-1.384 0.591-4.990 0.179-1.078 0.438-1.541 0.502-1.693 0.407-2.577
.165 .898 .052 .658 .695 .202 .321 .073 .540 .794 .961
0.999 1.163 0.886 1.012 0.982 0.563 1.276 0.339 1.932 0.663 1.424
0.970-1.029 0.520-2.605 0.808-0.971 0.993-1.032 0.939-1.026 0.183-1.732 0.392-4.153 0.103-1.112 0.775-4.814 0.291-1.509 0.480-4.229
.938 .713 .010 .210 .419 .316 .686 .074 .158 .327 .524
Ref 1.500 2.187 1.059 8.571
0.699-3.219 1.031-4.643 1.003-1.119 0.201-365.961
.298 .041 .040 .262
Ref 1.839 3.156 1.091 8.866
0.795-4.255 1.143-8.711 1.010-1.178 0.166-472.132
.155 .027 .028 .282
Abbreviations: AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; LA diameter/H, left atrial diameter/Height; LV, left ventricular; T1, LA diameter/H at first tertile, T2, LA diameter/H at second tertile, T3, LA diameter/H at third tertile.
Figure 2. Correlation between LA diameter/H and NIHSS score in in cardioembolic and cryptogenic subtypes; r [spearman] = 0.219, P< .01. Abbreviations: LA diameter/H, left.
size and stroke was undefined in 2 prospective studies.6,7 And some found that the association was influenced by gender.9,17,18 The different characteristics of enrolled subjects and different measurements for LA size might be the explanations. Recently, in a systematic review, the author looked through 9 cohort studies and concluded that LA enlargement may represent an important predictor of
stroke across a variety of patient populations in sinus rhythm.19 To the best of our knowledge, the correlation between LA size and clinical neurologic deficit has been reported in a retrospective study.11 Investigators found that LA enlargement is associated with severe ischemic stroke in men with nonvalvular AF, suggesting that LA enlargement may play a
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crucial role for thrombogenesis in AF.11 Recently, there is growing awareness that most of cryptogenic strokes are embolic, and propose the pragmatic clinical construct of embolic stroke of undetermined source.20,21 In previous studies, LA enlargement was shown to be an independent predictor of recurrent cardioembolic and cryptogenic stroke, indicating that 2 subtypes may share a common embolic mechanism.12,22 In this study, we focused on the association between LA size and stroke severity of patients with acute ischemic stroke, especially with cardioembolic and cryptogenic stroke. The results indicate that LA size was associated with stroke severity of embolic stroke (cardioembolic or cryptogenic stroke). The association between LA size and stroke severity might be partly explained by the relationship between LA enlargement and AF, a well-established condition that increases the risk of severe stroke.23 Indeed, LA enlargement is well known to be a high risk factor for the development of AF.3,24 However, we found that AF is a negative factor with stroke severity after analysis. The number of cardioembolic stroke patients were much lower than other subtypes in our study. As we all know, AF directly increases the risk of cardiogenic stroke severity but it is not clear that AF also increase other stroke subtypes. And the proportion of AF patients is only 6.8% in our study which is significantly lower than 20.6% reported in a previous study.23 All the above may be the causes. Another proposed mechanism is that approximately 90% of thrombi in the left atrium are known to be located in the LA appendage. It has been shown that with an increase in LA volume, reduced flow velocity in the LA appendage contribute to an increased risk for blood stasis, and thrombus formation for embolic stroke.17,18,25,26 This is supported by transesophageal echocardiographic data, suggesting the correlations between LA enlargement and spontaneous echocardiographic contrast and embolic events.17 Therefore, the severity of ischemic stroke might have been associated with the LA appendage size, which was indirectly demonstrated by an increase in LA diameter/H in this study. Our study has several important limitations. First, we enrolled patients capable of receiving echocardiography and the study design was retrospective, both of which could cause selection bias. Second, long-term heart-rhythm monitoring was not routinely performed in our study, so the paroxysmal AF status may be missed. In addition, the ratio of cryptogenic is quite a bit lower than prior studies which may cause classification bias. Finally, our study lacked the data of LA volume, which is more strongly associated with cardiovascular events, and is a more reliable estimator of LA size than LA diameter.27 However, LA diameter is more readily available and more widely used in clinic. In conclusion, this is the first study analyzing the association between LA size and stroke severity based on a Chinese population. Our study found that increased LA size was associated with more severe initial neurologic deficits of embolic subtypes (cardioembolic and cryptogenic stroke) in patients with acute ischemic stroke after adjusting for baseline
demographics characteristics, clinical factors, and echocardiographic LV ejection fraction.
Acknowledgement We thank Chun-chun Hu for the help of editing the figures.
Conflict of Interest The authors declare that they have no conflict of interests.
References 1. Mortality GBD, Causes of Death C. Global, regional, and national life expectancy, all-cause mortality, and causespecific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet 2016;388:1459-1544. 2. Liu L, Wang D, Wong KS, et al. Stroke and stroke care in China: huge burden, significant workload, and a national priority. Stroke 2011;42:3651-3654. 3. Vaziri SM, Larson MG, Benjamin EJ, et al. Echocardiographic predictors of nonrheumatic atrial fibrillation. The Framingham Heart Study. Circulation 1994;89:724-730. 4. Psaty BM, Manolio TA, Kuller LH, et al. Incidence of and risk factors for atrial fibrillation in older adults. Circulation 1997;96:2455-2461. 5. Tsang TS, Barnes ME, Bailey KR, et al. Left atrial volume: important risk marker of incident atrial fibrillation in 1655 older men and women. Mayo Clin Proc 2001;76:467-475. 6. Gardin JM, McClelland R, Kitzman D, et al. M-mode echocardiographic predictors of six- to seven-year incidence of coronary heart disease, stroke, congestive heart failure, and mortality in an elderly cohort (the Cardiovascular Health Study). Am J Cardiol 2001;87:1051-1057. 7. Kizer JR, Bella JN, Palmieri V, et al. Left atrial diameter as an independent predictor of first clinical cardiovascular events in middle-aged and elderly adults: the Strong Heart Study (SHS). Am Heart J 2006;151:412-418. 8. Nagarajarao HS, Penman AD, Taylor HA, et al. The predictive value of left atrial size for incident ischemic stroke and allcause mortality in African Americans: the Atherosclerosis Risk in Communities (ARIC) Study. Stroke 2008;39:2701-2706. 9. Bouzas-Mosquera A, Broull on FJ, Alvarez-García N, et al. Left atrial size and risk for all-cause mortality and ischemic stroke. CMAJ 2011;183:E657-E664. 10. Tziomalos K, Sofogianni A, Angelopoulou SM, et al. Left ventricular hypertrophy assessed by electrocardiogram is associated with more severe stroke and with higher inhospital mortality in patients with acute ischemic stroke. Atherosclerosis 2018;274:206-211. 11. Kim TW, Jung SW, Song IU, et al. Left atrial dilatation is associated with severe ischemic stroke in men with nonvalvular atrial fibrillation. Journal of the Neurological Sciences 2015;354:97-102. 12. Xue J, Lin Y, Huang W, et al. Left atrial size and risk of recurrent ischemic stroke in a Chinese population. Brain Behav 2017;7:e00702. 13. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993;24:35-41. 14. Sahn DJ, DeMaria A, Kisslo J, et al. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072-1083.
ARTICLE IN PRESS LEFT ATRIAL SIZE AND STROKE SEVERITY 15. Brott T, Adams HP, Olinger CP, et al. Measurements of acute cerebral infarction: a clinical examination scale. Stroke 1989;20:864-870. 16. Barnes ME, Miyasaka Y, Seward JB, et al. Left atrial volume in the prediction of first ischemic stroke in an elderly cohort without atrial fibrillation. Mayo Clin Proc 2004; 79:1008-1014. 17. Benjamin EJ, D’Agostino RB, Belanger AJ, et al. Left atrial size and the risk of stroke and death. The Framingham Heart Study. Circulation 1995;92:835-841. 18. Di Tullio MR, Sacco RL, Sciacca RR, et al. Left atrial size and the risk of ischemic stroke in an ethnically mixed population. Stroke 1999;30:2019-2024. 19. Overvad TF, Nielsen PB, Larsen TB, et al. Left atrial size and risk of stroke in patients in sinus rhythm. A systematic review. Thromb Haemost 2016;116:206-219. 20. Hart RG, Diener HC, Coutts SB, et al. Embolic strokes of undetermined source: the case for a new clinical construct. Lancet Neurol 2014;13:429-438. 21. Fonseca AC, Ferro JM. Cryptogenic stroke. Eur J Neurol 2015;22:618-623.
7 22. Yaghi S, Moon YP, Mora-McLaughlin C, et al. Left atrial enlargement and stroke recurrence: the Northern Manhattan Stroke Study. Stroke 2015;46:1488-1493. 23. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke 1996; 27:1760-1764. 24. Kannel WB, Wolf PA, Benjamin EJ, et al. Prevalence, incidence, prognosis, and predisposing conditions for atrial fibrillation: population-based estimates. Am J Cardiol 1998;82:2N-9N. 25. Daniel WG, Nellessen U, Schr€ oder E, et al. Left atrial spontaneous echo contrast in mitral valve disease: an indicator for an increased thromboembolic risk. J Am Coll Cardiol 1988;11:1204-1211. 26. Cujec B, Polasek P, Voll C, Shuaib A. Transesophageal echocardiography in the detection of potential cardiac source of embolism in stroke patients. Stroke 1991;22:727-733. 27. Khankirawatana B, Khankirawatana S, Porter T. How should left atrial size be reported? Comparative assessment with use of multiple echocardiographic methods. Am Heart J 2004;147:369-374.
Left Atrial Enlargement is Associated with Stroke Severity with Cardioembolic and Cryptogenic Subtypes in a Chinese Population Jie Xue, MD,# Xu shen Xu, MD,# Xiao qiong Zhu, MD,# Zhi zhang Li, MD, Xiao-guang Zhang, MD, Yan-ting Ma, MD, Wen-hao Yang, MD, Ling-yun Liu, PhD, and Yun-hua Yue, PhD
Background: Left atrial enlargement is associated with increased risk for stroke. However, few studies that evaluated the correlation between left atrial size and ischemic stroke severity. In this study, we aim to evaluate the association between left atrial size and stroke severity, especially with cardioembolic and cryptogenic stroke in the Chinese population. Methods: A total of 1271 patients with acute ischemic stroke were included in this study. Echocardiographic left atrial diameter was measured and indexed to height. Stroke severity was assessed at admission with the National Institutes of Health Stroke Scale (NIHSS). Moderate-to-severe neurologic deficit was defined as NIHSS greater than or equal to 5. Patients were divided into mild, moderate, or severe abnormal left atrial size by tertile distribution. Binary logistic regression analysis was used to identify independent predictors of severe stroke after adjustment. Results: Among all enrolled patients, 328 (25.8%) were classified into moderate-to severe stroke severity (NIHSS 5). In the multivariable model, compared with the lowest tertile of left atrial size, the odds ratio for moderate-to-severe neurologic deficit was 0.902 (95% CI, 0.644-1.264, P = .550) when left atrial size was the highest tertile. Of all patients, 190 patients were further categorized as cardioembolic and cryptogenic subtypes, and 70 (36.8%) were classified into moderate-to-severe stroke severity. After adjusting for confounders, compared with the lowest tertile, the top tertile of left atrial size was significantly associated with moderate-to-severe stroke (3.156, 95% CI, 1.1438.711, P = .027). Conclusion: Left atrial enlargement was associated with more severe initial neurologic deficits of embolic subtypes (cardioembolic and cryptogenic stroke) in patients with acute ischemic stroke. Key Words: Left atrial size—stroke severity—NIHSS—cardioembolic and cryptogenic stroke © 2020 Elsevier Inc. All rights reserved.
Introduction
From the Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, Shanghai, China. Received December 8, 2019; revision received February 10, 2020; accepted February 13, 2020. Financial disclosure: None. Address correspondence to Yun-hua Yue, PhD and Ling-yun Liu, PhD, Department of Neurology, Yangpu Hospital, Tongji University School of Medicine, 450 Tengyue Road, Shanghai 200090, China. Emails: [email protected], [email protected]. # These authors contributed equally to this work. 1052-3057/$ - see front matter © 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2020.104767
Ischemic stroke is the leading cause of death and adult disability in the world.1 In China, the annual stroke mortality rate reached approximately 157 per 100,000 people.2 Although a variety of risk factors have been identified for ischemic stroke, the severity of ischemic stroke can be very different. Therefore, it is important to predict the severity of stroke. Left atrium is 1 of the 4 chambers of the heart and increased left atrial (LA) size is shown to be correlated with higher risk of atrial fibrillation (AF),3-5 cardiovascular events6,7 and all-cause mortality.8,9 It has been newly reported that left ventricular hypertrophy was associated with more severe stroke and higher in-hospital mortality
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in patients with acute ischemic stroke.10 However, the relationship between LA size and the severity of ischemic stroke was less reported. Kim et al11 found that LA enlargement was correlated with stroke severity in ischemic stroke patients with AF.11 In previous study, we have found LA enlargement is an independent predictor of the composite of recurrent cardioembolic or cryptogenic stroke, suggesting that these 2 stroke subtypes may share a common embolic mechanism.12 The purpose of this study was to investigate the association between LA size and stroke severity of patients with acute ischemic stroke. We hypothesized that LA size would be an independent predictor of stroke severity, especially with cardioembolic and cryptogenic stroke.
Participants and Methods Study Population This is a hospital-based observational study performed in the Department of Neurology at Yangpu Hospital Tongji University School of Medicine. Patients who met all of the following inclusion criteria were enrolled: (1) age greater than or equal to 18 years; (2) a diagnosis of acute ischemic stroke. A total of 1271 patients with acute ischemic stroke were enrolled in the present study between December 2015 and September 2018. Ischemic stroke etiologic subtypes were classified according to the Trial of Org 10172 in Acute Stroke Treatment (Trial of Org 10172 in Acute Stroke Treatment) criteria.13 The study was approved by the ethics committee of the Yangpu Hospital Tongji University School of Medicine. Clinical information obtained included age, gender, body mass index (BMI), systolic blood pressure (BP), diastolic BP, diabetes mellitus, hyperlipidemia, coronary heart disease, AF, smoking, and alcohol drinking.
Echocardiography Measurements Transthoracic echocardiography was performed in the left lateral decubitus position using standard imaging planes, based on the recommendations of the American Society of Echocardiography.14 Left atrial diameter was measured using 2-dimensional echocardiography, from the posterior aortic wall to the posterior LA wall, in the parastemal longaxis view at the end-ventricular systole. LA diameter was measured and indexed to height (LA diameter/H) according to previous studies.8,12 Left ventricular (LV) ejection fraction was estimated using the Teichholz formula or the Simpson rule. The data of the echocardiographic measurements was recorded during hospitalization. The data of the echocardiographic measurements were blinded to the neurologists who evaluated the stroke subtypes.
Stroke Severity Stroke severity was assessed based on the National Institutes of Health Stroke Scale (NIHSS).15 The NIHSS score was assessed for all patients at admission. Ischemic
stroke severity fall into mild versus moderate-to-severe neurologic deficit using an NIHSS score cutoff of 5 based on a previous study.10
Statistical Analysis Statistical analysis were performed using the SPSS 22 software package for Windows (SPSS Inc., Chicago, IL, RRID: SCR_002865). Data are presented as mean § SD or median (interquartile range) for continuous variables and percentages for categorical variables. Distribution normality was analyzed with the Kolmogorov-Smirnov test. A 2-sided probability value less than .05 was used to assess statistical significance. Spearman’s rank correlation was performed for linear regression between LA diameter/H and NIHSS score as continuous variables. In the absence of any established standards for LA diameter/H, patients were divided into mild, moderate, or severe abnormal LA diameter /H by tertile distribution. Binary logistic regression analysis was used to identify independent predictors of severe stroke at admission. The same grouping methods were used in cardioembolic and cryptogenic subtypes. LA diameter/H was also used in the analysis as continuous variables and 95% confidence intervals (95% CI) were estimated. Covariates considered for inclusion in the multivariate analyses included demographics characteristics (age, sex, BMI), clinical risk factors (systolic BP, diastolic BP, diabetes mellitus, hyperlipidemia, coronary heart disease, AF, smoking, and alcohol drinking), echocardiographic LV ejection fraction based on a previous study.10
Results Baseline Characteristics Baseline characteristics of participants in the acute ischemic stroke group and different stroke subtypes are shown in Table 1. The median age of the patients was 69.0 years old (61.0-82.0) and 483 (38%) were female. The median BMI was 24.0 kg/m2 (22.0-26.1). Moderate-tosevere strokes on admission were found in 328 patients (25.8%) in all patients. And 70 (36.8%) patients in cardioembolic and cryptogenic group were classified as moderate-to-severe stroke.
Association between LA Size and Stroke Severity of Any Subtype Table 2 shows the risk factors estimated for ischemic stroke and stroke severity with and without adjustment for demographic information, clinical, and echocardiographic covariates in all patients. In the univariate analysis, AF is positively associated with moderate-to-severe stroke severity (P = .008). And older patients were likely to have higher NIHSS score, but the correlation was not statistically significant (P = .056). However, the highest tertile of LA diameter/ H is not associated with moderate-to-severe stroke severity (0.973, 95% CI, 0.715-1.323, P = .859) when compared with the lowest tertile of LA diameter/H. In the multivariable
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Table 1. Baseline demographics and clinical data in all patients different stroke subtypes at admission Total (1271) Age (years) Gender (female) BMI (kg/m2) Systolic BP, mmHg Diastolic BP, mmHg Diabetes (n) Hyperlipidemia (n) Coronary heart disease (n) AF (n) Smoking (n) Alcohol drinking (n) LA diameter/H T1 T2 T3 LV ejection fraction NIHSS NIHSS 5 Stroke etiologic subtypes Atherosclerotic Cardioembolic Lacunar Cryptogenic
Cardioembolic and Cryptogenic subtypes (190)
Atherosclerotic and Lacunar subtypes (1081)
P value
71.0 (61.8-84.0) 83 (43.7) 23.1 (20.7-26.0) 140 (130-151) 80 (74-87) 20 (10.5) 19 (10.0) 22 (11.6) 60 (31.6) 71 (37.4) 22 (17.3) 21.7 (19.1-26.0) 18.0 (16.9-18.8) 21.3 (20.6-23.0) 27.8 (26.3-31.6) 67 (62-71) 3 (1-6) 70 (36.8)
68.0 (61.0-81.0) 400 (37.0) 24.2 (22.2-26.2) 148 (136-160) 82 (78-90) 479 (44.3) 284 (26.3) 127 (11.7) 27 (2.5) 420 (38.9) 150 (13.9) 20.6 (18.8-22.5) 17.9 (16.8-18.8) 20.6 (20.0-21.0) 23.3 (22.5-25.0) 67 (62-71) 3 (1-4) 258 (23.9)
.109 .089 .001 <.001 .002 <.001 <.001 1.000 <.001 .747 .423 <.001
69.0 (61.0-82.0) 483 (38.0) 24.0 (22.0-26.1) 146 (135-160) 82 (78-90) 499 (39.3) 303 (23.8) 149 (11.7) 87 (6.8) 491 (38.6) 172 (13.5) 20.6 (18.8-22.9) 17.9 (16.8-18.8) 20.6 (20.0-21.2) 23.9 (22.8-25.9) 67 (62-71) 3 (1-5) 328 (25.8) 555 (43.7) 64 (5) 526 (41.4) 126 (9.9)
.793 .022 <.001
555 (51.3) 64 (33.7) 526 (48.7) 126 (66.3)
Abbreviations: AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; LA diameter/H, left atrial diameter/Height; LV, left ventricular; T1, LA diameter/H at first tertile, T2, LA diameter/H at second tertile, T3, LA diameter/H at third tertile. Data are presented as medians (IQR) or as number (percentage).
model adjusting for demographics characteristics (age, sex, BMI), clinical risk factors (systolic BP, diastolic BP, diabetes mellitus, hyperlipidemia, coronary heart disease, AF, smoking, and alcohol drinking), echocardiographic LV ejection fraction, compared with the lowest tertile of LA diameter/ H, the odds ratio for moderate-to-severe neurologic deficit was 0.902 (95% CI, 0.644-1.264, P = .550) when LA diameter/H was the highest tertile. Similar results were found when LA diameter/H was used as continuous variable for analysis. There was also no significant correlation between LA diameter/H and NIHSS score in all patients (r = 0.032, P = .254; Fig 1). The independent predictors of moderate-tosevere stroke were age, female gender and AF.
Association between LA Size and Stroke Severity of Cardioembolic and Cryptogenic Subtypes For cardioembolic and cryptogenic subtypes, we showed the risk factors for ischemic stroke severity with and without adjustment for demographic information, clinical, and echocardiographic covariates in Table 3. In the univariate analysis, the highest tertile of LA diameter/H is positively associated with moderate-to-severe stroke severity (2.187, 95% CI, 1.031-4.643, P = .041) when compared with the lowest tertile of LA diameter/H. After adjusting for demographics characteristics (age, sex, BMI), clinical risk factors (systolic BP, diastolic BP, diabetes mellitus, hyperlipidemia,
coronary heart disease, AF, smoking, and alcohol drinking), echocardiographic LV ejection fraction, patients in the top tertiles had higher odds ratio for moderate-to-severe stroke (3.156, 95% CI, 1.143-8.711, P = .027). BMI was also found as an independent predictors of moderate-to-severe stroke in cardioembolic and cryptogenic subtypes (0.886, 95% CI, 0.808-0.971, P = .010). In a secondary analysis, using LA diameter/H as a continuous variable, the association attenuated in the univariate and multivariable model after adjustment (unadjusted OR 1.059 per 1 mm/m change in LA diameter/H, 95% CI, 1.003-1.119, P = .040; adjusted OR 1.091 per 1 mm/m change in LA diameter/H, 95% CI, 1.010-1.178, P = .028). Moreover, there was a positive correlation between LA diameter/H and NIHSS score in cardioembolic and cryptogenic subtypes (r = 0.219, P< .01; Fig 2).
Discussion In this study performed in patients with acute ischemic stroke, LA diameter/H was not associated with stroke severity in patients of all stroke subtypes. However, in a further analysis, the highest tertile of LA diameter/H was associated with moderate-to-severe stroke in the composite of cardioembolic and cryptogenic subtypes in a multivariable model when compared with the lowest tertile of LA diameter/H, suggesting that LA diameter/H was a predictor of
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Table 2. Factors associated with severe stroke in univariate and multivariate analysis in all stroke subtypes Univariate analysis
Age Gender (female) BMI Systolic BP Diastolic BP Diabetes Hyperlipidemia Coronary heart disease AF Smoking Alcohol drinking LA diameter/H T1 T2 T3 Per 1 mm/m increase LV ejection fraction
Multivariate analysis
Odds ratio
95% Confidence interval
P value
Odds ratio
95% Confidence interval
P value
1.010 1.229 0.977 1.003 0.997 1.145 1.076 1.104 0.543 0.978 0.914
1.000-1.021 0.945-1.598 0.943-1.012 0.996-1.009 0.988-1.007 0.883-1.483 0.799-1.449 0.742-1.644 0.345-0.854 0.756-1.265 0.636-1.312
.056 .124 .194 .421 .595 .308 .631 .625 .008 .865 .624
1.012 1.430 0.986 1.005 0.997 1.098 0.960 1.164 0.509 1.069 0.914
1.000-1.024 1.034-1.978 0.950-1.024 0.997-1.012 0.985-1.008 0.841-1.433 0.705-1.309 0.767-1.767 0.312-0.832 0.763-1.499 0.607-1.378
.046 .030 .469 .211 .553 .493 .798 .474 .007 .698 .669
Ref 1.016 0.973 1.013 1.116
0.747-1.382 0.715-1.323 0.979-1.048 0.191-6.501
.919 .859 .455 .903
Ref 0.945 0.902 0.998 1.459
0.689-1.297 0.644-1.264 0.960-1.038 0.239-8.892
.726 .550 .932 .682
Abbreviations: AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; LA diameter/H, left atrial diameter/Height; LV, left ventricular; T1, LA diameter/H at first tertile, T2, LA diameter/H at second tertile, T3, LA diameter/H at third tertile.
Figure 1. Correlation between LA diameter/H and NIHSS score in all patients; r [spearman] = 0.032, P= .254. Abbreviations: LA diameter/H, left atrial diameter/Height.
moderate-to-severe stroke. This association persisted even when using LA diameter/H as a continuous variable. A number of studies have assessed the value of LA size for predicting stroke based on the general population, but the conclusions vary. Nagarajarao et al8 reported that LA diameter/H was an independent predictor of stroke in a
population of 1886 African Americans, but relationship did not remain significant after adjustment for LV hypertrophy and LV ejection fraction. Barnes et al16 found that LA size, as evaluated by LA volume, was associated with ischemic stroke in an elderly cohort with sinus rhythm. On the contrary, the relationship between LA
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Table 3. Factors associated with severe stroke in univariate and multivariate analysis in cardioembolic and cryptogenic subtypes Univariate analysis
Age Gender (female) BMI Systolic BP Diastolic BP Diabetes Hyperlipidemia Coronary heart disease AF Smoking Alcohol drinking LA diameter/H T1 T2 T3 Per 1 mm/m increase LV ejection fraction
Multivariate analysis
Odds ratio
95% Confidence interval
P value
Odds ratio
95% Confidence interval
P value
1.016 0.962 0.925 1.004 0.993 0.545 1.717 0.439 0.821 0.922 1.024
0.993-1.040 0.531-1.742 0.855-1.001 0.988-1.019 0.958-1.029 0.215-1.384 0.591-4.990 0.179-1.078 0.438-1.541 0.502-1.693 0.407-2.577
.165 .898 .052 .658 .695 .202 .321 .073 .540 .794 .961
0.999 1.163 0.886 1.012 0.982 0.563 1.276 0.339 1.932 0.663 1.424
0.970-1.029 0.520-2.605 0.808-0.971 0.993-1.032 0.939-1.026 0.183-1.732 0.392-4.153 0.103-1.112 0.775-4.814 0.291-1.509 0.480-4.229
.938 .713 .010 .210 .419 .316 .686 .074 .158 .327 .524
Ref 1.500 2.187 1.059 8.571
0.699-3.219 1.031-4.643 1.003-1.119 0.201-365.961
.298 .041 .040 .262
Ref 1.839 3.156 1.091 8.866
0.795-4.255 1.143-8.711 1.010-1.178 0.166-472.132
.155 .027 .028 .282
Abbreviations: AF, atrial fibrillation; BMI, body mass index; BP, blood pressure; LA diameter/H, left atrial diameter/Height; LV, left ventricular; T1, LA diameter/H at first tertile, T2, LA diameter/H at second tertile, T3, LA diameter/H at third tertile.
Figure 2. Correlation between LA diameter/H and NIHSS score in in cardioembolic and cryptogenic subtypes; r [spearman] = 0.219, P< .01. Abbreviations: LA diameter/H, left.
size and stroke was undefined in 2 prospective studies.6,7 And some found that the association was influenced by gender.9,17,18 The different characteristics of enrolled subjects and different measurements for LA size might be the explanations. Recently, in a systematic review, the author looked through 9 cohort studies and concluded that LA enlargement may represent an important predictor of
stroke across a variety of patient populations in sinus rhythm.19 To the best of our knowledge, the correlation between LA size and clinical neurologic deficit has been reported in a retrospective study.11 Investigators found that LA enlargement is associated with severe ischemic stroke in men with nonvalvular AF, suggesting that LA enlargement may play a
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crucial role for thrombogenesis in AF.11 Recently, there is growing awareness that most of cryptogenic strokes are embolic, and propose the pragmatic clinical construct of embolic stroke of undetermined source.20,21 In previous studies, LA enlargement was shown to be an independent predictor of recurrent cardioembolic and cryptogenic stroke, indicating that 2 subtypes may share a common embolic mechanism.12,22 In this study, we focused on the association between LA size and stroke severity of patients with acute ischemic stroke, especially with cardioembolic and cryptogenic stroke. The results indicate that LA size was associated with stroke severity of embolic stroke (cardioembolic or cryptogenic stroke). The association between LA size and stroke severity might be partly explained by the relationship between LA enlargement and AF, a well-established condition that increases the risk of severe stroke.23 Indeed, LA enlargement is well known to be a high risk factor for the development of AF.3,24 However, we found that AF is a negative factor with stroke severity after analysis. The number of cardioembolic stroke patients were much lower than other subtypes in our study. As we all know, AF directly increases the risk of cardiogenic stroke severity but it is not clear that AF also increase other stroke subtypes. And the proportion of AF patients is only 6.8% in our study which is significantly lower than 20.6% reported in a previous study.23 All the above may be the causes. Another proposed mechanism is that approximately 90% of thrombi in the left atrium are known to be located in the LA appendage. It has been shown that with an increase in LA volume, reduced flow velocity in the LA appendage contribute to an increased risk for blood stasis, and thrombus formation for embolic stroke.17,18,25,26 This is supported by transesophageal echocardiographic data, suggesting the correlations between LA enlargement and spontaneous echocardiographic contrast and embolic events.17 Therefore, the severity of ischemic stroke might have been associated with the LA appendage size, which was indirectly demonstrated by an increase in LA diameter/H in this study. Our study has several important limitations. First, we enrolled patients capable of receiving echocardiography and the study design was retrospective, both of which could cause selection bias. Second, long-term heart-rhythm monitoring was not routinely performed in our study, so the paroxysmal AF status may be missed. In addition, the ratio of cryptogenic is quite a bit lower than prior studies which may cause classification bias. Finally, our study lacked the data of LA volume, which is more strongly associated with cardiovascular events, and is a more reliable estimator of LA size than LA diameter.27 However, LA diameter is more readily available and more widely used in clinic. In conclusion, this is the first study analyzing the association between LA size and stroke severity based on a Chinese population. Our study found that increased LA size was associated with more severe initial neurologic deficits of embolic subtypes (cardioembolic and cryptogenic stroke) in patients with acute ischemic stroke after adjusting for baseline
demographics characteristics, clinical factors, and echocardiographic LV ejection fraction.
Acknowledgement We thank Chun-chun Hu for the help of editing the figures.
Conflict of Interest The authors declare that they have no conflict of interests.
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