A model of increasing predictability of atrial fibrillation related stroke in patients with non-valvular atrial fibrillation

Abstract

Objective: Our aim for this study was to develop a model using clinical, laboratory and echocardiographic factors, in addition to CHA2DS2-VASC score, to increase predictability of AF related stroke in patients with non-valvular atrial fibrillation (NVAF).

Methods: We retrospectively analyzed the medical history, clinical characteristics, laboratory and echocardiographic data of 373 patients with NVAF.

Results: In multiple logistic regression, CHA2DAS2 VASC score (OR 1.22 (95%CI 1.04-1.43), P=0.016), anion gap (OR 1.19 (95%CI 1.08-1.30), P < 0.001), e-peak deceleration time （EDT） (OR 1.01 (95%CI 1.00-1.01), P=0.001) and the left atrial appendage emptying rate （LAAEV） (OR 0.99 (95%CI 0.97-0.99), P=0.013) were risk factors for predicting stroke in NVAF patients. For patients with low CHA2DAS2 VASC score, anion gap (OR 1.35 (95%CI 1.03-1.77), P=0.028) and EDT (OR 1.01 (95%CI 1.00-1.02), P=0.043) were associated with stroke.

Receiver operating characteristic (ROC) curve showed that area under curve (AUC) is 11% higher in the model including anion gap, EDT， LAAEV and CHA2DS2-VASc score, compared to only using CHA2DS2-VASc score as predictor (0.70 (95%CI 0.64-0.75) vs 0.59 (95%CI 0.54-0.65)).

Conclusions: Our study showed that incorporating anion gap, EDT and LAAEV into CHA2DS2-VASC score increases the ability to predict atrial fibrillation related stroke.

Introduction

Atrial fibrillation is the most common cause of cardiogenic embolism, which can count for 20% onset of ischemic stroke^[1]. Patients with atrial fibrillation related stroke (AFRS) have a higher rate of stroke recurrence and mortality than patients with non-atrial fibrillation related stroke. Non-valvular atrial fibrillation (NVAF), as the most common type of atrial fibrillation, can lead to 5 times higher ischemic stroke comparing to individuals without atrial fibrillation^[2]. Therefore, evaluating the risk of thrombosis is crucial for preventing AFRS in patients with NVAF. 2020 European Society of Cardiology (ESC) atrial fibrillation management guidelines recommend the use of CHA2DS2-VASC score to assess the risk of thrombosis in patients with NVAF^[3]. However, studies have found that the incidence of AFRS can range from 0.38–1.15% and 8.7–15.49% for 0 and 9 CHA2DS2-VASC score respectively^[4–6]. Factors need to investigate to improve predictability of thrombosis risk in patients with NVAF.

Laboratory parameters, including NT proBNP, cTnI, eGFR, D-dimer and LDL-C, have proved to be predictive for stroke and systemic embolism in patients with NVAF^[7–9]. Left ventricular ejection fraction (LVEF), left atrial appendage blood flow velocity (LAAEV), left atrial size, left atrial appendage erythrocyte autoradiography in echocardiographic indexes are also highly related to the occurrence of stroke in patients with NVAF^[10–12]. However, the ability of laboratory parameters and echocardiographic indexes for predicting the risk of thrombosis in NVAF is controversial^[13].The purpose of this study is to analyze the medical history, clinical characteristics, laboratory and echocardiographic measurements, in addition to CHA2DS2-VASC score, of patients with NVAF to predict NVAF related stroke.

Methods

Study Population and Selection Criteria

Data in the Second Affiliated Hospital of Hebei Medical University from October 2015 to December 2021 were retrospectively collected. We reviewed the medical history, clinical characteristics, laboratory and echocardiographic measurements.

Patients aged 18 years or older with non-valvular atrial fibrillation and complete medical history, clinical, laboratory and echocardiographic data were included. Patients were excluded for moderate to severe aortic or mitral stenosis, or/and history of mitral or aortic valve surgery, or/and other factors causing cardiogenic stroke.

The atrial fibrillation was confirmed by 12 lead ECG or the duration of atrial fibrillation on 24h ambulatory ECG for more than 30 seconds. The diagnosis of non-lacunar stroke was confirmed by CT or MRI. A stroke occurring after atrial fibrillation was considered as atrial fibrillation related stroke. The definition of cardiogenic stroke used TOAST classification^[14]. Moderate to severe mitral or aortic stenosis was diagnosed as the valve orifice area measured by two-dimensional transthoracic echocardiography is no more than 1.5cm² and 1.0cm² respectively.

Diabetes mellitus (DM) was defined as a random glucose concentration over 200 mg/dL, or a fasting plasma glucose more than 126 mg/dL, or 2-hour blood glucose concentration greater than 200 mg/dL after 75g glucose load, or the use of hypoglycemic drugs or insulin. Hypertension was defined as systolic blood pressure 140 mmHg or higher, or diastolic blood pressure 90 mmHg or higher, or the use of antihypertensive drugs. Heart failure included the presence of pulmonary edema, edema of both lower limbs, orthopnea/nocturnal paroxysmal dyspnea, shortness of breath and fatigue and other clinical evidence of cardiac insufficiency. CT and MRI both were reviewed independently by two experienced radiologists. The data of transthoracic or transesophageal echocardiography were measured by an experienced ultrasound doctor and reviewed by an experienced senior ultrasound doctor. Transthoracic echocardiography used the modified Simpson method to measure the left ventricular ejection fraction^[15]. TOAST typing of cardiogenic stroke was performed independently by two experienced neurophysicians. eGFR was calculated from the patient's Scr by CKD-EPI formula^[16] .The CHA2DS2-VASC score of all patients before onset of stroke was recorded. Low CHA2DS2-VASC score was defined as 1 or less for males and 2 or less for females. All medical history, clinical, laboratory and echocardiographic data were collected at the first admission.

A total of 987 patients were with NVAF, of which 614 patients were excluded. 605 patients were excluded due to incomplete clinical data, 7 patients due to patent foramen ovale and 2 patients due to atrial septal defect. 373 patients were included in the final analysis.

All patients signed an informed consent form before their operation, and this study was approved by the ethics committee of the second hospital of Hebei Medical University. All treatments and surgical methods were carried out in accordance with relevant guidelines and regulations.

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

Statistical Analysis

SPSS (version 26.0, SPSS Inc. Chicago, IL, USA) was used for statistical analysis. Normally distributed data are represented by mean and standard deviation, and t-test is used for comparison between samples. Continuous variables that do not conform to the normal distribution are represented by median and interquartile spacing, and Mann–Whitney U is used for comparison between samples. Categorical variables are expressed in numbers and percentages, Chi square test or Fisher exact method were used for comparison.

Factors with P value less than 0.1 in univariate analysis were further included in multiple binary logistic regression to determine risk factors. To identify the ability of predicting stroke, area under curve (AUC) of receiver operating characteristic (ROC) curve was performed. As a retrospective study, the history of anticoagulant treatment and hypolipidemic therapy were not traceable. Thus, coagulation indexes and blood lipid indexes were not included in the analysis.

To investigate the predictability of factors found in the entire cohort, we perform sensitivity analysis only using patients with low CHA2DS2-VASC score.

P < 0.05 was considered statistically significant.

Results

Demographics

According to the presence of atrial fibrillation related stroke, the 373 patients were divided into stroke (169 patients) and non-stroke (204 patients) group. Of the 169 patients with stroke, 109 (64.5%) were males and 60 (35.5%) were females. Of the 204 patients without stroke, 121 (59.3%) were males and 83 (40.7%) were females. 60 (15.7%) patients were with low CHA2DS2-VASc score (Table 1).

Compared with the patients without stroke, patients with stroke were older (median age: 66 (57-70) vs 62 (54-69), P=0.006), higher in CHA2DS2-VASC score (median score: 3 (2-4) vs 2 (1-3), P =0.002) and HASBLED score (median score: 3 (2-3) vs 2 (1-3), P < 0.001), a higher rate of hypertension history (66.3% VS 51.0%, P=0.003), diabetes history (22.5% VS 14.2%, P=0.038) and heart failure (49.1% VS 21.1%, P<0.001). No statistical differences were observed in gender, types of atrial fibrillation, alcohol use, smoking history, coronary heart disease history and peripheral vascular disease history between the two groups. (Table 1)

Comparison for Patients with Low CHA2DS2-VASc Score

To investigate the predictability of factors found in the entire cohort, we perform sensitivity analysis only using patients with low CHA2DS2-VASC score.

60 patients in this study were with low CHA2DS2-VASc score, 21 (35.0%) in the stroke group and 39 (65.0%) in the non-stroke group. 11 males were in the stroke group (52.4%) and 26 males were in the non-stroke group (66.7%). The mean age of stroke group was 54.5±6.5 years, and that of non-stroke group was 52.7±10.2 years.

The demographics between the two groups showed statistically significant differences in history of hypertension (3 (14.3%) vs 0 (0%), P=0.039), heart failure (3 (14.9%) vs 0 (0%), P=0.039), and HASBLED score (2 (1-2) vs 1 (0-1), P< 0.001). (Table 3)

Direct bilirubin (5.2μmmol/L (3.9-8.0) vs 3.8μmmol/L (2.6-4.6), P=0.013), indirect bilirubin (8.9μmmol/L (6.4-12.9) vs 5.9μmmol/L (4.0-8.4), P=0.008), and anion gap (14.3 mmol/L (11.2-15.7) vs 11.9 mmol/L (10.4-13.8), P=0.013) were higher for stroke group than that for non-stroke group.(Table 4)

In the examination of transesophageal and transthoracic echocardiography, only the LVEF value (59.8% (55.7%-66.4 %) vs 63.9% (61.3%-67.7%), P=0.031) between the two groups was statistically significant. (Table 4).

Laboratory Parameters

Compared with non-stroke group, stroke group had a larger mean platelet volume (9.3 fL (8.5-10.4) vs 8.9 fL (8.1-10.0), P=0.010), higher γ Glutamyl transferase (26 U/L (17-41) vs 20 U/L (16-29), P<0.001) and anion gap (13.8±2.5 vs 12.7±2.5 mmol/L, P<0.001). Stroke patients were lower in thyrotropin releasing hormone (TSH) (1.78 mIU/L (1.12-2.94) vs 2.25 mIU/L (1.36-3.40), P=0.021) (Table 2)

Transthoracic and Transesophageal Ultrasound

Aortic annulus diameter in stroke group was smaller than non-stroke group (31 mm (28-33) vs 32 mm (29-34), P=0.008). Patients with stroke were higher in early mitral valve forward flow velocity (EMV) (82 cm/s (67-101) vs 77 cm/s (62-92), P=0.030) and left atrial diameter (38 mm (36-43) vs 37 mm (33-41), P=0.008). They were also with a larger diameter measured by 45° (18 mm (16-20) vs 17 mm (15-19), P=0.018) and 135° (19 mm (17-22) vs 18 mm (16-22), P=0.012) for left atrial appendage opening. Left atrial appendage emptying velocity (LAAEV) is lower in stroke group (43 cm/s (28-61) vs 52 cm/s (33-75), P=0.002) (Table 2).

Multivariate Analyses for the Predictors of Cardioembolic Stroke Due to Atrial Fibrillation

CHA2DAS2 VASC score is based on heart failure, hypertension, diabetes, peripheral vascular disease, gender and age. To avoid the collinearity between predictors, CHA2DAS2 VASC score was selected into multiple binary logistic regression instead of using heart failure, hypertension, diabetes, peripheral vascular disease, gender and age.

Due to the correlation between 45°, 90° and 135° diameters of the left atrial appendage, it is decided to only use the 135° diameter in the multiple logistic regression. Similarly, only direct bilirubin was included in the multiple logistic regression if direct bilirubin and indirect bilirubin are both P<0.01 in the univariate analysis.

Except for CHA2DAS2 VASC score, other factors with P < 0.1 in univariate analysis were include in the multiple logistic regression. The final model included CHA2DS2-VSC score, mean platelet volume,γGlutamyl transpeptidase, anion gap, alanine aminotransferase, thyroid-stimulating hormone, aortic diameter, e-peak deceleration time（EDT）, EMV, left atrial diameter, 135° left atrial appendage opening measured diameter, left atrial appendage emptying rate.

In multiple logistic regression, CHA2DAS2 VASC score (OR 1.22 (95%CI 1.04-1.43), P=0.016), anion gap (OR 1.19 (95%CI 1.08-1.30), P < 0.001), EDT (OR 1.01 (95%CI 1.00-1.01), P=0.001) and the LAAEV (OR 0.99 (95%CI 0.97-0.99), P=0.013) were risk factors for predicting stroke in patients with atrial fibrillation. (Table 5)

For patients with low CHA2DAS2 VASC score, direct bilirubin, anion gap, EDT, LV Ejection fraction and EMV were included in the multiple binary logistic regression. The results showed that anion gap (OR 1.35 (95%CI 1.03-1.77), P=0.028) and EDT (OR 1.01 (95%CI 1.00-1.02), P=0.043) were associated with stroke. (Table 6)

ROC Analysis for Predictors of Cardioembolic Stroke Due to Atrial Fibrillation

To investigate the predictability of the statistically significant factors in multivariate logistic regression, we compared two models using AUC of ROC curve.

Model 1: Predictor included CHA2DS2-VASc score

Model 2: Predictors included anion gap, e-peak deceleration time, left atrial appendage emptying rate and CHA2DS2-VASc score in patients with atrial fibrillation

ROC curve showed that model 2 had a higher AUC for predicting stroke onset (AUC 0.70 (95%CI 0.64-0.75)) compared to model 1 (AUC 0.59 (95%CI 0.54-0.65)) (Figure 1 (a)).

Considering the effects in patients with low CHA2DAS2 VASC score, we did a sensitivity analysis using the same selection criteria.

Model 3: Predictor included low CHA2DS2-VASc score

Model 4: Predictors included anion gap, e-peak deceleration time and CHA2DS2-VASc score in low CHA2DS2-VASc score patients with atrial fibrillation

For patients with low CHA2DAS2 VASC score, ROC curve analysis also showed that model 4 (AUC 0.74 (95% CI 0.61-0.88)) had a higher AUC compared to model 3 (AUC 0.55 (95% CI 0.40-0.70)) (Figure 1 (b)).

Discussion

This study analyzes the medical history, clinical, laboratory and echocardiographic characteristics of patients with non-valvular atrial fibrillation complicated with or without stroke. The results of this study showed that in addition to CHA2DAS2 VSC score, serum anion gap, e-peak deceleration time and left atrial appendage emptying velocity were risk factors for stroke in patients with non-valvular atrial fibrillation. For patients with low CHA2DAS2 VASC score, serum anion gap and e-peak deceleration time was also a predictor for the onset of stroke.

Serum anion gap is a laboratory test index calculated according to serum electrolyte concentration, indicating the difference between measured anions and undetected cations in serum. Serum anion gap is mainly affected by the production and excretion of organic acid anion in serum, as well as the content of total protein, phosphorus, potassium and calcium in serum, which is widely used in clinical practice^[17].

Recent studies have found that the increase of serum anion gap is related to the poor prognosis of various diseases. It is associated with the risk of all-cause death in patients with severe acute myocardial infarction, in-hospital death in patients with acute ischemic stroke, all-cause death in congestive heart failure and the progression of end-stage renal disease^{[18, 19]}. The study also found that the levels of leukocytes, C-reactive protein, lactic acid and ketone body raised up with the increase of serum anion gap in acute myocardial infarction patients^{[20, 21]}. We have not found reports on the association between serum anion gap levels and stroke, especially in patients with atrial fibrillation. To our knowledge, this is the first study to investigate the prediction of serum anion gap for ischemic stroke in patients with AF. The increasing level of serum anion gap can be caused by a higher level of inflammatory factor, lactic acid and ketone body in patients with AF, which may leads to an onset of stroke.

Our finding of mitral e-peak deceleration time is consistent with previous study, which has shown that left ventricular diastolic dysfunction was associated with stroke in patients with non-valvular atrial fibrillation^[22]. Mitral e-peak deceleration time is an index to measure left ventricular diastolic function. The extension of mitral e-peak deceleration time indicates the impairment of cardiac diastolic function^[23]. The decline of cardiac diastolic function lead to slow blood flow and blood stasis, and finally thrombosis occurs. This association was also found in patients with low CHA2DAS2-VASC score.

The left atrial appendage is an appendage of the left atrium. Previous studies have shown that 90% of thrombus in patients with atrial fibrillation occurs in the left atrial appendage ^[24]. A prospective study showed that the LAAEV measured by transesophageal ultrasound was associated with left atrial appendage thrombosis in patients with atrial fibrillation ^[25].The LAAEV represents the left atrial systolic function. The decrease of LAAEV indicate a lower level of left atrial systolic function, which results to slow blood flow, blood stasis and thrombosis. In the subgroup analysis of patients with low CHA2DAS2-VASC score, the difference of LAAEV between stoke and non-stroke groups was considerable, but not statistically significant. The potential reason can be the limited number of cases.

In addition to CHA2DS2-VASc score, model using anion gap, e-peak deceleration time, LAAEV has a significant increase of AUC from ROC curve. That means the ability to detect thrombus increased considerably if using our model. Anion gap, e-peak cancellation time, LAAEV all are included in a routine test for all hospitalizations patients in most of the countries. All the predictors finding from our study are easy accessible from the routine examinations. There is no additional burden for patients or hospitals. If our model is applied to the clinical assessment, it’s more accurate for patients with atrial fibrillation to receive antithrombotic therapy and reduce the incidence of stroke.

Limitations

Firstly, this study is a single center cross-sectional retrospective study. Information, such as anticoagulant application history, statin application history, BMI was not collected historically. Their roles in the onset of stroke in patients with non-valvular atrial fibrillation need further investigations. Secondly, all patients in our study were from Hebei, China. The expansion of the results to other population need to be verified. Thirdly, the number of patients with low CHA2DAS2-VASC score is limited in this study although it is not our focus in this study.

Conclusion

In conclusion, our study showed that EDT, serum anion gap and LAAEV, in addition to CHA2DAS2 VASC score, were risk factors of stroke in patients with non-valvular atrial fibrillation. For non-valvular atrial fibrillation patients with low CHA2DAS2 VASC scores, serum anion gap and EDT was also associated with the onset of stroke. Incorporating anion gap, EDT and LAAEV into CHA2DS2-VASC score increases the ability to predict atrial fibrillation related stroke.

Declarations

The all authors have nothing to disclose.

This work was generously supported by grants from the Natural Science Foundation of Hebei Province (Grant No.H2020206037 to Ling You)

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Tables

Table 1: Clinical characteristic of atrial fibrillation patients by onset of stroke.

	Stroke (n=169)	Non-stroke (n=204)	P value
Male, n (%)	109 (64.5%)	121 (59.3%)	0.305
Age, year	66 (57-70)	62 (54-69)	0.006
Smoking, n (%)	37 (21.9%)	50 (24.5%)	0.552
Alcohol Use, n (%)	34 (20.1%)	43 (21.1%)	0.820
History of hypertension, n (%)	112 (66.3%)	104 (51.0%)	0.003
History of diabetes, n (%)	38 (22.5%)	29 (14.2%)	0.038
History of CHD, n (%)	80 (47.3%)	81 (39.7%)	0.139
Heart failure, n (%)	83 (49.1%)	43 (21.1%)	<0.001
Peripheral vascular disease, n (%)	87 (50.6%)	85 (41.7%)	0.058
Types of AF, Paroxysmal AF, n (%)	103 (60.9%)	135 (66.2%)	0.295
CHA2DS2-VASc score, point	3 (2-4)	2 (1-3)	0.002
Low CHA2DS2-VASc score, n (%)	21 (12.4)	39 (19.1)	0.080
HAS-BLED score, point	3 (2-3)	2 (1-3)	<0.001

CHD: Coronary heart disease; AF: atrial fibrillation

Table 2: Laboratory and echocardiographic parameters of atrial fibrillation patients by onset of stroke.

	Stroke (n=169)	Non-stroke (n=204)	P value
Laboratory parameters
Mean platelet volume, fL	9.3 (8.5-10.4)	8.9 (8.1-10.0)	0.010
Platelet distribution width, fL	16.3 (12.8-17.0)	16.5 (14.3-16.9)	0.457
Direct bilirubin, μmmol/L	4.7 (3.2-6.4)	4.3 (2.9-5.6)	0.111
Indirect bilirubin, μmmol/L	7.3 (4.7-10.1)	7.0 (4.8-9.3)	0.363
alanine aminotransferase, U/L	21.0 (13.3-32.2)	18.0 (13.1-25.4)	0.060
γ-glutamyl transferase, U/L	26.0 (17.0-41)	20.0 (16.0-29.0)	<0.001
eGFR, mL/min/1.73m2	89.8 (80.1-99.1)	91.7 (81.8-99.2)	0.340
Uric acid, μmmol/L	315 (264-372)	312 (252-389)	0.957
Anion gap, mmol/L	13.8±2.5	12.7±2.5	<0.001
Thyroid-stimulating hormone, mIU/L	1.78 (1.12-2.94)	2.25 (1.36-3.40)	0.021
HbA1c, %	5.9 (5.6-6.4)	5.9 (5.5-6.3)	0.150
Echocardiographic parameters
Aorta, mm	31 (28-33)	32 (29-34)	0.008
EDT, ms	203 (174-243)	193 (164-232)	0.050
LV Ejection fraction, %	63.1 (57.3-67.2)	64.1 (60.8-68.0)	0.126
EMV, cm/s	82 (67-101)	77 (62-92)	0.030
IVS, mm	10 (9-11)	10 (9-11)	0.730
Left atrium, mm	38 (36-43)	37 (33-41)	0.008
Right atrium, mm	36 (31-40)	34.5 (31-38)	0.113
LAA diameter(45°), mm	18 (16-20)	17 (15-19)	0.018
LAA depth (45°), mm	22 (18-27)	22 (19-27)	0.620
LAA diameter (90°), mm	18 (16-20)	18 (15-20)	0.078
LAA depth (90°), mm	22 (19-27)	22 (19-27)	0.814
LAA diameter (135°), mm	19 (17-22)	18 (16-22)	0.012
LAA depth (135°), mm	21 (18-25)	20 (17-24)	0.168
LAAEV, cm/s	43 (28-61)	52 (33-75)	0.002
Morphology of LAA, n (%)
Cauliflower, n (%)	67 (39.6%)	81 (39.7%)	0.283
WindSock, n (%)	20 (11.8%)	26 (12.7%)
Chicken Wing, n (%)	11 (6.5%)	5 (2.5%)
Cactus, n (%)	71 (42.0%)	92 (45.1%)

APTT: Activated Partial thromboplastin time; EDT: E peak deceleration time; EMV: Early mitral valve forward flow velocity; IVS: interventricular septum; LV: left ventricle; LAA: left atrial appendage; LAAEV: left atrial appendage emptying velocity

Table 3: Clinical characteristic of atrial fibrillation patients with low CHA2DS2-VASc score by onset of stroke

	Stroke (n=21)	Non-stroke (n=39)	P value
Male, n (%)	11 (52.4%)	26 (66.7%)	0.280
Age, year	54.5±6.5	52.7±10.2	0.850
Smoking, n (%)	4 (19.1%)	14 (35.9%)	0.174
Alcohol use, n (%)	5 (23.8%)	11 (28.2%)	0.713
History of hypertension, n (%)	3 (14.3%)	0 (0%)	0.039
History of diabetes, n (%)	0	0	-
History of CHD, n (%)	2 (9.5%)	0	0.119
Heart failure, n (%)	3 (14.3%)	0	0.039
Peripheral vascular disease, n (%)	2 (9.5%)	0	0.119
Types of AF, Paroxysmal AF,n (%)	13 (61.9%)	26 (66.7%)	0.780
CHA2DS2-VASc score, point	0 (0-1)	0 (0-1)	0.469
HAS-BLED score, point	2 (1-2)	1 (0-1)	<0.001

CHD: Coronary heart disease; AF: atrial fibrillation

Table 4: The laboratory, and echocardiographic data of atrial fibrillation patients with low CHA2DS2-VASc score by onset of stroke

	Stroke (n=21)	Non-stroke (n=39)	P value
Laboratory parameters
Mean platelet volume	9.2±1.1	9.1±1.3	0.590
Platelet distribution width, fL	16.2 (12.0-16.8)	16.5 (16.1-17.0)	0.180
Direct bilirubin, μmmol/L	5.2 (3.9-8.0)	3.8 (2.6-4.6)	0.013
Indirect bilirubin, μmmol/L	8.9 (6.4-12.9)	5.9 (4.0-8.4)	0.008
alanine aminotransferase, U/L	20.8 (16.0-37.9)	20.0 (14.2-24.3)	0.577
γ-glutamyl transferase, U/L	28 (15-35.5)	20 (15-33)	0.429
eGFR, mL/min/1.73m2	99.8 (90.6-107.3)	97.3 (91.1-105.8)	0.739
Uric acid, μmmol/L	321 (258-376)	289 (246-387)	0.975
Anion gap, mmol/L	14.3 (11.2-15.7)	11.9 (10.4-13.8)	0.013
Thyroid-stimulating hormone, mIU/L	1.93 (1.03-2.86)	2.22 (1.34-3.04)	0.500
HbA1c, %	5.5 (5.4-5.8)	5.6 (5.3-5.9)	0.685
Echocardiographic parameters
Aorta, mm	31 (28-33)	31 (28-33)	0.703
EDT, ms	211 (188-268)	185 (164-232)	0.084
LV Ejection fraction, %	59.8 (55.7-66.4)	63.9 (61.3-67.7)	0.031
EMV, cm/s	88 (69-107)	78 (66-85)	0.071
IVS, mm	9 (9-11)	10 (9-10)	0.968
Left atrium, mm	36 (33-41.5)	35 (32-37)	0.194
Right atrium, mm	34 (32-39)	34 (33-41)	0.709
LAA diameter(45°), mm	17.3±3.7	16.6±2.8	0.387
LAA depth (45°), mm	21.9±6.1	22.2±4.5	0.831
LAA diameter (90°), mm	18 (15-19)	17 (15-19)	0.975
LAA depth (90°), mm	20.8±4.5	22.4±5.0	0.233
LAA diameter (135°), mm	19.0±4.2	18.5±3.5	0.580
LAA depth (135°), mm	20.2±4.3	19.7±4.5	0.712
LAAEV, cm/s	36 (23-75)	52 (30-80)	0.143
Morphology of LAA, n (%)
Cauliflower, n (%)	10 (47.6%)	20 (51.3%)	0.271
WindSock, n (%)	1 (4.76%)	6 (15.4%)
Chicken Wing, n (%)	3 (14.3%)	1 (2.6%)
Cactus, n (%)	7 (33.3%)	12 (30.8%)

APTT: Activated Partial thromboplastin time; EDT: E peak deceleration time; EDV:end-diastolic volume; ESV: end-systole volume; EMV: Early mitral valve forward flow velocity; IVS: interventricular septum; LV: left ventricle; LAA: left atrial appendage; LAAEV: left atrial appendage emptying velocity

Table 5: Multivariate analyses for the predictors of cardioembolic stroke due to atrial fibrillation

	Multivariate
Variables	OR	CI	P value
CHA2DS2-VASc score, point	1.22	1.04-1.43	0.016
Mean platelet volume, fL	1.16	0.98-1.37	0.081
γ-glutamyl transferase, U/L	1.01	0.99-1.02	0.267
Anion gap, mmol/L	1.19	1.08-1.30	<0.001
alanine aminotransferase, U/L	1.01	0.99-1.02	0.153
Thyroid-stimulating hormone, mIU/L	0.92	0.84-1.01	0.092
Aorta, mm	0.98	0.94-1.00	0.331
EDT, ms	1.01	1.00-1.01	0.001
EMV, cm/s	1.00	0.99-1.02	0.469
Left atrial diameter, mm	1.00	0.95-1.05	0.903
LAA diameter (135°), mm	1.02	0.96-1.09	0.441
LAAEV, cm/s	0.99	0.97-0.99	0.013

EDT: E peak deceleration time; EMV: Early mitral valve forward flow velocity; LV: left ventricle; LAA: left atrial appendage; LAAEV: left atrial appendage emptying velocity

Table 6: Multivariate analyses for the predictors of cardioembolic stroke due to atrial fibrillation in patients with low CHA2DS2-VASc score

	Multivariate
Variables	OR	CI	P value
Direct bilirubin，μmmol/L	1.10	0.84-1.43	0.487
Anion gap，mmol/L	1.35	1.03-1.77	0.028
EDT，ms	1.01	1.00-1.02	0.043
LV Ejection fraction，%	0.36	0.88-1.46	0.357
EMV，cm/s	1.03	0.99-1.06	0.118

EDT: E peak deceleration time; EMV: Early mitral valve forward flow velocity; LV: left ventricle