Nutrition, Metabolism & Cardiovascular Diseases (2021) 31, 3176e3183

Available online at www.sciencedirect.com

Nutrition, Metabolism & Cardiovascular Diseases

journal homepage: www.elsevier.com/locate/nmcd

Increased hemoglobin A1c level associates with low left atrial

appendage flow velocity in patients of atrial fibrillation
Ying Wei a,b,c,d,1, Ming Cui a,b,c,d, Shuwang Liu a,b,c,d, Haiyi Yu a,b,c,d, Jieli Feng a,b,c,d,
Wei Gao a,b,c,d, Lei Li a,b,c,d,*
a
Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, 100191, China
b
Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, Beijing, 100191, China
c
Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, 100191, China
d
Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China

Received 16 March 2021; received in revised form 15 July 2021; accepted 23 July 2021
Handling Editor: L. D’Erasmo
Available online 30 July 2021

KEYWORDS Abstract Background and aims: High hemoglobin A1c (HbAlc) level is associated with increased
Atrial fibrillation; cardiovascular disease risk and thromboembolic events [1]. The study sought to explored the as-
Hemoglobin A1c; sociation between HbAlc and left atrial appendage flow velocity (LAAV) among non-valvular
Left atrial appendage atrial fibrillation (AF) patients.
flow velocity Methods and results: A total of 249 consecutive non-valvular AF patients who underwent trans-
esophageal echocardiography (TEE) were divided into two subgroups according to the median of
LAAV level (<45 cm/s, 45 cm/s). Blood samples and other baseline clinical data of all patients
were collected and analyzed. The low LAAV group included 126 patients and the high LAAV
group included 123 patients. Patients in the low LAAV group were older and had a higher per-
centage of persistent AF, chronic heart failure, and higher CHA2DS2-VASc score (P < 0.05). HbAlc
level in the low LAAV group was significantly higher than the high LAAV group [6.1 (5.7e6.5)% vs
5.9 (5.6e6.2)%, P Z 0.010]. The low LAAV group had larger left atrial diameter (LAD), left atrial
area (LAA), higher left atrial pressure (LAP), and lower left ventricular ejection fraction (LVEF)
(P < 0.05). Spearman rank correlation analysis showed that the HbAlc level was negatively corre-
lated with LAAV (r Z 0.211, P Z 0.001). Multivariate analysis indicated that female gender
(OR Z 2.233, 95% CI 1.110e4.492, P Z 0.024), persistent AF (OR Z 6.610, 95% CI 3.109e14.052,
P < 0.001), and HbAlc (OR Z 1.903, 95% CI 1.092e3.317, P Z 0.023) were independent factors
that associated with low LAAV in AF patients.
Conclusion: Increased HbAlc level is associated with decreased LAAV and may reflect a low con-
tractile function of the left atrial appendage.
ª 2021 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Ital-
ian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the
Department of Clinical Medicine and Surgery, Federico II University. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction

Atrial fibrillation (AF), the incidence of which increases

* Corresponding author. Department of Cardiology, Peking University
Third Hospital, 49 North Garden Rd., Haidian District, Beijing, 100191,
with age, is the most common form of arrhythmia in the
China. world. The worldwide prevalence of AF is about 0.51%,
E-mail address: dr_lilei@bjmu.edu.cn (L. Li). increased by 33% during the last 20 years [2]. AF is
1
First author.

https://doi.org/10.1016/j.numecd.2021.07.024
0939-4753/ª 2021 The Authors. Published by Elsevier B.V. on behalf of The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of
Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. This is an open access article under the CC BY-NC-ND license (http://
creativecommons.org/licenses/by-nc-nd/4.0/).
Low left atrial appendage flow velocity
associated with a greater risk of stroke, death, heart fail-
ure, and hospital admission [3] and bears a heavy public
health burden. The association of AF with ischemic stroke
of cardioembolic origin is well recognized, and AF is found
in a third of all ischemic strokes [4]. It is well known that
the left atrial (LA) plays a critical role in the etiology of AF.
LA enlargement and dysfunction are common in AF and
are related to poor prognosis. As the adjacent structure of
LA, the structure and morphology of left atrial appendage
(LAA) have substantial effects on AF. Recent studies had
demonstrated the decreased LAA function is intimately
related to thrombus events among AF patients [5,6]. LAA
flow velocity (LAAV) has been identified as a surrogate
factor of LA function during AF. However, the reliable
parameter for influencing LAAV in AF patients is absent.
Hemoglobin A1c (HbAlc) is a marker of glycemic control
within the prior two to three months. It has been shown
that diabetes mellitus (DM) could increase the risk of
developing cardiovascular diseases. Studies have indicated
higher HbA1c was associated with an increased occurrence
of AF [7e9] and other cardiovascular outcomes [1]. How-
ever, the mechanism underlying HbAlc and AF is not well
concerned, and the correlation between HbAlc and LAAV
in AF patients was limitedly documented. Our study aims
to explore the relationship between HbAlc and LAAV in AF
patients.
Methods
Patient enrollment
From January 2018 to January 2020, we recruited a total of
249 consecutive non-valvular AF patients, who underwent
transesophageal echocardiography (TEE) for their initial
pulmonary vein atrium isolation by catheter ablation in
Peking University Third Hospital.
The exclusion criteria were the presence of intra-atrial
thrombus, in particular of LAA thrombus, severe liver
disorders, current infection, renal insufficiency, heart valve
disease, severe heart failure (NYHA  III class), and
thyroid-related hospital diagnoses. The study was
approved by the Ethics Review Boards of Peking University
Third Hospital (Approval number: 077-02, Beijing, China).
Written informed consent was obtained from all
participants.
Clinical data and measurement
Collection of clinical information
The demographic and clinical information of all patients
were collected, including age, gender, body mass index
(BMI), previous history, and the use of medications.
Measurement of LAAV
TEE equipped with a multi-plane TEE probe was per-
formed using GE Vivid E9. We obtained LAA images with
transverse scan and vertical scan, further evaluated the
presence of thrombi, and measured the flow velocity in
and out of LAA. LAAV was defined as the average value of
3177
10 consecutive fibrillatory emptying waves by pulsed-
wave Doppler interrogation at the LAA ostium. All TEE
images were stored for offline analysis (QLAB cardiac 3DQ,
Philips Medical Systems).
Two-dimensional transthoracic echocardiography was
performed using GE Vivid E9 with a 3.5-MHz transducer.
From the parasternal and apical views, we acquired M-
mode, 2D images, Doppler and color-Doppler data, and
collected parameters.
Measurement of blood parameters
Complete blood count, fasting blood glucose (FBG), HbAlc,
high-sensitivity C-reaction protein (hs-CRP), blood urea
nitrogen (BUN), and uric acid (UA) were measured by the
clinical laboratory in Peking University Third Hospital
using the standard laboratory procedures. The creatinine
clearance (CCr) was obtained by Cockcroft-Gault formula:
CCr(mL/min) Z [140-age (years)]  weight (kg)/
[0.818  Cr (mmol/L)] for male subjects and multiplied by
an adjustive factor 0.85 for female patients.
Statistical analysis
Descriptive statistics were presented as the mean
value  standard deviation (XSD) for normal distribution,
as median (interquartile range) for abnormal distribution,
and frequencies or percentages for categorical variables.
Continuous variables with normal distribution were
analyzed by independent t test, while variables with
abnormal distribution were compared by the
ManneWhitney U test, and chi-square tests for categorical
data. Univariate and multivariate logistic regression anal-
ysis was performed to identify factors associated with
reduced LAAV. Receiver operating characteristic (ROC)
analysis was made to further explore the influence value of
factors on LAAV. Spearman’s correlations were used to
examine the relationship between LAAV and other vari-
ables. Multivariate linear regression analysis was per-
formed to identify risk factors for LAAV. All statistical
analyses were computed in a commercially available sta-
tistical calculation program (SPSS 23.0, SPSS Inc, Chicago,
IL). Figures were analyzed using GraphPad Prism (Graph-
Pad Software Inc, San Diego, CA). Significance was
assumed at two-sided P value < 0.05.
Results
Baseline characteristics
Patients were divided into two groups according to the
median of LAAV: 126 patients with LAAV<45 cm/s and 123
patients with LAAV 45 cm/s. Baseline clinical character-
istics were summarized in Table 1. Patients in the low
LAAV group were older [(65  10) vs (60  12) years,
P Z 0.001] and had a higher percentage of persistent AF
(65.9% vs 26.0%, P < 0.001), chronic heart failure (10.3% vs
0.8%, P Z 0.001), and higher CHA2DS2-VASc score [2 (1e4)
% vs 2 (1e3) %, P Z 0.015]. HbAlc level in the low LAAV
group was significantly higher than the high LAAV group
3178 Y. Wei et al.

Table 1 Baseline clinical data of all patients.

33.9% with metformin, 23.7% with sulfonylurea, and 18.6%
with insulin. Only 5.1% of DM patients took nateglinide
Characteristics Low LAAV High LAAV P value and 3.4% with dipeptidyl peptidase Ⅳ inhibitor (DPP-4i).
(n Z 126) (n Z 123)
However, there was no significant difference in diabetic
Clinical characters duration and therapy between the low LAAV group and the
Age (years) 65  10 60  12 0.001*
high LAAV group (P > 0.05).
Female, n (%) 57 (45.2) 42 (34.1) 0.074
BMI (kg/m2) 26 4 26 4 0.290 As for other subgroups, there were 27 (10.8%) patients
HR (bpm) 81  16 78  17 0.166 with stroke with a median LAAV of 30 (26e57) cm/s, 148
Persistent AF, 83 (65.9) 32 (26.0) <0.001* (59.4%) patients suffered from hypertension with a median
n (%) LAAV of 40 (30e56) cm/s, and 36 (14.5%) patients suffered
AF duration 24 (5e78) 24 (5e60) 0.748
from coronary heart disease (CHD) with a median LAAV of
(months)
Stroke, n (%) 17 (13.5) 10 (8.1) 0.174 44 (34e55) cm/s.
Hypertension, 82 (65.1) 66 (53.7) 0.067
n (%) Univariate and multivariate analysis for reduced LAAV
DM, n (%) 33 (26.2) 26 (21.1) 0.349
CHD, n (%) 18 (14.3) 18 (14.6) 0.938
Smoker, n (%) 44 (34.9) 32 (26.0) 0.127
Univariate and multivariate analysis results for reduced
CHF, n (%) 13 (10.3) 1 (0.8) 0.001* LAAV (<45 cm/s) in all patients are shown in Table 3.
CHA2DS2-VASc 2 (1e4) 2 (1e3) 0.015* Variables with P < 0.10 shown in Table 1 and some diabetic
score medications were included. In the multivariate analysis,
HAS-BLED score 1 (0e1) 1 (0e1.5) 0.387 female gender (OR Z 2.233, 95% CI 1.110e4.492,
Medications
b-blockers, n (%) 75 (59.5) 77 (62.6) 0.619
P Z 0.024), persistent AF (OR Z 6.610, 95% CI
ACEI/ARB, n (%) 48 (38.1) 41 (33.3) 0.433 3.109e14.052, P < 0.001), and HbAlc (OR Z 1.903, 95% CI
Laboratory results 1.092e3.317, P Z 0.023) were independent factors asso-
WBC (  109/L) 6.1  1.8 6.2  1.6 0.528 ciated with low LAAV in AF patients.
FBG (mmol/L) 5.5 (4.8e6.2) 5.3 (4.8e6.0) 0.264 We further performed these analyses in patients
HGB (g/L) 143  15 144  16 0.509
HbAlc (%) 6.1 (5.7e6.5) 5.9 (5.6e6.2) 0.010*
without diabetes (Table 4). In the multivariate analysis,
hs-CRP (mg/L) 1.14 (0.51e 1.05 (0.51e 0.498 female gender (OR Z 2.484, 95% CI 1.175e5.247,
2.93) 2.39) P Z 0.017), persistent AF (OR Z 6.421, 95% CI
BUN (mmol/L) 5.6  1.6 5.7  1.4 0.711 3.107e13.270, P < 0.001), and HbAlc (OR Z 2.542, 95% CI
UA (mmol/L) 348 (294e 330 (285e 0.114 1.093e5.912, P Z 0.030) were still independent factors
426) 390)
CCr (ml/min) 82  21 87  26 0.067
associated with low LAAV in non-diabetes subgroup.
Echocardiographic
data ROC analysis for reduced LAAV
LAD (mm) 40 4 37  4 <0.001*
LAA (cm2) 24 5 21  4 <0.001*
In a joint model of HbAlc and AF type (persistent AF) for
LVEDD (mm) 48 5 47  5 0.830
LAP (mmHg) 11 (9e13) 9 (8e11) <0.001* influencing reduced LAAV obtained by ROC curve analysis
LVEF (%) 69 (64e72) 70 (66e73) 0.016* in all patients, the area under the curve (AUC) was 0.744
LAAV (cm/s) 30 (25e38) 60 (52e70) <0.001* (95%CI 0.679e0.809, P < 0.001, sensitivity: 74.5%, speci-
LAAV: left atrial appendage flow velocity, BMI: body mass index, ficity: 68.6%, as shown in Fig. 1). In the subgroup of pa-
HR: heart rate, AF: atrial fibrillation, DM: diabetes mellitus, CHD: tients without DM (n Z 190), the AUC were 0.746 (95%CI
coronary heart disease, CHF: chronic heart failure, ACEI: 0.672e0.820, P < 0.001, sensitivity: 75.6%, specificity:
angiotensin-converting enzyme inhibitors, ARB: angiotensin re-
69.3%, as shown in Fig. 1).
ceptor blocker. WBC: white blood cell, FBG: fasting blood glucose,
HGB: hemoglobin, HbAlc: hemoglobin A1c, hs-CRP: high-sensitivity
C-reaction protein, BUN: blood urea nitrogen, UA: uric acid, CCr: Relationship between LAAV and other variables
creatinine clearance, LAD: left atrial diameter, LAA: left atrial area,
LVEDD: left ventricular end-diastolic diameter, LAP: left atrial We choose continuous variables into Spearman’s correla-
pressure, LVEF: left ventricular ejection fraction, LAAV: left atrial
appendage flow velocity. *: P < 0.05.
tions to further explore influencing factors of LAAV. As a
surrogate factor of LA function during AF, LAAV is related
to other transthoracic echocardiography data of LA,
including LAD (r Z 0.363, P < 0.001), LAA (r Z 0.408,
[6.1 (5.7e6.5) % vs 5.9 (5.6e6.2) %, P Z 0.010]. The low P < 0.001), and LAP (r Z 0.337, P < 0.001) in our study.
LAAV group had larger LAD, LAA, higher LAP, and lower Also, LAAV level was associated with age (r Z 0.236,
LVEF and LAAV (P < 0.05). Other clinical, laboratory factors P < 0.001), HR (r Z 0.188, P Z 0.003), CHA2DS2-VASc
and medications were similar between the two groups score (r Z 0.200, P Z 0.001), HbAlc (r Z 0.211,
(P > 0.05). P Z 0.001), and LVEF (r Z 0.206, P Z 0.001) (Table 5,
As shown in Table 2, there were 59 (23.7%) DM patients Fig. 2). Multivariable analysis was performed and potential
altogether. The median duration of DM was 60 (30e120) confounders in the model were determined by P < 0.10 as
months and the median LAAV was 30 (26e57) cm/s. As for shown in Table 5, including age, HR, CHA2DS2-VASc score,
diabetic therapy, 45.8% of DM patients took acarbose, HbAlc, UA, LAD, and LVEF. Results showed that age
Low left atrial appendage flow velocity 3179

Table 2 Baseline clinical data of diabetes subgroup.

Characteristics Total (n Z 59) Low LAAV (n Z 33) High LAAV (n Z 26) P value
Diabetes duration (months) 60 (30e120) 60 (36e120) 60 (21e120) 0.530
Insulin, n (%) 11 (18.6) 5 (15.2) 6 (23.1) 0.511
Metformin, n (%) 20 (33.9) 9 (27.3) 11 (42.3) 0.226
Acarbose, n (%) 27 (45.8) 15 (45.5) 12 (46.2) 0.957
Sulfonylurea, n (%) 14 (23.7) 7 (21.2) 7 (26.9) 0.609
Nateglinide, n (%) 3 (5.1) 1 (3.0) 2 (7.7) 0.578
DPP-4i, n (%) 2 (3.4) 1 (3.0) 1 (3.8) 1.000
LAAV: left atrial appendage flow velocity, DPP-4i: dipeptidyl peptidase Ⅳ inhibitor.

Table 3 Univariate and multivariate analysis for reduced LAAV (<45 cm/s) in all patients.

Variables Univariate analysis Multivariate analysis

OR 95% CI P OR 95% CI P
Age (years) 1.039 1.015e1.064 0.001* 1.015 0.969e1.062 0.533
Female 1.593 0.955e2.658 0.075 2.233 1.110e4.492 0.024*
Persistent AF 5.489 3.180e9.474 <0.001* 6.610 3.109e14.052 <0.001*
Hypertension 1.610 0.967e2.679 0.067 1.061 0.520e2.168 0.871
DM 1.324 0.736e2.382 0.349 0.714 0.215e2.377 0.583
Insulin 0.806 0.239e2.712 0.727 0.280 0.043e1.804 0.180
Metformin 0.783 0.313e1.962 0.602 0.421 0.105e1.688 0.222
CHA2DS2-VASc 1.258 1.057e1.498 0.010* 1.020 0.750e1.386 0.900
HbAlc (%) 1.667 1.162e2.392 0.006* 1.903 1.092e3.317 0.023*
CCr (ml/min) 0.990 0.979e1.001 0.071 0.987 0.968e1.006 0.172
LAD (mm) 1.141 1.070e1.216 <0.001* 1.031 0.947e1.123 0.480
LVEF (%) 0.942 0.905e0.980 0.003* 0.983 0.933e1.037 0.530
OR: odds ratio, CI: confidence interval, other abbreviations as in Table 1. *: P < 0.05.

Table 4 Univariate and multivariate analysis for reduced LAAV (<45 cm/s) in patients without diabetes.

Variables Univariate analysis Multivariate analysis

OR 95% CI P OR 95% CI P
Age (years) 1.039 1.013e1.066 0.003* 1.015 0.965e1.067 0.566
Female 1.509 0.832e2.736 0.175 2.484 1.175e5.247 0.017*
Persistent AF 5.558 2.970e10.40 <0.001* 6.421 3.107e13.270 <0.001*
Hypertension 1.408 0.793e2.502 0.243 1.024 0.453e2.314 0.954
CHA2DS2-VASc 1.209 0.980e1.493 0.077 0.974 0.698e1.360 0.879
HbAlc (%) 2.698 1.238e5.881 0.013* 2.542 1.093e5.912 0.030*
CCr (ml/min) 0.998 0.975e1.001 0.075 0.992 0.971e1.013 0.440
LAD (mm) 1.135 1.051e1.225 0.001* 1.023 0.925e1.132 0.658
LVEF (%) 0.938 0.896e0.982 0.006* 0.987 0.931e1.046 0.663
OR: odds ratio, CI: confidence interval, other abbreviations as in Table 1. *: P < 0.05.

(Beta Z 0.219, P Z 0.004), HbAlc (Beta Z 0.163,
P Z 0.012), LAD (Beta Z 0.241, P Z 0.001), and LVEF
(Beta Z 0.151, P Z 0.024) remained significantly associ-
ated with LAAV level.
Discussion
This study investigated the association between pre-
procedural LAAV and HbAlc in 249 AF patients before
their initial catheter ablation. To the best of our knowl-
edge, this is the first study that demonstrates patients with
higher HbAlc are prone to suffer lower LAAV, meaning that
HbAlc could have some relationship with a low contractile
function of LAA.
LA enlargement and dysfunction are common in pa-
tients with AF. It is well known that LA plays a critical role
in the etiology of AF. The LAA is adjacent to the LA, and
they have many anatomic and histologic similarities.
Recently, the role of LAA in atrial arrhythmias has aroused
the interest of electrophysiologists. TEE can evaluate the
structure and function of LAA accurately. Our data showed
that LAAV was negatively related to the echocardiography
data of LA including LAD, LAA, and LAP (Table 5), which
indicated a low LAAV paralleled to the LA remodeling. The
3180 Y. Wei et al.

A autonomic, electrical, electromechanical, and structural

100 remodeling, oxidative stress, connexin remodeling, and
glycemic fluctuations [12].
80 Our study showed that increased HbAlc level was
associated with decreased LAAV, which reflected a low
Sensitivity%

contractile function of LAA. Also, HbAlc was an inde-

60 pendent factor associated with low LAAV, even in the
Sensitivity: 74.5% non-diabetes subgroup, which adjusted for the influence
Specificity: 68.6%
40 AUC: 0.744
of diabetes. Reduced LAAV increases the risk of LA/LAA
95%CI: 0.679-0.809 thrombus formation. In sustaining AF status, LA has
P<0.001 changes in tissue, cells, hemodynamics, and electrical and
20
structural remodeling, resulting in LA’s progressive
expansion. With the enlargement of LAA opening, LAA
0 loses effective and regular contraction, thus blood flow
0 20 40 60 80 100 emptying is restricted, and finally LAAV reduces. Com-
100% - Specificity% bined with comb-like structures of LAA, reduced LAAV is
easy for thrombus formation. Ren [13] found that elevated
HbA1c indicated a significantly increased risk for left
atrial thrombus/spontaneous echo contrast in non-
B
100 valvular AF patients. Furthermore, LA/LAA thrombus is a
potential source of thromboembolic events such as
ischemic stroke. Many studies have shown that HbA1c is
80 associated with thromboembolic events. Chan et al. [14]
Sensitivity%

found that stroke risk significantly increased when the

60
Sensitivity: 75.6%
Specificity: 69.3%
40 AUC: 0.746
95%CI: 0.672-0.820
P<0.001
20
0 stroke compared with AF patients who had HbA1c <7.0%.
0 20 40 60 80 100
100% - Specificity%
Figure 1 A. ROC analysis for reduced LAAV in all patients. B. ROC
analysis for reduced LAAV in patients without diabetes. AUC: area
under the curve, CI: confidence interval, ROC: receiver operating
characteristic, LAAV: left atrial appendage flow velocity.
LAAV mainly depends on the contraction of the LAA and
reflects a more comprehensive LA remodeling.
HbAlc results from the addition of glucose to the NH2-
terminal valine of the hemoglobin b chain and accumu-
lates slowly over the life of each red cell [10]. It has been
demonstrated as a marker of glycemic control within the
prior two to three months. HbAlc is a diagnostic criterion
for diabetes and also a vital measurement for blood
glucose monitoring. Previous studies have found a rela-
tionship between AF and HbAlc. Rachel [9] found that
higher HbA1c level and poor glycemic control were inde-
pendently associated with an increased risk of AF in those
with and without diabetes. Another study showed that the
presence of AF appeared to be associated with the level of
HbA1c, especially in patients with HbA1c <6.5% [11]. A
meta-analysis also suggested that HbA1c level in DM pa-
tients with AF was higher than that in DM patients
without AF (P < 0.001) [8]. Pathophysiological mecha-
nisms implicating hyperglycemia in AF occurrence include
HbA1c levels exceeded 6.5% in AF patients. Another study
showed that HbA1c was directly associated with stroke
risk in diabetic patients with AF [15]. However, some
studies showed different results [16,17]. Jeffrey [16] found
that neither poor glycemic control (HbA1c  9.0%) nor
moderately increased HbA1c (7.0%e8.9%) was signifi-
cantly associated with an increased rate of ischemic
Fangel’s study [17] suggested that there was no associa-
tion between HbA1c and thromboembolism among pa-
tients with DM duration 10 years. Our study observed
no obvious difference in the percentage of DM between
low LAAV and high LAAV groups. One explanation may be
that hypoglycemic drugs, diet control, and exercise could
affect HbA1c level; thus, some DM patients who have
good glycemic control may present a low HbA1c level. We
should further take these factors into account in our
future study.
Scarce data are available regarding the performance of
HbAlc in LAAV, and the potential mechanism of LAAV and
HbAlc in AF has not been elucidated. HbAlc, one of the
Amadori products, is also one precursor of advanced gly-
cation end products (AGEs) [10]. AGEs are important ini-
tiators of inflammatory responses. AGE and receptor for
AGE (RAGE) interaction elicit oxidative stress, inflamma-
tory reactions, and thrombosis, thereby involves in
vascular aging and damage [18]. The activation of AGEs-
RAGE system with upregulating connective tissue growth
factor could promote interstitial fibrosis of the atrial
myocardium and atrial structural remodeling [19]. In the
atrial appendage tissue of diabetic patients, there exist
mitochondrial dysfunction and oxidative stress [20], which
are also the pathogenesis of atrial structural remodeling. In
AF patients, the intramyocardial blood vessels of the LAA
have an increased AGEs presence [21]. The previous study
Low left atrial appendage flow velocity 3181

Table 5 Relationship between LAAV and other variables.

than our results. In our previous study, we measured LAAV
in 40 healthy people and found that the LAAV in the
Variables Univariate analysis Multivariate analysis control group was notably higher than this AF group [64
Correlation P Beta P (52e77) vs 45 (30e60) cm/s, P < 0.001]. Patients with AF,
coefficient (r) especially persistent AF have longer AF duration, more
Age (years) 0.236 <0.001* 0.219 0.004* severe AF burdens and LA structural remodeling [29] and
BMI (kg/m2) 0.037 0.570 e e thus probably associate with lower LAAV. Gawałko’s study
HR (bpm) 0.188 0.003* 0.022 0.730 [24] showed that non-paroxysmal AF might increase LAA
CHA2DS2-VASc 0.200 0.001* 0.022 0.781
HASBLED score 0.113 0.180 e e
thrombus risk via reduced LAAV. Age is an independent
WBC (  109/L) 0.066 0.301 e e risk factor for thromboembolism in AF and a few studies
FBG (mmol/L) 0.074 0.260 e e have found that LAAV decreases with age [25,28].
HGB (g/L) 0.056 0.378 e e Compared with younger patients, Ilercil [25] found that
HbAlc (%) 0.211 0.001* 0.163 0.012* older patients had lower LAAV despite higher LVEF, smaller
hs-CRP (mg/L) 0.096 0.144 e e
BUN (mmol/L) 0.005 0.939 e e
left ventricle size, and similar LA and LAA volumes.
UA (mmol/L) 0.113 0.078 0.029 0.648 Gawałko’s study [24] showed that age>65 years indepen-
CCr (ml/min) 0.099 0.121 e e dently related to LAAV<20 cm/s. Female gender is one
LAD (mm) 0.363 <0.001* 0.241 0.001* variable in CHA2DS2-VASc score, which represents the risk
LAA (cm2) 0.408 <0.001* e e of stroke for AF. Murat [26] found that gender differences
LVEDD (mm) 0.011 0.861 e e
LAP (mmHg) 0.337 <0.001* e e
(female) were significant factors of the low LAA peak flow
LVEF (%) 0.206 0.001* 0.151 0.024* velocity. However, our study found that the percentage of
stroke was not significantly different between the low
All abbreviations as in Table 1. *: P < 0.05.
LAAV and high LAAV groups, which was contradicted to
the previous study [30]. We further analyzed data and our
results showed that LAAV level in the stroke group was
found that AGE carboxymethyl lysine (CML) was also lower than the non-stroke group [30 (26e57) vs 47
abundant within human cardiomyocytes and significantly (32e60) cm/s, P Z 0.058]. As a surrogate factor of LA
correlated with left atrial volume (r Z 0.41, P Z 0.004) function during AF, lower LAAV reflects the blood stasis,
[22]. In summary, we hypothesize that hyperglycemia or associates with LA/LAA thrombus [31,32], and represents
other AGEs in the left atrial cardiomyocytes might influ- severe atrial remodeling [33,34]. This cardiogenic
ence LAAV, and HbAlc is mainly a proxy of hyperglycemia thrombus is a potential source of stroke. However, the
and other AGEs. Hyperglycemic status might affect atrial number of patients with stroke in our study was relatively
structural remodeling via oxidative stress, inflammatory small (only 17 patients in the low LAAV group and 10 in
reactions and thus has an association with LAAV, which the high LAAV group, separately), so the number of pa-
warrants further investigation. tients with cardiogenic stroke was even less. This may
We also found that reduced LAAV related to several cause a statistical bias that there was no difference in the
factors, including age, female gender, and persistent AF, percentage of stroke between the low LAAV and high LAAV
which were paralleled to previous studies [23e26]. The groups in our study. We still need to recruit more patients
mean LAAV of AF patients in our study was 47  19 cm/s, with stroke in our research to further investigate their
significantly lower than non-AF control patients in one relationship.
previous study (61  22 cm/s) [27]. Another study of 50 As mentioned above, a close relation has been observed
normal subjects showed that LAAV was 60  14 cm/s for between LAAV and HbA1c. We hypothesize that LAAV may
the atrial systolic forward wave, and 52  13 cm/s for the be influenced by HbA1c level in non-valvular AF patients.
atrial systolic backward wave [28], which were both higher Improving glycemic control, such as exercise, diet control,
and drug therapy may be helpful in reducing the risk of
thrombus events in AF patients.

Limitations

This is a single-center study with its inherent limitations.

Figure 2 Correlation between HbAlc and LAAV level. HbAlc: Hemo-
globin A1c, LAAV: left atrial appendage flow velocity.
Firstly, the standard cutoff value of LAAV has not been
established, and the association between HbAlc and LAAV
doesn’t illustrate causeeeffect relation. The exact effects of
HbAlc on LAAV remain to be investigated. Secondly, the
sample size of the present study was not large enough, and
the number of patients taking diabetic therapy, which was
also a possible confounding factor of HbAlc, was also
relatively small. These may cause a statistical bias. There-
fore, future studies are required to further evaluate the
potential mechanism of HbAlc in AF patients.
3182
Conclusion
The current study demonstrated that increased HbAlc level
is associated with decreased pre-procedural LAAV and may
reflect a low contractile function of LAA, which suggested us
to distinguish AF patients at high risk of thrombus events.
Furthermore, we should pay more attention to glucose
control in this population for preventing thrombotic events.
Funding
This work was supported by the National Natural Science
Foundation of China (grant No. 31700674 to Lei Li).
Data availability
The data used to support the findings of this study are
available from the corresponding author upon request.
Declaration of competing interest
The authors report no conflicts of interest. The authors alone
are responsible for the content and writing of this article.
References
[1] Fralick M, Colacci M, Odutayo A, Siemieniuk R, Glynn RJ. Lowering of
hemoglobin A1C and risk of cardiovascular outcomes and all-cause
mortality, a meta-regression analysis. J Diabetes Complicat 2020;
34(11):107704. https://doi.org/10.1016/j.jdiacomp.2020.107704.
[2] Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial
fibrillation: an increasing epidemic and public health challenge. Int J
Stroke 2021;16(2):217e21. https://doi.org/10.1177/1747493019897870.
[3] Zulkifly H, Lip GYH, Lane DA. Epidemiology of atrial fibrillation. Int J
Clin Pract 2018;72(3):e13070. https://doi.org/10.1111/ijcp.13070.
[4] Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibril-
lation. Lancet (Lond, Engl) 2016;388(10046):806e17. https:
//doi.org/10.1016/s0140-6736(16)31257-0.
[5] Burrell LD, Horne BD, Anderson JL, Muhlestein JB, Whisenant BK.
Usefulness of left atrial appendage volume as a predictor of embolic
stroke in patients with atrial fibrillation. Am J Cardiol 2013;112(8):
1148e52. https://doi.org/10.1016/j.amjcard.2013.05.062.
[6] Li J, Li Q, Alqahtany FS, Algahtani FH, Kim HJ, Li Y, et al. Evaluating
the novel parameters for assessing the LAA function and thrombus
formation with nonvalvular atrial fibrillation. Saudi J Biol Sci 2021;
28(1):560e5. https://doi.org/10.1016/j.sjbs.2020.10.041.
[7] Zhao H, Liu M, Chen Z, Mei K, Yu P, Xie L. Dose-response analysis
between hemoglobin A1c and risk of atrial fibrillation in patients
with and without known diabetes. PloS One 2020;15(2):e0227262.
https://doi.org/10.1371/journal.pone.0227262.
[8] Yang YF, Zhu WQ, Cheng K, Chen QX, Xu Y, Pang Y, et al. Elevated
glycated hemoglobin levels may increase the risk of atrial fibrilla-
tion in patients with diabetes mellitus. Int J Clin Exp Med 2015;
8(3):3271e80.
[9] Huxley RR, Alonso A, Lopez FL, Filion KB, Agarwal SK, Loehr LR, et al.
Type 2 diabetes, glucose homeostasis and incident atrial fibrilla-
tion: the Atherosclerosis Risk in Communities study. Heart 2012;
98(2):133e8. https://doi.org/10.1136/heartjnl-2011-300503.
[10] Makita Z, Vlassara H, Rayfield E, Cartwright K, Friedman E,
Rodby R, et al. Hemoglobin-AGE: a circulating marker of advanced
glycosylation. Science 1992;258(5082):651e3. https://doi.org/10.
1126/science.1411574.
[11] Iguchi Y, Kimura K, Shibazaki K, Aoki J, Sakai K, Sakamoto Y, et al. HbA1c
and atrial fibrillation: a cross-sectional study in Japan. Int J Cardiol
2012;156(2):156e9. https://doi.org/10.1016/j.ijcard.2010.10.039.
Y. Wei et al.
[12] Goudis CA, Korantzopoulos P, Ntalas IV, Kallergis EM, Liu T,
Ketikoglou DG. Diabetes mellitus and atrial fibrillation: pathophysio-
logical mechanisms and potential upstream therapies. Int J Cardiol
2015;184:617e22. https://doi.org/10.1016/j.ijcard.2015.03.052.
[13] Kuang RR, Liu FZ, Li YP, Lin WD, Liang HS, Chen AH. Hemoglobin
A1c and risk of left atrial thrombus and spontaneous echo contrast
in non-valvular atrial fibrillation patients. Eur J Med Res 2017;
22(1):15. https://doi.org/10.1186/s40001-017-0257-x.
[14] Chan YH, Chuang C, Chan CC, Lee HF, Huang YC, Huang YT, et al.
Glycemic status and risks of thromboembolism and major
bleeding in patients with atrial fibrillation. Cardiovasc Diabetol
2020;19(1):30. https://doi.org/10.1186/s12933-020-01005-8.
[15] Saliba W, Barnett-Griness O, Elias M, Rennert G. Glycated he-
moglobin and risk of first episode stroke in diabetic patients
with atrial fibrillation: a cohort study. Heart Rhythm 2015;
12(5):886e92. https://doi.org/10.1016/j.hrthm.2015.01.025.
[16] Ashburner JM, Go AS, Chang Y, Fang MC, Fredman L,
Applebaum KM, et al. Effect of diabetes and glycemic control on
ischemic stroke risk in AF patients: ATRIA study. J Am Coll Cardiol
2016;67(3):239e47. https://doi.org/10.1016/j.jacc.2015.10.080.
[17] Fangel MV, Nielsen PB, Kristensen JK, Larsen TB, Overvad TF,
Lip GYH, et al. Glycemic status and thromboembolic risk in pa-
tients with atrial fibrillation and type 2 diabetes mellitus: a Danish
cohort study. Circ Arrhythm Electrophysiol 2019;12(5):e007030.
https://doi.org/10.1161/CIRCEP.118.007030.
[18] Yamagishi S. Role of advanced glycation end products (AGEs) and
receptor for AGEs (RAGE) in vascular damage in diabetes. Exp
Gerontol 2011;46(4):217e24. https://doi.org/10.1016/j.exger.2010.
11.007.
[19] Kato T, Yamashita T, Sekiguchi A, Tsuneda T, Sagara K, Takamura M,
et al. AGEs-RAGE system mediates atrial structural remodeling in
the diabetic rat. J Cardiovasc Electrophysiol 2008;19(4):415e20.
https://doi.org/10.1111/j.1540-8167.2007.01037.x.
[20] Anderson EJ, Kypson AP, Rodriguez E, Anderson CA, Lehr EJ,
Neufer PD. Substrate-specific derangements in mitochondrial
metabolism and redox balance in the atrium of the type 2 diabetic
human heart. J Am Coll Cardiol 2009;54(20):1891e8. https:
//doi.org/10.1016/j.jacc.2009.07.031.
[21] Begieneman MP, Rijvers L, Kubat B, Paulus WJ, Vonk AB, van
Rossum AC, et al. Atrial fibrillation coincides with the advanced
glycation end product N(ε)-(carboxymethyl)lysine in the atrium.
Am J Pathol 2015;185(8):2096e104. https://doi.org/10.1016/j.
ajpath.2015.04.018.
[22] LeWinter MM, Taatjes D, Ashikaga T, Palmer B, Bishop N,
VanBuren P, et al. Abundance, localization, and functional corre-
lates of the advanced glycation end-product carboxymethyl lysine
in human myocardium. Physiol Rep 2017;5(20). https://doi.org/10.
14814/phy2.13462.
[23] Fukuhara E, Mine T, Kishima H, Ishihara M. Predictors for reduced
flow velocity in left atrial appendage during sinus rhythm in pa-
tients with atrial fibrillation. Heart Ves 2021;36(3):393e400.
https://doi.org/10.1007/s00380-020-01702-0.
_
[24] Gawałko M, Budnik M, Uzie˛ bło-Zyczkowska B, Krzesin  ski P,
Scisło P, Kochanowski J, et al. Decreased left atrial appendage
emptying velocity as a link between atrial fibrillation type, heart
failure and older age and the risk of left atrial thrombus in atrial
fibrillation. Int J Clin Pract 2020;74(11):e13609. https://doi.org/10.
1111/ijcp.13609.
[25] Ilercil A, Kondapaneni J, Hla A, Shirani J. Influence of age on left
atrial appendage function in patients with nonvalvular atrial
fibrillation. Clin Cardiol 2001;24(1):39e44. https://doi.org/10.
1002/clc.4960240107.
[26] Celik M, Yalcinkaya E, Yuksel UC, Gokoglan Y, Bugan B, Kabul HK,
et al. Increased serum uric acid levels are correlated with
decreased left atrial appendage peak flow velocity in patients with
atrial fibrillation. Med Princ Pract 2015;24(3):263e8. https:
//doi.org/10.1159/000373892.
[27] Kim BK, Heo JH, Lee JW, Kim HS, Choi BJ, Cha TJ. Correlation of
right atrial appendage velocity with left atrial appendage velocity
and brain natriuretic Peptide. J Cardiovasc Ultrasound 2012;20(1):
37e41. https://doi.org/10.4250/jcu.2012.20.1.37.
[28] Tabata T, Oki T, Fukuda N, Iuchi A, Manabe K, Kageji Y, et al. In-
fluence of aging on left atrial appendage flow velocity patterns in
normal subjects. J Am Soc Echocardiogr : Offic Publ Am Soc
Low left atrial appendage flow velocity
Echocardiogr 1996;9(3):274e80. https://doi.org/10.1016/s0894-
7317(96)90140-6.
[29] Corradi D, Callegari S, Maestri R, Ferrara D, Mangieri D, Alinovi R,
et al. Differential structural remodeling of the left-atrial posterior
wall in patients affected by mitral regurgitation with or without
persistent atrial fibrillation: a morphological and molecular study.
J Cardiovasc Electrophysiol 2012;23(3):271e9. https://doi.org/10.
1111/j.1540-8167.2011.02187.x.
[30] Zabalgoitia M, Halperin JL, Pearce LA, Blackshear JL, Asinger RW,
Hart RG. Transesophageal echocardiographic correlates of clin-
ical risk of thromboembolism in nonvalvular atrial fibrillation.
Stroke Prevention in Atrial Fibrillation III Investigators. J Am Coll
Cardiol 1998;31(7):1622e6. https://doi.org/10.1016/s0735-
1097(98)00146-6.
[31] Fatkin D, Kelly RP, Feneley MP. Relations between left atrial
appendage blood flow velocity, spontaneous echocardiographic
contrast and thromboembolic risk in vivo. J Am Coll Cardiol 1994;
23(4):961e9. https://doi.org/10.1016/0735-1097(94)90644-0.
3183
[32] Zateyshchikov DA, Brovkin AN, Chistiakov DA, Nosikov VV.
Advanced age, low left atrial appendage velocity, and factor V
promoter sequence variation as predictors of left atrial thrombosis
in patients with nonvalvular atrial fibrillation. J Thromb Throm-
bolysis 2010;30(2):192e9. https://doi.org/10.1007/s11239-010-
0440-1.
[33] Watanabe A, Suzuki S, Kano H, Matsuno S, Takai H, Kato Y, et al.
Left atrial remodeling assessed by transthoracic echocardiography
predicts left atrial appendage flow velocity in patients with
paroxysmal atrial fibrillation. Int Heart J 2016;57(2):177e82.
https://doi.org/10.1536/ihj.15-345.
[34] Zuo K, Sun L, Yang X, Lyu X, Li K. Correlation between cardiac
rhythm, left atrial appendage flow velocity, and CHA(2) DS(2)
-VASc score: study based on transesophageal echocardiography
and 2-dimensional speckle tracking. Clin Cardiol 2017;40(2):
120e5. https://doi.org/10.1002/clc.22639.