Endothelial dysfunction predicted increased left atrial volume index in newly diagnosed nondiabetic hypertensive patients

Abstract

Background:
Arterial hypertension is associated with cardiovascular morbidity and mortality. It was previously shown that left atrium volume increase associated with mortality and atherosclerotic heart disease. The aim of the present study was to demonstrate the value of endothelial dysfunction in predicting left atrium volume increase in newly diagnosed hypertension patients.

Methods:
This study included 96 consecutive newly diagnosed hypertensive patients. Left atrium volume and left ventricular ejection fraction were calculated. Pulse wave velocity and brachial artery flow-mediated dilation measurements were obtained from each patient.

Results:
Left Ventricle Mass Index (114 ± 29 g/m, 91 ± 17 g/m, P < 001), left ventricular septum (P < 0.001) and posterior wall thickness (P = 0.001), left ventricular end diastolic diameter (P = 0.016) were significantly higher in patients with higher left atrial volume index. FMD% was lower in patients with higher left atrial volume index those without (9.7 ± 3.5 vs. 13.31 ± 6.01, P = 0.004). Lateral wall E wave velocity was significantly lower (8.68 ± 2.8, 10.2 ± 2.8; P = 0.009), while isovolumetric relaxation time (101.9 ± 19.9 ms, 85.7 ± 15.2 ms; P < 0.001), and ejection time was longer (101.9 ± 19.9 ms, 85.7 ± 15.2 ms; P = 0.077) and Mitral E/ lateral wall E ratio (E/E relation) was significantly higher (P = 0.031) in patients with higher left atrial volume index.

Conclusion:
The rate of isovolumetric relaxation time, FMD% and E/E' ratio independently predicted left atrial volume index increase in newly diagnosed hypertension patients.

Full text

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Original article 1
1359-5237 Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/MBP.0000000000000419
Endothelial dysfunction predicted increased left atrial volume
index in newly diagnosed nondiabetic hypertensive patients
Mustafa Çetina, Turan Erdoğana, Tuncay Kırışb, Ahmet Çağrı Aykanc,
Göksel Çinierd, Nadir Emleka, Hüseyin Duraka, Ezgi Kalaycıoğlue and
Ahmet Seyda Yılmaza
Background Arterial hypertension is associated with
cardiovascular morbidity and mortality. It was previously
shown that left atrium volume increase associated with
mortality and atherosclerotic heart disease. The aim of the
present study was to demonstrate the value of endothelial
dysfunction in predicting left atrium volume increase in
newly diagnosed hypertension patients.
Methods This study included 96 consecutive newly
diagnosed hypertensive patients. Left atrium volume and
left ventricular ejection fraction were calculated. Pulse
wave velocity and brachial artery flow-mediated dilation
measurements were obtained from each patient.
Results Left Ventricle Mass Index (114 ± 29 g/m2, 91 ±
17 g/m2, P < 001), left ventricular septum (P < 0.001) and
posterior wall thickness (P = 0.001), left ventricular end
diastolic diameter (P = 0.016) were significantly higher in
patients with higher left atrial volume index. FMD% was
lower in patients with higher left atrial volume index those
without (9.7 ± 3.5 vs. 13.31 ± 6.01, P = 0.004). Lateral
wall E wave velocity was significantly lower (8.68 ± 2.8,
10.2 ± 2.8; P = 0.009), while isovolumetric relaxation time
(101.9 ± 19.9 ms, 85.7 ± 15.2 ms; P < 0.001), and ejection
time was longer (101.9 ± 19.9 ms, 85.7 ± 15.2 ms; P =
0.077) and Mitral E/ lateral wall E ratio (E/E relation) was
significantly higher (P = 0.031) in patients with higher left
atrial volume index.
Conclusion The rate of isovolumetric relaxation time,
FMD% and E/E′ ratio independently predicted left atrial
volume index increase in newly diagnosed hypertension
patients Blood Press Monit XXX:000–000 Copyright ©
2019 Wolters Kluwer Health, Inc. All rights reserved.
Blood Pressure Monitoring 2019, XXX:000–000
Keywords: arterial hypertension, left atrium, left atrium volume index,
left ventricular mass, endothelial dysfunction
aDepartment of Cardiology, Recep Tayyip Erdogan Research and Training
Hospital, Rize, bDepartment of Cardiology, Katip Celebi University Atatürk
Research and Training Hospital, Izmir, cDepartment of Cardiology, Sutcu Imam
University, Kahramanmaras, dDepartment of Cardiology, Kackar State Hospital,
Rize and eDepartment of Cardiology, Ahi Evren Research and Training Hospital,
Trabzon, Turkey
Correspondence to Ahmet Seyda Yılmaz, Department of Cardiology, Recep
Tayyip Erdogan Research and Training Hospital, Postal codes: 53020, Rize,
Turkey
Tel: +90 464 2130491; fax: +90 464 2130644;
e-mail: ahmetseydayilmaz@gmail.com
Received 4 June 2019 Accepted 20 October 2019
Introduction
Arterial hypertension (HT) is one of modiable risk
factors and associated with signicant cardiovascular
morbidity and mortality despite advances in modern
treatment methods [1]. High blood pressure exerts
deteriorating effects on the arterial system which is
considered as an important trigger for hypertensive car-
diomyopathy [1]. It is well documented that elevated
workload of left ventricle secondary to HT causes left
ventricular hypertrophy (LVH), left ventricular systolic
and diastolic dysfunction [1].
HT disrupts not only the left ventricular (LV) functions
but also the left atrial (LA) systolic and diastolic func-
tions. LA has a signicant role in the lling of the LV,
and its active contraction provides nearly 20%–25% of
the left ventricular stroke volume in sinus rhythm [2,3].
Disturbances in LA expansion can be easily identied
during routine transthoracic echocardiographic (TTE)
examinations and it is also strongly associated with the
development of atrial brillation (AF). On the other hand,
LA volume increase is associated with death, atheroscle-
rotic heart disease, myocardial infarction (MI) and stroke
[6–11]. Several comorbid conditions including HT, LV
diastolic and systolic dysfunction, aortic and mitral valve
diseases, diabetes mellitus (DM), obesity and aging are
previously demonstrated to cause increase in LA [2,3].
Similar to entire circulatory system, LA is covered with
endothelial cells. Which act as an endocrine organ and
interact actively with the vessel wall [12–14]. Endothelial
dysfunction (ED) is particularly important in the devel-
opment of vascular wall inammation and atherosclero-
sis through increasing lipid permeability and secretion
of chemoattractant mediators [12,14,15]. Although there
are many clinical studies that are mainly focused on the
association of HT and LA volume increase, data on the
effect of ED on LA volume is limited [15]. Therefore,
we aimed to demonstrate the role of ED in LA volume
increase among newly diagnosed HT patients.

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2 Blood Pressure Monitoring 2019, Vol XXX No XXX
Methods
Study population
This study was a cross-sectional, observational study
which included 96 consecutive newly diagnosed HT
patients that were admitted to a cardiology clinic. The
study was performed in accordance with the principles
stated in the Declaration of Helsinki and approved by
the local Ethics Committee.
Exclusion criteria
We excluded patients with previously diagnosed HT or
prior prescription of antihypertensive medications. Other
exclusion criteria were as follows: patients with white
coat hypertension, masked hypertension, history of cor-
onary artery disease, DM, LV systolic dysfunction, val-
vular heart diseases more than moderate in severity, any
form of malignancy, chronic renal failure [estimated glo-
merular ltration rate (eGFR < 60ml/min/1.73m2)], cere-
brovascular disease, peripheral artery disease, endocrine
disorders and secondary hypertension.
Data collection
Demographic data were obtained by physical exam-
ination of all patients. The diagnosis of hypertension
was conrmed by ambulatory 24-hour blood pressure
recorder. HT was diagnosed according to current the
guidelines [1]. White coat HT was excluded as every
patient underwent 24-hour ambulatory blood pressure
monitoring. Venous blood samples were collected after at
least 8 hours of fasting and routine hemogram and bio-
chemical tests were performed. Serum C-reactive protein
(CRP) was analyzed using a nephelometric technique
(Beckman Coulter Image 800; Fullerton, Brea, California,
USA; normal range: 0–0.8mg/dl). Weight and height were
measured while the subjects were fasting and wearing
only their undergarments.
Patients underwent standard 2D TTE examination in the
left lateral decubitus position with commercially availa-
ble systems using a GE-Vingmed Vivid S5 (GE-Vingmed
Ultrasound AS, Horten, Norway) with a 2.5–3.5-MHz
transducer. Echocardiography was performed by two
experienced cardiologists who were blinded to other
relevant data. Standard chamber measurements and
quantications were made in accordance with the latest
guidelines [1]. LA volume and left ventricular ejection
fraction (LVEF) were calculated using the modied
Simpson method. Left ventricular mass (LVM) was cal-
culated according to the formula of LVM = 1.04 ([LVIDD
+ PWTD + IVSTD]3 − [LVIDD]3) − 13.6g [1,16]. BMI
was determined by the following formula: BMI = weight
(kg)/height2 (m). LA volume index (LAVI) was calcu-
lated as LA volume/Body surface area. LV mass index
was calculated as LVM/body surface area. Standard meas-
urements based on height and weight were used as body
surface area.
Measurement of carotid intima-media thickness
Measurement of carotid intima-media thickness (CIMT)
ultrasonography was performed on all patients using
a high-resolution ultrasonography scanner (VingMed
Vivid S3; GE Medical System, Horten, Norway) with a
7.0-MHz linear array transducer. Measurements were
performed for the right and left carotid arteries [2]. The
patient was lying supine, with the head directed away
from the side of interest, and the neck slightly extended.
The transducer was manipulated so that the near and far
walls of the CCA were parallel, and the lumen diame-
ter was maximized in the longitudinal plane. The region
1cm proximal to the carotid bifurcation was identied,
and the CIMT of the far wall was evaluated as the dis-
tance between the lumen-intima interface and the
media-adventitia interface. The CIMT was measured on
the frozen frame of a suitable longitudinal image, with
the image magnied to achieve a higher resolution of
detail. The CIMT measurement was obtained from four
contiguous sites at 1-mm intervals, and the average of
all eight measurements was used for analyses [17]. All
measurements were performed by the same investigator
blinded to patient data. The intra-observer mean abso-
lute difference in measuring the common CIMT thick-
ness was 0.026 ± 0.043mm (coefcient of variation: 1.4%,
intraclass correlation: 0.96).
Pulse wave velocity and augmentation index
measurements
Pulse wave velocity (PWV) was measured in duplicate
with patients in the supine position after 10 minutes of
rest. PWV was measured by sequentially recording ECG-
gated carotid and femoral artery waveforms. Wave transit
time was calculated by the system software, using the R
wave of a simultaneously recorded ECG as a reference
frame (Sphygmocor; At Cor Medical, Sydney, Australia).
The distance from the sternal notch to the femoral and
carotid probe recording sites was obtained with a tape
measure. PWV was determined by dividing the distance
between the two recording sites by the wave transit time.
Mean arterial pressure in phase 5 was derived from dupli-
cate peripheral blood pressure measurements using an
automatic Omron 711 [3].
The augmentation index, in turn, was calculated from the
radial wave pulse as follows (second peak systolic blood
pressure [SBP] (SBP2) − diastolic blood pressure [DBP])/
(rst peak SBP − DBP) × 100 [4,19]. The quality of meas-
urement was ≥80% in all cases, with a mean of 88.11 ±
5.14.
Brachial artery flow-mediated dilation
A standard protocol was used to assess endothelial func-
tion, as previously reported [5]. Briey, for the ow-medi-
ated dilation (FMD) of the brachial artery (BA), patients
fasted 8 hours before the study. The FMD was evaluated

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ED predicted increased LAVI Çetin et al. 3
at the same time of the day, at 9 a.m. The study took
place in a quiet, temperature-controlled room. Caffeine
intake and cigarette smoking were prohibited for at least
4–6 h before the study. The right arm was immobilized
using two cushions supporting the elbow and the wrist.
A sphygmomanometric cuff was placed on the forearm.
After 10–15 minutes of rest, the BA was visualized lon-
gitudinally with the ultrasonic scanner operating in B
mode. After an optimal image of the artery was obtained,
the ultrasonic transducer was xed in this position with a
custom-built probe holder. The BA diameter was deter-
mined manually in end-diastole.
After three baseline measurements were obtained,
ischemia was induced by inating the cuff to 10mmHg
greater than the systolic arterial pressure so as to occlude
arterial ow for 5 minutes. After deating the cuff, the
diameter was measured at 60 seconds. Following this, we
used FMD at 1 minute after ischemia to represent the
spontaneous endothelial function. The maximal diam-
eter obtained during ischemia-induced hyperemia was
used for the calculation of the percentage of FMD (max-
imum diameter − baseline diameter)/baseline diameter ×
100 [20]. The endothelial function study was performed
by a single experienced operator. The intra-observer
reproducibility of the resting arterial diameter was 0.01
± 0.01mm.
Statistical analysis
The SPSS statistical software (SPSS 18.0 for windows,
Inc., Chicago, Illinois, USA) was used for all statistical
calculations. Continuous variables are given as mean ±
SD and median; categorical variables are dened as per-
centages. Data were tested for normal distribution using
the Kolmogorov–Smirnov test. Continuous variables with
normal distribution were compared by Student’s t-test
and abnormal disturbed variables by Mann–Whitney U
test, and the Chi-square test was used for the categorical
variables between two groups. Mean values were com-
pared by analysis of variance for normal distributed var-
iables and Kruskal–Wallis test for non-normal disturbed
ones among different groups. Linear and logistic regres-
sion analyses were used for the multivariate analysis of
independent variables which were included if they were
signicantly different in the univariate analyses. All tests
of signicance were two-tailed. Statistical signicance
was dened as P < 0.05.
Results
Among 92 newly diagnosed HT patients, 49 (53.3%) were
female and mean age was 49.2 ± 8.9. The mean LAVI of
the patients was 29.63ml/m2. Patients were divided into
two groups according to the mean LAVI value; 50 patients
were below the mean LAVI and 42 patients were in the
remaining group. When we compared the two groups in
terms of demographic characteristics, higher LAVI group
was older (P = 0.031). No other differences between the
two groups were noted in terms of demographic param-
eters (Table1).
Left Ventricle Mass Index (114 ± 29g/m2, 91 ± 17g/m2, P
< 001), left ventricular septum (P < 0.001) and posterior
wall thickness (P = 0.001), left ventricular end-diastolic
diameter (P = 0.016) were signicantly higher among
patients in higher LAVI group. LVEF and end-systolic
diameter were similar (Table1). Concentric remodeling
was more common in low LAVI group compared to those
without (72% vs. 33%, P < 001), while concentric hyper-
trophy was more prominent in patients with higher LAVI
(59.5 vs. 18, P < 001).
We compared diastolic dysfunction parameters between
groups and found that the lateral wall E wave velocity
was signicantly lower (8.68 ± 2.8, 10.2 ± 2.8; P = 0.009),
while isovolumetric relaxation time (IVRT) (101.9 ±
19.9ms, 85.7 ± 15.2ms; P < 0.001) and ejection time was
longer (101.9 ± 19.9ms, 85.7 ± 15.2ms; P = 0.077) in high
LAVI group. Mitral E/lateral wall E ratio (E/E relation)
was signicantly higher (P = 0.031), suggesting a relation-
ship between increased LAVI and LV end-diastolic pres-
sure (Table1).
Right CIMT (0.84 ± 0.12 mm, 0.93 ± 0.15 mm; P =
0.004), left CIMT (0.93 ± 0.14mm, 0.86 ±) 0.12mm; P =
0.020) and mean CIMT thickness (0.93 ± 0.14mm, 0.85
± 0.12mm; P = 0.007) was higher and plaque develop-
ment was signicantly more frequent (45% vs. 13%, P
= 0.001) in high LAVI group. Flow mediated dilatation
LAVI was worse in the high LAVI group (9.7 ± 3.5%,
13.31 ± 6.01%; P = 0.004). LDL and HDL levels were
similar (Table2).
We performed backward logistic regression analysis to
identify the independent variables predicting higher
LAVI. IVRT [odds ratio (OR) = 1.085; P = 0.002], E/E′
(OR = 1.760; P = 0.003) and FMD% (OR = 0.765; P =
0.012) independently predicted increase in LAVI. ROC
analysis was performed for demonstrating the sensitivity
and specicity of each parameter for predicting LAVI.
Area under curve for IVRT, E/E RT ratio and FMD%
were found as 0.747, 0.702 and 0.709, respectively
(Fig.1)
Discussion
In the present study, we found that IVRT, FMD%, and
E/E′ ratio independently predicted higher LAVI in newly
diagnosed HT patients without masked hypertension or
white coat hypertension. The novelty of our study was
based on being the rst one to evaluate the role of ED for
the prediction of LAVI increase among otherwise healthy
newly diagnosed hypertensive patients.
Previously Xu et al. showed the presence of signi-
cant association between ED and LA dilatation among

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4 Blood Pressure Monitoring 2019, Vol XXX No XXX
hypertensive patients with target organ damage [6].
However, diabetic patients were included and patients
were under antihypertensive therapy in that study. In
addition, diastolic parameters were not studied in detail,
most patients had target organ damage and the study
included a population which had relatively a higher risk
than of ours. In accordance to our ndings, low HDL
cholesterol was correlated with LA volume increase and
no difference was noted in CRP level between low and
high LAVI groups.
Table 1 The patients characteristics according to left atrial volume index group
Variable LAVI ≤ mean (n = 50) LAVI > mean (n = 42) All patient (n = 92) P value
Age (years) 47.4 ± 8.56 51.38 ± 8.8 49.22 ± 8.89 0.031
Sex (male), n (%) 50% 57% 53% 0.499
Office SBP (mmHg) 156.4 ± 13.4 158.1 ± 18.7 157.2 ± 15.9 0.602
Office DBP (mmHg) 98 ± 8 98.1 ± 11.7 98.1 ± 9.8 0.935
Total mean SBP (mmHg) 142.8 ± 12.7 144.8 ± 12.6 143.8 ± 12.6 0.550
Total mean DBP (mmHg) 94.6 ± 9.5 94.7 ± 9.4 94.65 ± 9.4 0.968
Day mean SBP (mmHg) 144.5 ± 12.9 146.6 ± 13.1 145.6 ± 12.8 0.990
Day mean DBP (mmHg) 96.8 ± 9.6 96.8 ± 10.1 96.8 ± 9.8 0.762
Night mean SBP (mmHg) 137.7 ± 14.8 138.8 ± 14.4 138.8 ± 14.5 0.762
Night mean DBP (mmHg) 87.4 ± 10.3 87.24 ± 10.7 87.3 ± 10.4 0.990
BMI (kg/m2) 31.9 ± 4.5 31.7 ± 4.5 21.85 ± 4.4 0.862
Weight (kg) 89.7 ± 14.8 89.2 ± 13.8 89.49 ± 14.31 0.878
Waist circumference (cm) 104.19 ± 10.1 104.5 ± 11.2 104.35 ± 10.56 0.879
Smoking, n (%) 26% 36% 30% 0.318
Dyslipidemia, n (%) 86% 79% 83% 0.355
PWV femoral (m/s) 8.8 ± 1.84 9.3 ± 2.3 9.09 ± 2.08 0.302
PWV radial (m/s) 7.9 ± 1.6 7.9 ± 2.01 7.9 ± 1.8 0.999
Augmentation index (%) 24.81 ± 12.6 27.43 ± 10.9 26.03 ± 11.8 0.397
NYHA 0.097
1, n (%) 47 (94) 35 (83.3) 82 (89.1)
>1, n (%) 3 (6) 7 (16.7) 10 (10.9)
LVEF (%) 68 ± 3.1 64.6 ± 4.1 64.7 ± 3.6 0.728
LVEDD (mm) 44.16 ± 6.9 47.2 ± 4.4 45.5 ± 6.1 0.016
LVESD (mm) 28.6 ± 7.6 29.3 ± 4.5 28.9 ± 5.1 0.500
IVS (mm) 11.7 ± 1.4 13.5 ± 2.3 12.5 ± 2.07 <0.001
PW (mm) 11.1 ± 1.23 12.23 ± 1.8 11.6 ± 1.8 0.001
LV mass index (g/m2) 91 ± 17 114 ± 29 101 ± 26 <0.001
Type of LVH <0.001
No LVH, n (%) 4 (8) 1 (2.4) 5 (5.4)
Concentric remodeling n (%) 36 (72) 14 (33.3) 50 (54.3)
Concentric hypertrophy n (%) 9 (18) 25 (59.5) 34 (37)
Eccentric hypertrophy n (%) 1 (2) 2 (4.8) 3 (3.3)
LAVI (ml/m2) 24.46 ± 3.39 35.79 ± 5.2 29.63 ± 7.1 <0.001
Mitral E (cm/s) 68.8 ± 16.5 67.1 ± 18.4 68.07 ± 17.1 0.659
Mitral A (cm/s) 79.7 ± 16.1 83.2 ± 17.9 81.3 ± 17.02 0.322
E/A 0.89 ± 0.3 0.84 ± 0.3 0.87 ± 0.3 0.427
Lat. E (cm/s) 10.2 ± 2.8 8.68 ± 2.8 9.58 ± 2.9 0.009
E/E′7.12 ± 2.3 8.2 ± 2.3 7.6 ± 2.4 0.031
Lat. A (cm/s) 11.04 ± 2.7 10.4 ± 3.02 10.7 ± 2.8 0.305
EDT (ms) 223.7 ± 49.5 223.4 ± 41.2 223.6 ± 45.7 0.983
IVRT (ms) 85.7 ± 15.2 101.9 ± 19.9 93.23 ± 19.2 <0.001
Ejection time (ms) 262.9 ± 29.8 273.2 ± 21.8 267 ± 26.9 0.077
LV Tei index 0.46 ± 0.18 0.53 ± 0.13 0.49 ± 0.16 0.072
Right CIMT (mm) 0.84 ± 0.12 0.93 ± 0.15 0.88 ± 0.14 0.004
Left CIMT (mm) 0.86 ± 0.13 0.93 ± 0.14 0.89 ± 0.14 0.020
Mean CIMT (mm) 0.85 ± 0.12 0.93 ± 0.14 0.89 ± 0.14 0.007
Carotid plaque (%) 13% 45% 28% 0.001
Baseline BA diameter (mm) 37.28 ± 5.3 40.5 ± 7.37 38.78 ± 6.5 0.037
BA diameter after obst. (mm) 42.14 ± 4.7 44.24 ± 7.2 43.2 ± 6.09 0.117
FMD (%) 13.31 ± 6.01 9.7 ± 3.5 11.6 ± 5.2 0.004
Fasting glucose (mg/dl) 98.13 ± 14.06 102.13 ± 19 99.9 ± 16.6 0.269
Total cholesterol (mg/dl) 229 ± 41.4 212 ± 36 221.4 ± 40 0.046
LDL-C (mg/dl) 146 ± 34.4 131 ± 40.9 139 ± 37 0.090
HDL-C (mg/dl) 50 ± 15 44.9 ± 9.8 47.6 ± 13 0.076
Triglyceride (mg/dl) 167.2 ± 73.8 160 ± 98 164 ± 85 0.131
Non-HDL cholesterol (mg/dl) 179.5 ± 38.8 167.12 ± 35 173 ± 37 0.735
Serum creatinine (mg/dl) 0.8 ± 0.13 0.7 ± 0.12 0.79 ± 0.13 0.241
eGFR (ml/min/1.73 m2) 79.17 ± 13.08 82.5 ± 12.4 80.7 ± 12.8 0.135
CRP (mg/dl) 0.47 ± 0.41 0.49 ± 0.48 0.48 ± 0.44 0.851
WBC (103/μl) 7.42 ± 1.5 7.4 ± 1.4 7.4 ± 1.5 0.873
Hemoglobin (g/dl) 14.4 ± 1.36 14.1 ± 1.5 14.2 ± 1.4 0.434
BA, brachial artery; CIMT, carotid intima-media thickness; CRP, C-reactive protein; DBP, diastolic blood pressure; EDT, E deceleration time; eGFR, estimated glomerular
filtration rate; FMD, flow-mediated dilation; HDL-C, high-density lipoprotein cholesterol; IVRT, isovolumetric relaxation time; IVS, interventricular septum; Lat, lateral wall;
LAVI, left atrial volume index; LDL-C, low-density lipoprotein cholesterol; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD,
left ventricular end-systolic diameter; LVH, left ventricular hypertrophy; NYHA, New York Heart Association; PW, posterior wall; PWV, pulse wave velocity; SBP, systolic
blood pressure; WBC, white blood cell.

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ED predicted increased LAVI Çetin et al. 5
LA consists of a dynamic structure and its wall is thin-
ner than of ventricle. Innermost layer is endothelial part
and underneath there are myocytes which are responsi-
ble for contraction and relaxation. The outermost layer
is called adventitia. Mean wall thickness of LA is near
4.5mm [21,22]. LA function has three phases, serving as
a reservoir in systole, as a conduit in early diastole, and
as a booster [7,23,24]. LA conduit function is reliant on
LV diastolic function, including both the suction force
dependent on LV relaxation and LV chamber stiffness,
whereas LA booster function is based on intrinsic LA
contractility, LV end-diastolic compliance and pressure
pump in late diastole [8,25]. Elevated LA volume is an
indicator of LV diastolic dysfunction and it has a more
reliable prognostic indicator than LA diameter for car-
diovascular diseases [7,8]. LA dysfunction is considered
to result from LA brosis, and several biological factors
have been implicated in this process [9]. LA remodeling
is a complex process that is poorly understood, but it is
dened as a persistent change in LA [9,10]. Long-term
exposure to increased volume, pressure or both in LA
results in myocyte loss and leads to remodeling of LA
structure [10,18,24]. Metabolic changes in myocytes trig-
ger toxic process in LA in time, and with the contribution
Table 2 Independent predictors of left atrial volume index
Variable
Univariate Multivariate
HR 95% CI P value HR 95% CI P value
Age (years) 1.056 1.003–1.112 0.037
LVMI (g/m2) 1.047 1.022–1.072 <0.001
Lat E (cm/s) 0.816 0.696–0.956 0.012
IVRT (ms) 1.056 1.023–1.089 0.001 1.062 1.018–1.109 0.005
E/E 1.218 1.013–1.465 0.036 1.559 1.115–2.179 0.009
Mean CIMT(mm) 89.523 3.47–23.09 0.007
Plaque (%) 5.645 1.975–16.136 0.001
FMD % 0.856 0.763–0.960 0.008 0.836 0.707–0.989 0.037
LDL-C (mg/dl) 0.990 0.978–1.002 0.095
HDL-C (mg/dl) 0.965 0.926–1.005 0.086
Type of LVH 4.547 2.027–10.201 <0.001
CIMT, carotid intima-media thickness; FMD, flow-mediated dilation; HDL-C, high-density lipoprotein cholesterol; IVRT, isovolumetric relaxation time; Lat, lateral wall; LAVI,
left atrial volume index; LDL-C, low-density lipoprotein cholesterol; LVH, left ventricular hypertrophy; LVMI, left ventricular mass index.
Fig. 1
ROC curves of IVRT, E/E′ and FMD (%) decrease in determination of increased LAVI. FMD, flow-mediated dilation; IVRT, isovolumetric relaxation
time; LAVI, left atrial volume index.

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6 Blood Pressure Monitoring 2019, Vol XXX No XXX
of neurohormonal factors, the brosis occurs in interstitial
space. In addition to inammatory factors including trans-
forming growth factor-beta, interleukins and cytokines;
angiotensin 2 and aldosterone also play a major role in
remodeling of LA [10]. As long as the stimulant factors
for interstitial brosis persist, function of LA deteriorates
progressively leading to left atrial myopathy.
Endothelial cells have important regulatory functions in
the vascular bed through a variety of mediators. ED con-
stitutes a major challenge from both the biological and
clinical standpoints as it is fundamentally associated to
the vascular damage present in major pathological enti-
ties such as HT, diabetes, atherosclerosis and aging [11].
ED is particularly important in migration of lipoprotein
particles into the subendothelial space and in the devel-
opment of atherosclerotic process and in the continuation
of chronic inammation [26]. Endothelial cells are active
during the chronic inammatory process through forming
leukocyte adhesion molecules (VCAM-1, ELAM-1) and
secreting chemoattractant proteins such as interleukin 8
and Monocyte Chemoattractant Protein-1 [27]. Arenas
et al. showed that angiotensin II increased the secretion
of TNF-α and MMP-2 from endothelial cells [28]. In
another study, Wu et al. reported increased sensitivity to
the renin angiotensin aldosterone system in the vascu-
lar bed [29]. As a result, LA endothelial cell dysfunction
might be formed by the HT induced interstitial bro-
sis due to a chronic inammation in the LA wall like in
the vascular bed. Cristina et al. showed that antioxidant
capacity deterioration in endothelial cells increases the
development of renal brosis in animal experiments [30].
On the other hand, Todd et al. showed that ED was asso-
ciated with aortic stiffness, which was associated with
increased arterial wall collagen [31]. This suggested that
endothelial cell dysfunction might play an important role
in chronic remodeling in LA wall and might increase
brosis formation. The relationship between ED and AF
supported our theory [3]. Although, our study was not
designed to reveal the cellular mechanisms of ED and
LA dilatation, we found a relationship between FMD
showing ED and LAVI in presented study.
There are different results in studies investigating the
relationship between LV geometry and LAVI [32,33].
In the Losartan Intervention for Endpoint Reduction
(LIFE) trial, LA diameter was associated with the pres-
ence of eccentric hypertrophy compared with concentric
hypertrophy [32]. On the contrary to the LIFE study,
in another study, concentric hypertrophy was related to
greater LA size compared with eccentric hypertrophy
[33]. In presented study, concentric hypertrophy was more
common in patients with higher LAVI. However, this was
not statistically signicant after adjustment for confound-
ers. The relationship between diastolic parameters and
the increase in LAVI was remarkable and was shown in
previous studies [34,35]. As found in our study, IVRT was
signicantly prolonged in patients with increased LAVI
and was an independent predictor of LAVI. The E/E′
ratio, which was correlated with LV end-diastolic pres-
sure increase, was increased in the group with high LAVI
and the New York Heart Association (NYHA) class was
worse in this LAVI group [34,35]. In our study, we showed
that the patients with higher LAVI had a high E/E′ ratio
similar to the above-mentioned study. Also, NYHA class
>1 was more common in higher LAVI group. Ristow et
al. reported that LAVI was as effective as LVEF in pre-
dicting hospital admission [35]. In addition, subclinical
atherosclerosis was more prominent in the group with a
high LAVI and had a strong relationship with LAVI. As
a result, the increase in LAVI in HT patients was highly
correlated with subclinical atherosclerosis, ED, LV hyper-
trophy, diastolic dysfunction, and possibly LV end-dias-
tolic pressure increase. Our research suggested that LAVI
could help identifying HT patients at increased risk.
Limitations
Our study was conducted with relatively few patients.
The mechanisms of the relationship between ED and
LAVI increase could not be fully established. For this
reason, additional research might be helpful in explain-
ing our ndings.
Conclusion
ED as determined by FMD, IVRT and E/E′ ratio were
independently predicted increased LAVI in the newly
diagnosed HT patients.
Acknowledgements
Conflicts of interest
There are no conicts of interest.
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